gebhart/patrepeval huggingface dataset:
Rapid Reversion of Sequence Polymorphisms Dominates Early Human Immunodeficiency Virus Type 1 Evolution (2006)

The error-prone replication of human immunodeficiency virus type 1 (HIV-1) enables it to continuously evade host CD8+ T-cell responses. The observed transmission, and potential accumulation, of CD8+ T-cell escape mutations in the population may suggest a gradual adaptation of HIV-1 to immune pressures. Recent reports, however, have highlighted the propensity of some escape mutations to revert upon transmission to a new host in order to restore efficient replication capacity. To more specifically address the role of reversions in early HIV-1 evolution, we examined sequence polymorphisms arising across the HIV-1 genome in seven subjects followed longitudinally 1 year from primary infection. As expected, numerous nonsynonymous mutations were associated with described CD8+ T-cell epitopes, supporting a prominent role for cellular immune responses in driving early HIV-1 evolution. Strikingly, however, a substantial proportion of substitutions (42%) reverted toward the clade B consensus sequence, with nearly one-quarter of them located within defined CD8 epitopes not restricted by the contemporary host's HLA. More importantly, these reversions arose significantly faster than forward mutations, with the most rapidly reverting mutations preferentially arising within structurally conserved residues. These data suggest that many transmitted mutations likely incur a fitness cost that is recovered through retrieval of an optimal, or ancestral, form of the virus. The propensity of mutations to revert may limit the accumulation of immune pressure-driven mutations in the population, thus preserving critical CD8+ T-cell epitopes as vaccine targets, and argue against an unremitting adaptation of HIV-1 to host immune pressures.
Atlas for Stereotaxy of the Human Brain (1977)

- Index of Anatomical Abbreviations - Synonyma Table for the Thalamus - Synonyma Table for the Hypothalamus - Unstained Series with Overlays for Variations of the Structures of the Brain - Microscopic Series with fixed Overlays for Anatomic Explanations - Electroanatomical Observations
Stem-cell based therapies for brain tumors. (2008)

Advances in understanding neural stem cell (NSC) biology have facilitated the development of novel cell-based therapies for brain malignancies. NSCs are the most immature progenitor cells in the nervous system that have the ability to self-renew, differentiate into terminal neural cell types, and extensively migrate to areas of pathology in the central nervous system. Because of their inherent tumor-trophic properties and their capacity to differentiate into all neural phenotypes, NSCs represent a powerful tool for the treatment of both diffuse and localized neurological disorders. Progress has validated the feasibility of using engineered NSCs as cell-based therapeutic agents to eliminate malignant cells in the brain. This review discusses the therapeutic potential of NSCs focusing on brain tumors.
Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer (2004)

The categorization of prostate cancers that are progressing after castration as 'hormone-refractory' evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a 'hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as 'castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant tumor. In this article, we detail strategies to inhibit the growth of prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.
Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes (2003)

Chondrocyte proliferation and differentiation requires their attachment to the collagen type II-rich matrix of developing bone. This interaction is mediated by integrins and their cytoplasmic effectors, such as the integrin-linked kinase (ILK). To elucidate the molecular mechanisms whereby integrins control these processes, we have specifically inactivated the ILK gene in growth plate chondrocytes using the Cre-lox methodology. Mice carrying an ILK allele flanked by loxP sites (ILK-fl) were crossed to transgenic mice expressing the Cre recombinase under the control of the collagen type II promoter. Inactivation of both copies of the ILK-fl allele lead to a chondrodysplasia characterized by a disorganized growth plate and to dwarfism. Expression of chondrocyte differentiation markers such as collagen type II, collagen type X, Indian hedgehog and the PTH-PTHrP receptor was normal in ILK-deficient growth plates. In contrast, chondrocyte proliferation, assessed by BrdU or proliferating cell nuclear antigen labeling, was markedly reduced in the mutant growth plates. Cell-based assays showed that integrin-mediated adhesion of primary cultures of chondrocytes from mutant animals to collagen type II was impaired. ILK inactivation in chondrocytes resulted in reduced cyclin D1 expression, and this most likely explains the defect in chondrocyte proliferation observed when ILK is inactivated in growth plate cells.
Isolation and Characterization of the Human tRNA-(N1G37) Methyltransferase (TRM5) and Comparison to the Escherichia coli TrmD Protein (2004)

A human TRM5 cDNA has been cloned and recombinant tRNA-N(1)G37 methyltransferase was produced. The recombinant enzyme methylates the N1 position of guanosine 37 (G37) in selected tRNA transcripts utilizing S-adenosyl methionine. The effects of RNA sequence and structure on the methylation reaction in comparison between the Escherichia coli TrmD and human TRM5 recombinant enzymes are presented. G37-methylation by TRM5 occurs regardless of the nature of the nucleotide at position 36. TRM5 also methylates inosine at position 37 unlike TrmD, which recognizes the G36pG37 motif preferentially and does not methylate inosine. New evidence is presented concerning TrmD showing that with some tRNA species, A at position 36 is also recognized. The TRM5 enzyme is sensitive to subtle changes in the tRNA-protein tertiary interaction leading to loss of activity. The TrmD enzyme is more tolerant of alterations in tRNA-protein tertiary interactions as long as the core tRNA structure and the G36pG37 are present. The TRM5 enzyme does not have an absolute requirement for magnesium ions, whereas TrmD requires magnesium to express activity. TRM5 demonstrates much higher affinity for substrates with K(m) values for tRNA that are nanomolar. TrmD has K(m) values for tRNA in the micromolar range. Recombinant TRM5 appears to function as a 60 772 Da monomer, while recombinant TrmD functions as a homodimer of 30 586 Da subunits. Bioinformatic analysis of the human TRM5 genomic locus (KIAA1393) have identified TRM5 homologues in eukaryotes and archaea; however, no significantly homologous regions were identified in any prokaryotes including the TrmD gene.
Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma (2010)

In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.
The Technique of Free Skin Grafting in Mammals (1951)

ABSTRACT Methods are described for the execution of free skin grafts in rabbits, guinea-pigs and mice. Much of the work in which use has been made of the techniques described above has been generously supported over a period of years by the Department of Plastic Surgery, University of Oxford (Prof. T. Pomfret Kilner, F.R.C.S.).
Calcineurin Blockade Prevents Cardiac Mitogen-activated Protein Kinase Activation and Hypertrophy in Renovascular Hypertension (2000)

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
Screening for Colorectal Cancer With Fecal Occult Blood Testing and Sigmoidoscopy (1993)

The screening of average-risk individuals (aged 50 and older) for colorectal cancer through use of the fecal occult blood test in conjunction with sigmoidoscopy can increase the likelihood of early detection of this disease. This practice, coupled with prompt diagnostic work-up following positive tests, will result in treatment of earlier stage cancers and increased survival after treatment.
Prediction of the three‐dimensional structure of human growth hormone (1987)

In recent years, the protein-folding problem has attracted the attention of molecular biologists. Efforts have focused on developing heuristic and energy-based algorithms to predict the three-dimensional structure of a protein from its amino acid sequence. We have applied a series of heuristic algorithms to the sequence of human growth hormone. A family of five structures which are generically right-handed fourfold alpha-helical bundles are found from an investigation of approximately 10(8) structures. A plausible receptor binding site is suggested. Independent crystallographic analysis confirms some aspects of these predictions. These methods only deal with the "core" structure, and conformations of many residues are not defined. Further work is required to identify a unique set of coordinates and to clarify the topological alternative available to alpha-helical proteins.
Suppression of the anti-DNP IgE response with tolerogenic conjugates of DNP with polyvinyl alcohol. I. Specific suppression of the anti-DNP IgE response. (1981)

Abstract The capacity of B6D2F1 mice to produce anti-DNP re-aginic (IgE) antibodies and anti-DNP plaque-forming cells as a result of immunization with DNP3-OA in presence of A1(OH);3 was specifically suppressed by treatment of mice—before or after immunization—with tolerogenic conjugates consisting of the hapten coupled to polyvinyl alcohol (PVA) with m.w. of 10,000 or 14,000. The suppression was dose-dependent, and the effectiveness of the suppression increased with increasing epitope density (DNPn-PVA; n = 0.5 to 4.3). Thus, although a single dose of 0.1 mg of DNP1.4-PVA14 depressed significantly an ongoing anti-DNP IgE response, complete suppression of this response was achieved with 1 mg of the conjugate; significantly lower amounts of the conjugate were needed to dampen the de novo anti-DNP IgE response. This mode of suppression was uniquely hapten specific, since it did not affect the immune response of the host to the carrier. Further evidence for the specific unresponsiveness to DNP of the mice treated with DNP-PVA conjugates was provided by the finding that although mice immunized to DNP3-OA in the presence of Bordetella pertussis died of anaphylaxis on i.v. challenge with 2 mg of DNPg-MγG or OA, mice that had been immunosuppressed did not show any discomfort on challenge with DNPg-MγG, but died within 30 min after i.v. administration of OA. The unresponsive state of the spleen cells of mice that had been rendered tolerant to DNP was maintained even after cell transfer into x-irradiated syngeneic mice. It was also demonstrated that i) the interaction of DNP-specific Bε cells with OA-specific T cells resulted in a marked anti-DNP IgE response, whereas the B cells of mice that had been treated with DNPn-PVA cooperated poorly with OA-specific T cells and produced only a low level of anti-DNP IgE antibody; ii) the B cells of tolerized mice did not affect the cooperation of B and T cells of immune mice in the production of IgE responses.
Uncertainty and Value in Integrated Asset Modelling (2005)

Abstract The paper will illustrate the application of asset-scale modelling and the benefits thereof, including an analysis of the effect of quantifiable risk on development strategy selection. While integration asset modelling (IAM) is not of itself a novel topic, practical applications of the technique applied from sub-surface calculations through to commercial/financial analysis are nevertheless uncommon and those including a rigorous treatment of uncertainty still rarer. Included in the paper will be a brief analysis of both the benefits of IAM and suggestions on why it is perhaps not more widely applied. The main body of the paper, however, will cover two case studies - descriptions of projects carried out using the RAVE (Risk And Value Engineering) IAM software. The first case study will be based upon the Brae asset, operated by Marathon Oil UK. The Brae asset is complex, both technically and commercially, and represents a huge infrastructural investment in the CNS. The paper will illustrate the means by which IAM was used to "see through" this complexity to assist in the forward strategic planning of the asset. The second case study will describe the development of a reserve as a third party tie back to an existing host platform. Use of the approach in this case allowed rapid, value-based analysis of competing development alternatives (such as host selection, artificial lift techniques and well count) including the sub-surface uncertainty inherent in pre-FEED development studies. From the case studies presented here and numerous similar projects, the authors will present the conclusions that risk- inclusive integrated asset modelling is both feasible and valuable in marginal and mature environments.
An analyzable annotation language (2002)

The Alloy Annotation Language (AAL) is a language (under development) for annotating Java code based on the Alloy modeling language. It offers a syntax similar to the Java Modeling Language (JML), and the same opportunities for generation of run-time assertions. In addition, however, AAL offers the possibility of fully automatic compile-time analysis. Several kinds of analysis are supported, including: checking the code of a method against its specification; checking that the specification of a method in a subclass is compatible with the specification in the superclass; and checking properties relating method calls on different objects, such as that the equals methods of a class (and its overridings) induce an equivalence. Using partial models in place of code, it is also possible to analyze object-oriented designs in the abstract: investigating, for example, a view relationship amongst objects.The paper gives examples of annotations and such analyses. It presents (informally) a systematic translation of annotations into Alloy, a simple first-order logic with relational operators. By doing so, it makes Alloy's automatic analysis, which is based on state-of-the-art SAT solvers, applicable to the analysis of object-oriented programs, and demonstrates the power of a simple logic as the basis for an annotation language.
ZnO Nanowires for Sensing and Device Applications (2007)

We have fabricated many types of ZnO nanowire devices, including MOSFETs, diodes, UV sensors and pH sensors. ZnO has been effectively used as a gas sensor material based on the near-surface modification of charge distribution with surface-absorbed species. The large surface area of the nanorods makes them attractive for gas and chemical sensing, and the ability to control their nucleation sites makes them candidates for high density sensor arrays.
<title>Single-level electric testsites for phase-shifting masks</title> (1992)

The phase shifting mask technology has quickly progressed from the exploratory phase to a serious development phase. This requires high resolution measurement techniques to quantify experimental results to optimize the designs. This paper describes a set of electrical linewidth measurement testsites which covers all five representative lithographic features in combination of dark-field and light-field patterns, positive and negative resists. The testsites can investigate binary intensity mask, attenuated, alternating, subresolution-assisted, rim, unattenuated, edge, and covered edge phase shifting masks. All testsites can be used with a single-level wafer exposure. There is no need to remove extra shorts or opens induced by uncovered phase shifters.
Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: Trophic and tropic effects in a rodent model of Huntington's disease (1997)

The present study examined whether implants of epidermal growth factor (EGF)-responsive stems cells derived from transgenic mice in which the glial fibrillary acid protein (GFAP) promoter directs the expression of human nerve growth factor (hNGF) could prevent the degeneration of striatal neurons in a rodent model of Huntington's disease (HD). Rats received intrastriatal transplants of GFAP-hNGF stem cells or control stem cells followed 9 days later by an intrastriatal injection of quinolinic acid (QA). Nissl stains revealed large striatal lesions in rats receiving control grafts, which, on average, encompassed 12.78 mm3. The size of the lesion was significantly reduced (1.92 mm3) in rats receiving lesions and GFAP-hNGF transplants. Rats receiving QA lesions and GFAP-hNGF-secreting grafts stem cell grafts displayed a sparing of striatal neurons immunoreactive (ir) for glutamic acid decarboxylase, choline acetyltransferase, and neurons histochemically positive for nicotinamide adenosine diphosphate. Intrastriatal GFAP-hNGF-secreting implants also induced a robust sprouting of cholinergic fibers from subjacent basal forebrain neurons. The lesioned striatum in control-grafted animals displayed numerous p75 neurotrophin-ir (p75NTR) astrocytes, which enveloped host vasculature. In rats receiving GFAP-hNGF-secreting stem cell grafts, the astroglial staining pattern was absent. By using a mouse-specific probe, stem cells were identified in all animals. These data indicate that cellular delivery of hNGF by genetic modification of stem cells can prevent the degeneration of vulnerable striatal neural populations, including those destined to die in a rodent model of HD, and supports the emerging concept that this technology may be a valuable therapeutic strategy for patients suffering from this disease.
A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes (2004)

Epithelial ovarian tumours represent a complex group of histological subtypes and there has long been controversy over the question of a precursor lesion for these neoplasms. The application of mutation analysis of the KRAS and BRAF genes (members of the RAS-RAF-MEK-ERK-MAP kinase pathway) is consistent with the model for progression of mucinous carcinomas and a subset of serous carcinomas (the so-called low-grade serous carcinomas) through benign and borderline lesions. The relatively high incidence of BRAF and KRAS mutations in serous borderline tumours and low-grade serous carcinomas, and their extremely low incidence/absence in high-grade serous carcinomas, provide strong evidence that high-grade carcinomas do not arise through this intermediate step.
Monotone and Partially Monotone Neural Networks (2010)

In many classification and prediction problems it is known that the response variable depends on certain explanatory variables. Monotone neural networks can be used as powerful tools to build monotone models with better accuracy and lower variance compared to ordinary nonmonotone models. Monotonicity is usually obtained by putting constraints on the parameters of the network. In this paper, we will clarify some of the theoretical results on monotone neural networks with positive weights, issues that are sometimes misunderstood in the neural network literature. Furthermore, we will generalize some of the results obtained by Sill for the so-called min-max networks to the case of partially monotone problems. The method is illustrated in practical case studies.