gebhart/patrepeval huggingface dataset:
The Remarkable Pliability and Promiscuity of Specialized Metabolism (2012)

Metabolic pathways are often considered "perfected" or at least predictable as substrates efficiently rearrange into products through the intervention of an optimized enzyme. Moreover, single catalytic steps link up, forming a myriad of metabolic circuits that are often modeled with a high degree of certainty. However, on closer examination, most enzymes are not precise with respect to their activity, using not just one substrate but often a variety and producing not just one product but a diversity. Hence, the metabolic systems assembled from enzymes possessing varying degrees of what can be termed catalytic promiscuity are not clear-cut and restrictive; rather, they may at times operate stochastically in the intracellular milieu. This "messiness" complicates our understanding of normal and aberrant cellular behavior, while paradoxically sowing the seeds for future advantageous metabolic adaptations for host organisms. Catalytic promiscuity is intrinsically associated with the dynamic nature of enzyme structures and their chemical mechanisms, both key to enzyme and metabolic evolvability. In addition to primary (core) metabolism, which is essential for survival, organisms also possess highly elaborated secondary (specialized) metabolic systems. These specialized enzymes and pathways often provide unique adaptive strategies for a myriad of organisms and their populations in challenging and changing ecosystems. Generally, enzymes of specialized metabolism show attenuated kinetic activities and expanded catalytic promiscuity compared with their phylogenetic relatives rooted in primary metabolism. We propose that evolvability may be a selected trait in many specialized metabolic systems spread across populations of organisms exposed to continually fluctuating biotic and abiotic environmental pressures. As minor metabolites arising from catalytic messiness provided enhanced population fitness, specificity relaxed, and catalytic efficiency was attenuated. This updated view provides a mechanistic basis for reaching a deeper understanding of the evolutionary underpinnings of the explosion of chemodiversity in nature.
A Novel Linear Code Nomenclature for Complex Carbohydrates. (2002)

The Linear Code is a new syntax for representing glycoconjugates and their associated molecules in a simple linear fashion. Similar to the straightforward single letter nomenclature of DNA and proteins, Linear Code presents glycoconjugates in a canonic, compact and practical form while accounting for all relevant stereochemical and structural configurations. It uses a single letter code to represent each monosaccharide and includes a condensed description of the connections between monosaccharides and their modifications, allowing a simple linear representation of these compounds. The new linear syntax enables the implementation of bioinformatics tools for investigation and analysis of glyco-molecules and their biology.
Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy (2007)

The structural origin of scattering contrast from single cells is examined by using a combined optical coherence and multiphoton microscope based on a 12 fs Ti:sapphire source and a 0.95 NA objective. High-resolution coherence-gated scattering images from single cells are coregistered and compared with two-photon-excited fluorescence images. Scattering contrast is observed from mitochondria, plasma membrane, actin filaments, and the boundary between cytoplasm and nucleus. There is little contribution to scattering from regions inside the nuclear core. These results confirm that light scattering signals from specific subcellular structures can be visualized by using coherent reflectance geometry.
The prevalence of unsuspected thyroid pathology in 300 sequential autopsies, with special reference to the incidental carcinoma (1989)

Three-hundred whole thyroid glands were collected at autopsy from patients who had no known clinical history of thyroid disease, and who varied from 13 to 82 years of age; 200 were male and 100 female. Thyroid glands were weighed, measured, and examined after previous formalin fixation. Histologic examination was done in 16 areas from both lobes and isthmus, and divided into three levels, anterior, medial, and posterior. All areas suspected of neoplasia macroscopically were identified and studied microscopically; other areas were collected randomly for microscopic examination in the proportion of one fragment per 5 grams of tissue. In all cases both benign and malignant neoplasias were an incidental finding, seen in 6.6% of the cases and with no relation to the patient's main disease. Overall, there were malignant neoplasias in 2.33% but occult carcinoma comprised 1% of the cases. The incidence of other thyroid pathologies, all of them unrelated to the main disease of the patient, are also reported.
Testing mutual exclusivity of ETS rearranged prostate cancer (2010)

Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5' fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements.
Agonistic antibodies stimulate the kinase encoded by the neu protooncogene in living cells but the oncogenic mutant is constitutively active. (1990)

The neu protooncogene (also called c-erbB2 and HER-2) undergoes oncogenic activation through a single mutation. The product of the protooncogene, p185neu, probably functions as a receptor for a peptide growth factor. To circumvent the absence of a well-characterized ligand, I generated ligand-mimicking monoclonal antibodies directed to the presumed receptor. These antibodies stimulated tyrosine phosphorylation of p185neu in living cells and also accelerated the rate of endocytosis and degradation of p185neu. A monovalent Fab fragment of such an antibody was ineffective, suggesting a role for receptor dimerization in signal transduction. Unlike the product of the protooncogene, the transforming mutant was not affected by the ligand-like antibodies. However, it undergoes constitutively high phosphorylation on tyrosine residues in living cells, and its turnover rate is remarkably rapid. Nevertheless, the pattern of phosphorylation of the mutant protein is similar to the one exhibited by an antibody-stimulated p185neu, suggesting that the mutation mimics activation by the antibody. These results suggest that the kinase of p185neu is under allosteric control that may involve ligand-induced dimerization of receptors. This mechanism is deregulated in the oncogenic mutant, which is functionally equivalent to ligand-stimulated receptor.
VLSI implementation of encoder and decoder for low-density parity-check codes (2001)

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Clinical impact of delaying initiation of radiotherapy in patients with breast cancer: stages 0, I and II, a retrospective observational study (2015)

BackgroundThere is no consensus on how long the initiation of radiotherapy (RT) can be delayed after surgery without a negative impact on survival.Materials and methodsWe conducted a retrospective study of 278 patients with stage 0–II breast cancer, all of whom were treated with surgery and RT, with those at stages I–II also receiving chemotherapy. Patients were followed-up for 5 years after diagnosis to assess disease-free and overall survival.The independent variable was the delay in the initiation of RT, assessed by two criteria: time since the last treatment, considered acceptable if ≤6 weeks, and time since surgery, considered acceptable if ≤7 months, these cut-offs being used to categorise patients into two groups according to the length of delay.ResultsNo statistically significant differences were observed in the probability of disease-free survival (p=0·412) or overall survival (p=0·890). The appearance of recurrence was 5–59 months, with an average of 38·50 (14·31).ConclusionsDelaying the initiation of RT for more than 6 weeks after last treatment does not seem to have a negative impact on disease-free or overall survival.
Silicon Nanocrystals: Size Matters (2005)

Abstract This paper reviews new approaches to size‐controlled silicon‐nanocrystal synthesis. These approaches allow narrowing of the size distribution of the nanocrystals compared with those obtained by conventional synthesis processes such as ion implantation into SiO 2 or phase separation of sub‐stoichiometric SiO x layers. This size control is realized by different approaches to introducing a superlattice‐like structure into the synthesis process, by velocity selection of silicon aerosols, or by the use of electron lithography and subsequent oxidation processes. Nanocrystals between 2 and 20 nm in size with a full width at half maximum of the size distribution of 1 nm can be synthesized and area densities above 10 12 cm –2 can be achieved. The role of surface passivation is elucidated by comparing Si/SiO 2 layers with superlattices of fully passivated silicon nanocrystals within a SiO 2 matrix. The demands on silicon nanocrystals for various applications such as non‐volatile memories or light‐emitting devices are discussed for different size‐controlled nanocrystal synthesis approaches.
Developing industrial strength simulation models using Visual Basic for Applications (VBA) (2002)

Since 1984 the author has been developing simulation models that use input data from spreadsheets. These original applications used a standalone Basic program to convert Lotus 123(R) data into Siman Experiment Frames. While this process has evolved overtime, it did not reach a truly viable level until Arena(R) 3.0 introduced Visual Basic(R) for Applications (VBA) by Microsoft(R). This advanced tutorial demonstrates the basic concepts developed by the author to transfer data between Excel(R) and Arena. The same techniques can be used to communicate simulation data with a wide range of VBA supported tools, such as Access(R), AutoCAD(R) and Visio(R). Arena permits the model developer to use VBA as the model file is loaded, executed, or terminated or as entities flow through the Arena model modules. The article focuses on the design of Excel workbooks for simulation applications and the transfer of data to/from Arena using VBA.
Adeno-Associated Virus Type 2 VP2 Capsid Protein Is Nonessential and Can Tolerate Large Peptide Insertions at Its N Terminus (2004)

Direct insertion of amino acid sequences into the adeno-associated virus type 2 (AAV) capsid open reading frame (cap ORF) is one strategy currently being developed for retargeting this prototypical gene therapy vector. While this approach has successfully resulted in the formation of AAV particles that have expanded or retargeted viral tropism, the inserted sequences have been relatively short, linear receptor binding ligands. Since many receptor-ligand interactions involve nonlinear, conformation-dependent binding domains, we investigated the insertion of full-length peptides into the AAV cap ORF. To minimize disruption of critical VP3 structural domains, we confined the insertions to residue 138 within the VP1-VP2 overlap, which has been shown to be on the surface of the particle following insertion of smaller epitopes. The insertion of coding sequences for the 8-kDa chemokine binding domain of rat fractalkine (CX3CL1), the 18-kDa human hormone leptin, and the 30-kDa green fluorescent protein (GFP) after residue 138 failed to lead to formation of particles due to the loss of VP3 expression. To test the ability to complement these insertions with the missing capsid proteins in trans, we designed a system for producing AAV vectors in which expression of one capsid protein is isolated and combined with the remaining two capsid proteins expressed separately. Such an approach allows for genetic modification of a specific capsid protein across its entire coding sequence leaving the remaining capsid proteins unaffected. An examination of particle formation from the individual components of the system revealed that genome-containing particles formed as long as the VP3 capsid protein was present and demonstrated that the VP2 capsid protein is nonessential for viral infectivity. Viable particles composed of all three capsid proteins were obtained from the capsid complementation groups regardless of which capsid proteins were supplied separately in trans. Significant overexpression of VP2 resulted in the formation of particles with altered capsid protein stoichiometry. The key finding was that by using this system we successfully obtained nearly wild-type levels of recombinant AAV-like particles with large ligands inserted after residue 138 in VP1 and VP2 or in VP2 exclusively. While insertions at residue 138 in VP1 significantly decreased infectivity, insertions at residue 138 that were exclusively in VP2 had a minimal effect on viral assembly or infectivity. Finally, insertion of GFP into VP1 and VP2 resulted in a particle whose trafficking could be temporally monitored by using confocal microscopy. Thus, we have demonstrated a method that can be used to insert large (up to 30-kDa) peptide ligands into the AAV particle. This system allows greater flexibility than current approaches in genetically manipulating the composition of the AAV particle and, in particular, may allow vector retargeting to alternative receptors requiring interaction with full-length conformation-dependent peptide ligands.
CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity (2008)

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.
Object-oriented displays: a new type of display systems-from immersive display to object-oriented displays (2003)

We propose the concept of the "object-oriented display", which should enable an operator to perceive and operate a virtual object as if it were a real one. The object-oriented display (OOD) is a type of display system in which the surfaces of the display surround the object and not the operator. The purpose of the OOD is the presentation of virtual objects, whereas the purpose of ordinary display systems is the presentation of the virtual environment. In this project, we also describe the design and implementation of three types of object-oriented displays, (i) MEDIA-A (MEDIA-Ace), (ii) MEDIA/sup 3/ (MEDIA-Cube) and (iii) MEDIA X'tal (MEDIA-Crystal). MEDIA-A is a type of object-oriented display that is compact, light, and inexpensive. It consists of a single LCD panel and a tilt sensor. MEDIA/sup 3/ consists of four LCD panels in the shape of a cubic body. A position and orientation sensor is installed in MEDIA/sup 3/. Using MEDIA/sup 3/, a virtual object is adequately displayed by controlling the image displayed on each LCD panel, corresponding to the position of the operator's head. Thus, the virtual object appears in MEDIA/sup 3/ in its entirety. Therefore, the operator can recognize easily and intuitively the three-dimensional form and structure of the virtual object. For MEDIA X'tal, on the other hand, we use optical projection. The MEDIA X'tal solves several problems which occur when using ordinary display devices for the OOD.
New thin film epitaxial polysilicon encapsulation for piezoresistive accelerometers (2002)

This paper reports a new method of thin film encapsulation for surface micromachined sensors using an epitaxially grown polysilicon cap layer. This technique saves die area and enables the sensors to be handled in standard mounting processes such as pick and place and is suitable for injection plastic molding. The 'epipoly' encapsulation is designed for a lateral piezoresistive accelerometer, but is broadly applicable. This paper presents an analytic model that describes the deflection of the epipoly encapsulation as a function of pressure, thickness, length, shape, standoff height, venting, sealing, and material properties. This model is verified with Finite Element Analysis (FEA) and experiment.
Reduced In Vivo Aortic Uptake of Radiolabeled Oxidation-Specific Antibodies Reflects Changes in Plaque Composition Consistent With Plaque Stabilization (2004)

Ox-AB uptake is focally diminished in plaques displaying accepted features of plaque stability. Imaging techniques to detect the presence and depletion of OxLDL may be useful in assessing plaque stabilization.
dMi-2, a Hunchback-Interacting Protein That Functions in Polycomb Repression (1998)

Early in Drosophila embryogenesis, gap gene products directly repress transcription of homeotic (HOX) genes and thereby delimit HOX expression domains. Subsequently, Polycomb-group proteins maintain this repression. Currently, there is no known molecular link between gap and Polycomb-group proteins. Here, dMi-2 is identified as a protein that binds to a domain in the gap protein Hunchback that is specifically required for the repression of HOX genes. Genetic analyses show that dMi-2 participates in both Hunchback and Polycomb repression in vivo. Hence, recruitment of dMi-2 may serve as a link between repression of HOX genes by Hunchback and Polycomb proteins.
Sense and antisense transcripts of the apolipoprotein E gene in normal and ApoE knockout mice, their expression after spinal cord injury and corresponding human transcripts (2005)

The apolipoprotein E (ApoE) gene has been linked to maladies such as hypercholesterolemia, CNS injury and disease. In this study, we present evidence that, in addition to the known transcript (ApoE S1) that translates into ApoE, there are three additional transcripts in mice. Two of these transcripts, ApoE S2 and ApoE S3, which are predicted to be transmembrane proteins, are transcribed from the sense strand. ApoE AS1 is transcribed from the antisense strand and is complementary to exon 4 of ApoE S1. The open reading frame of ApoE AS1 is conserved between human and mouse. The antisense transcript falls within the region of the human epsilon 4 allele that has been linked to the familial onset form of Alzheimer's disease. We also demonstrate the expression of ApoE S3 and ApoE AS1 in ApoE knockout mice, and ApoE S1 and ApoE S2 do not get transcribed. We had previously identified ApoE S1 as being upregulated in mice after spinal cord injury. In this study, we show that in spinal cord-injured C57BL/6 mice, both ApoE S1 and ApoE S3 transcripts are 10-fold upregulated and the antisense ApoE AS1 is 100-fold upregulated compared with normal levels. Such data suggest that these alternate transcripts are involved in the molecular pathogenesis of CNS disease and perhaps in ApoE expression in general, as we show that ApoE S2 and AS1 are also transcribed in human.
Structural Analysis of Multiprotein Complexes by Cross-linking, Mass Spectrometry, and Database Searching (2007)

Most protein complexes are inaccessible to high resolution structural analysis. We report the results of a combined approach of cross-linking, mass spectrometry, and bioinformatics to two human complexes containing large coiled-coil segments, the NDEL1 homodimer and the NDC80 heterotetramer. An important limitation of the cross-linking approach, so far, was the identification of cross-linked peptides from fragmentation spectra. Our novel approach overcomes the data analysis bottleneck of cross-linking and mass spectrometry. We constructed a purpose-built database to match spectra with cross-linked peptides, define a score that expresses the quality of our identification, and estimate false positive rates. We show that our analysis sheds light on critical structural parameters such as the directionality of the homodimeric coiled coil of NDEL1, the register of the heterodimeric coiled coils of the NDC80 complex, and the organization of a tetramerization region in the NDC80 complex. Our approach is especially useful to address complexes that are difficult in addressing by standard structural methods.