gebhart/patrepeval huggingface dataset:
Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions (2014)

Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.
Multiple Myeloma and Immunosecretory Disorders (2008)

The immunosecretory disorders are a diverse group of diseases associated with proliferation of an abnormal clone of immunoglobulin (Ig)-synthesizing, terminally differentiated B cells. These disorders include multiple myeloma (MM) and its variants, plasmacytoma, Waldenstrom macroglobulinemia, monoclonal gammopathy of undetermined significance, and monoclonal Ig deposition diseases, the latter including primary amyloidosis and nonamyloidotic types. These disorders are histologically composed of plasma cells, or plasmacytoid cells which produce Ig that is synthesized and usually secreted and can be deposited in some diseases. The Ig can be complete or can be composed of either heavy or light chains and is termed M-(monoclonal) protein. In MM, this proliferation overwhelms the normal cellular counterparts that synthesize and secrete appropriate levels of Ig. Immunosecretory disorders have been classified in multiple schemes, mostly morphologic, to such a degree that the classification of these entities has become a challenge to pathologists. The World Health Organization classification in 2001 was helpful because it provided specific clinicopathologic criteria for diagnosis. However, terms such as "progressive" disease were not well defined. In 2003, the International Myeloma Group defined MM as a disease with related organ and tissue injury, serving to better explain progressive in terms of deterioration of organ (renal, bone, and bone marrow) function over time. Therefore, modern classification of immunosecretory diseases is based on integration of clinical, morphologic, laboratory, radiographic, and biologic (including molecular) parameters, which we review here.
Wafer-scale room-temperature bonding between silicon and ceramic wafers by means of argon-beam surface activation (2002)

A room-temperature wafer bonding method between dissimilar materials is developed. 4-inch Si wafers and 3 or 4-inch ceramic wafers are bonded in vacuum after surface sputter etching by Ar beam. Strong bonding equivalent to bulk material is achieved by room-temperature process. The method enables the bonding between dissimilar materials regardless the thermal expansion mismatch and crystal lattice mismatch. In addition, it also realizes very low damage bonding because it does not require any heating process and external load to force two specimens together.
Cognitive-Behavioral Profiles of Neurodegenerative Dementias: Beyond Alzheimer's Disease (2007)

The neurocognitive and behavioral profiles of vascular dementia and vascular cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia, and dementia syndromes associated with frontotemporal lobar degenerations are compared and contrasted with Alzheimer's dementia (AD). Vascular dementia/vascular cognitive impairment is characterized by better verbal memory performance, worse quantitative executive functioning, and prominent depressed mood. Dementia with Lewy bodies and Parkinson's disease with dementia are equally contrasted with AD by defective processing of visual information, better performance on executively supported verbal learning tasks, greater attentional variability, poorer qualitative executive functioning, and the presence of mood-congruent visual hallucinations. The frontal variant of frontotemporal lobar degeneration (frontotemporal dementia) differs from AD by better multimodal retention on learning tasks, different patterns of generative word fluency, defective qualitative executive functioning, and by markedly impairment of comportment. For temporal variants of frontotemporal lobar degenerations, progressive aphasia and semantic dementia, worse language performance relative to AD is typically characteristic.
Combining hierarchical clusterings using min-transitive closure (2008)

In the past, clusterings combination approaches are based on ldquoflatrdquo clustering algorithms, i.e. algorithms that operate on non-hierarchical clustering schemes. These approaches, once applied to a hierarchical clusterings combination problem, are not capable of taking advantage of the information inherent in the input clusterings hierarchy, and may thus be suboptimal. In this paper, a new hierarchical clusterings combination framework is proposed for combining multiple dendrograms directly. In this framework, the description matrices of the primary hierarchical clusterings are aggregated into a transitive consensus matrix with which the final clustering is formed. Experiments on real-world datasets indicate that this framework provides solutions of improved quality.
Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers (2014)

Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).
Dynamic programming for detecting, tracking, and matching deformable contours (1995)

The problem of segmenting an image into separate regions and tracking them over time is one of the most significant problems in vision. Terzopoulos et al. (1987) proposed an approach to detect the contour regions of complex shapes, assuming a user selected initial contour not very far from the desired solution. We propose to further explore the information provided by the user's selected points and apply an optimal method to detect contours which allows a segmentation of the image. The method is based on dynamic programming (DP), and applies to a wide variety of shapes. It is exact and not iterative. We also consider a multiscale approach capable of speeding up the algorithm by a factor of 20, although at the expense of losing the guaranteed optimality characteristic. The problem of tracking and matching these contours is addressed. For tracking, the final contour obtained at one frame is sampled and used as initial points for the next frame. Then, the same DP process is applied. For matching, a novel strategy is proposed where the solution is a smooth displacement field in which unmatched regions are allowed while cross vectors are not. The algorithm is again based on DP and the optimal solution is guaranteed. We have demonstrated the algorithms on natural objects in a large spectrum of applications, including interactive segmentation and automatic tracking of the regions of interest in medical images.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Fatty acids and insulin resistance (1998)

We have demonstrated that physiological elevations in plasma free fatty acid concentrations inhibit insulin-stimulated glucose uptake in a dose-dependent manner in normal control subjects and in patients with NIDDM. Two possible mechanisms were identified: 1) a fat-related inhibition of glucose transport or phosphorylation that appeared after 3-4 h of fat infusion and 2) a decrease in muscle glycogen synthase activity that appeared after 4-6 h of fat infusion. We conclude that elevations of plasma FFAs caused insulin resistance and hence may play a significant role in the pathogenesis of insulin resistance in obesity and NIDDM.
L-ficolin Is a Pattern Recognition Molecule Specific for Acetyl Groups (2004)

L-ficolin and H-ficolin are molecules of the innate immune system. Upon recognition of a suitable target they activate the complement system. The ligand recognition structure of ficolins is contained within a fibrinogen-like domain. We examined the selectivity of the ficolins through inhibiting the binding to bacteria or to beads coupled with N-acetylglucosamine. The binding of L-ficolin to Streptococcus pneumoniae 11F and the beads was inhibited by N-acetylated sugars and not by non-acetylated sugars. However, it was also inhibited by other acetylated compounds. Based on this selectivity L-ficolin is not easily defined as a lectin. The binding of H-ficolin to Aerococcus viridans was not inhibited by any of the sugars or other compounds examined. Based on the selectivity of L-ficolin we developed a new purification procedure involving affinity chromatography on N-acetylcysteine-derivatized Sepharose. The column was loaded in the presence of EDTA and high salt, and L-ficolin was eluted by decreasing the salt concentration. Further purification was achieved by ion exchange chromatography.
Probability-based protein identification by searching sequence databases using mass spectrometry data (1999)

Several algorithms have been described in the literature for protein identification by searching a sequence database using mass spectrometry data. In some approaches, the experimental data are peptide molecular weights from the digestion of a protein by an enzyme. Other approaches use tandem mass spectrometry (MS/MS) data from one or more peptides. Still others combine mass data with amino acid sequence data. We present results from a new computer program, Mascot, which integrates all three types of search. The scoring algorithm is probability based, which has a number of advantages: (i) A simple rule can be used to judge whether a result is significant or not. This is particularly useful in guarding against false positives. (ii) Scores can be compared with those from other types of search, such as sequence homology. (iii) Search parameters can be readily optimised by iteration. The strengths and limitations of probability-based scoring are discussed, particularly in the context of high throughput, fully automated protein identification.
Ion transport in complex layered graphene-based membranes with tuneable interlayer spacing (2016)

Investigation of the transport properties of ions confined in nanoporous carbon is generally difficult because of the stochastic nature and distribution of multiscale complex and imperfect pore structures within the bulk material. We demonstrate a combined approach of experiment and simulation to describe the structure of complex layered graphene-based membranes, which allows their use as a unique porous platform to gain unprecedented insights into nanoconfined transport phenomena across the entire sub-10-nm scales. By correlation of experimental results with simulation of concentration-driven ion diffusion through the cascading layered graphene structure with sub-10-nm tuneable interlayer spacing, we are able to construct a robust, representative structural model that allows the establishment of a quantitative relationship among the nanoconfined ion transport properties in relation to the complex nanoporous structure of the layered membrane. This correlation reveals the remarkable effect of the structural imperfections of the membranes on ion transport and particularly the scaling behaviors of both diffusive and electrokinetic ion transport in graphene-based cascading nanochannels as a function of channel size from 10 nm down to subnanometer. Our analysis shows that the range of ion transport effects previously observed in simple one-dimensional nanofluidic systems will translate themselves into bulk, complex nanoslit porous systems in a very different manner, and the complex cascading porous circuities can enable new transport phenomena that are unattainable in simple fluidic systems.
Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. (1997)

We have examined the mechanism by which the cAMP-responsive factor CREB stimulates target gene expression following its phosphorylation at Ser-133. Using an in vitro transcription assay, we found that two signals were required for target gene activation: a phospho(Ser-133)-dependent interaction of CREB with RNA polymerase II via the coactivator CBP and a glutamine-rich domain interaction with TFIID via hTAF(II)130. The adenovirus E1A oncoprotein was found to inhibit phospho(Ser-133) CREB activity by binding to CBP and specifically blocking recruitment of RNA Pol II to the promoter. Our results suggest that the recruitment of CBP-RNA Pol II complexes per se is not sufficient for transcriptional activation and that activator-mediated recruitment of TFIID is additionally required for induction of signal-dependent genes.
Redox properties of protein disulfide isomerase (dsba) from escherichia coli (1993)

The redox properties of periplasmic protein disulfide isomerase (DsbA) from Escherichia coli were analyzed by measuring the equilibrium constant of the oxidation of reduced DsbA by oxidized glutathione. The experiments are based on the finding that the intrinsic tryptophan fluorescence of DsbA increases about threefold upon reduction of the enzyme, which can be explained by the catalytic disulfide bridge quenching the fluorescence of a neighboring tryptophan residue. From the specific fluorescence of DsbA equilibrated in the presence of different ratios of reduced and oxidized glutathione at pH 7, an equilibrium constant of 1.2 x 10(-4) M was determined, corresponding to a standard redox potential (E'0) of DsbA of -0.089 V. Thus, DsbA is a significantly stronger oxidant than cytoplasmic thioredoxins and its redox properties are similar to those of eukaryotic protein disulfide isomerase. The equilibrium constants for the DsbA/glutathione equilibrium were found to be strongly dependent on pH and varied from 2.5 x 10(-3) M to 3.9 x 10(-5) M between pH 4 and 8.5. The redox state-dependent fluorescence properties of DsbA should allow detailed physicochemical studies of the enzyme as well as the quantitative determination of the oxidized protein by fluorescence titration with dithiothreitol and open the possibility to observe bacterial protein disulfide isomerase "at work" during catalysis of oxidative protein folding.
Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations. (1994)

An equilibrium binding assay was used to directly measure the relative affinities of naturally processed 9-mer, 10-mer, and 12-mer peptides for the human class I MHC molecule HLA-A2.1. The peptides exhibited a range of affinities with IC50 values of 11 to 214 nM. The mode of interaction between these peptides and HLA-A2.1 was examined using peptides in which Asp had been substituted for suspected anchor residues. Regardless of length, the previously identified Leu at position 2 relative to the amino terminus was critical for peptide binding. While the carboxyl terminal residue was also critical for the binding of a 9-mer peptide, it was much less important in the binding of longer peptides. Additional residues close to the carboxyl terminus that contained aliphatic hydrocarbon side chains were of similar or greater importance in peptide binding. In addition, residue at position 3 also appeared to be important for the binding of longer peptides. The data suggest that different naturally occurring longer peptides can bind in different conformations to class I MHC molecules. While one of these is similar to the kinked conformation described by others, another conformation would involve an extension of the carboxyl terminus out of the class I binding site. The ability of MHC molecules to accommodate the same peptide in different conformations would appear to have distinct advantages to the immune system.
Obesity, Hypertension, and the Risk of Kidney Cancer in Men (2000)

Higher body-mass index and elevated blood pressure independently increase the long-term risk of renal-cell cancer in men. A reduction in blood pressure lowers the risk.
Productivity and selective accumulation of carotenoids of the novel extremophile microalga Chlamydomonas acidophila grown with different carbon sources in batch systems (2010)

Cultivation of extremophile microorganisms has attracted interest due to their ability to accumulate high-value compounds. Chlamydomonas acidophila is an acidophile green microalga isolated by our group from Tinto River, an acidic river that flows down from the mining area in Huelva, Spain. This microalga accumulates high concentrations of lutein, a very well-known natural antioxidant. The aim of this study is to assess use of different carbon sources (CO(2), glucose, glycerol, starch, urea, and glycine) for efficient growth of and carotenoid production by C. acidophila. Our results reveal that growth of the microalga on different carbon sources resulted in different algal biomass productivities, urea being as efficient as CO(2) when used as sole carbon source (~20 g dry biomass m(-2) day(-1)). Mixotrophic growth on glucose was also efficient in terms of biomass production (~14 g dry biomass m(-2) day(-1)). In terms of carotenoid accumulation, mixotrophic growth on urea resulted in even higher productivity of carotenoids (mainly lutein, probably via α-carotene) than obtained with photoautotrophic cultures (70% versus 65% relative abundance of lutein, respectively). The accumulated lutein concentrations of C. acidophila reported in this work (about 10 g/kg dry weight, produced in batch systems) are among the highest reported for a microalga. Glycerol and glycine seem to enhance β-carotene biosynthesis, and when glycine is used as carbon source, zeaxanthin becomes the most accumulated carotenoid in the microalga. Strategies for production of lutein and zeaxanthin are suggested based on the obtained results.
Sulphide as an inhibitor and electron donor for the cytochrome c oxidase system (1982)

Anomalies both kinetic and equilibrium in nature are described for the inhibition of cytochrome c oxidase activity by sulphide in the isolated enzyme and in submitochondrial particles. These anomalies are related to the involvement of more than 1 mol of sulphide in the blockage of one cytochrome aa 3 centre. Sulphide reduces resting cytochrome a 3 , a reaction that results in oxygen uptake and the loss of a sulphide molecule. Sulphide can also reduce cytochromes c and a; in the former case, a part of the one-equivalent oxidation product, presumed to be the SH ∙ radical, reacts with oxygen. Such oxygen uptake is also seen under aerobic conditions when ferricyanide reacts with sulphide. Three phases are identified in the inhibitory interaction of sulphide with the cytochrome c oxidase enzyme itself: an initial rapid reaction involving sulphide oxidation, oxygen uptake, and conversion of cytochrome aa 3 into the low-spin "oxyferri" form; a subsequent step in which sulphide reduces cytochrome a; and the final inhibitory step in which a third molecule of sulphide binds the a 3 iron centre in the cytochrome [Formula: see text] (oxy) species to give cytochrome [Formula: see text]. The initial events parallel some of the events in the interaction of the cytochrome c – cytochrome aa 3 system with monothiols; the final inhibitory event resembles that with cyanide.
A DYNAMIC GAME OF OFFENDING AND LAW ENFORCEMENT (2002)

In this paper, we analyse a differential game describing the interactions between a potential offender and the law enforcement agency. We assume that both players want to maximise their welfare expressed in monetary units, and compare the results obtained by applying the Nash equilibrium concept under symmetric with that under asymmetric information. The comparison reveals that under asymmetric information the offence rate is lower, due to the deterrence caused by the activities of the law enforcement agency. Both players' controls start at a steady state value and stick to it until close to the end of the planning horizon, when they leave the steady state to take into account the scrap value; this can be interpreted as a turnpike property of Nash equilibria. Furthermore, a sensitivity analysis is carried out. Among others, it turns out that a myopic offender tends to a higher offence level.
On the nature of IgG dimers. I. Dimers in human polyclonal IgG preparations: kinetic studies. (1988)

Human polyclonal IgG for therapeutic or prophylactic purposes is usually prepared from pooled plasmas taken from more than 1000 donors. After storage in solution under physiological conditions for a sufficiently long period, a considerable percentage of dimers (approx. 10-30% [w/w] at a protein concentration of approx. 160 mg/ml) represents the main component of aggregates in contrast to the essentially monomeric IgGs of monoclonal or single donor origin. Analysing the kinetics of monomer-dimer equilibration suggests assuming approx. 10(6) different antibody (ab) populations interacting independently and simultaneously with a specific partner of the reaction. Concerning the average apparent (functional) equilibrium constant of association, Kapp., a distinction could be made between two main populations characterized by values in the range if approx. 2.5-3.0 X 10(10) M-1 and 1.0 X 10(12) M-1, respectively. The results were obtained by computer simulation, taking an association rate constant, k+1, of 5 X 10(5) M-1 s-1 as a basis. Since the main part of the individual populations was found to interact Fc-independently via Fab-located binding sites, we suppose that the dimers are for the most part complexes of idiotypic (Ids) and anti-idiotypic abs (anti-Ids). Moreover, dimerization seems to be mainly a bivalent binding reaction, at least at the experimental concentrations. The results are in line with the concept of an idiotypic network regulation in man.
Genomic changes associated with antigenic variation of visna virus durig persistent infection. (1980)

Visna virus undergoes antigenic change during persistent infection of sheep. Antigenic variants of visna virus were compared by using the genomic RNA and analyzing the large RNase T1-resistant oligonucleotides. Mutants isolated from a persistently infected sheep contained a small number of changes in their oligonucleotide patterns when compared with parental virus. To determine whether the changes in the nucleotide structure were clustered in one region of the genome, we determined the order of the oligonucleotides of the parental and mutant RNAs along the genome with respect to the 3' polyadenylylated end. All but one difference between the parental strain and the antigenic mutant used for mapping were located within 2 kilobases from the 3' terminus. Nucleotide sequence analyses showed that several of the oligonucleotides that differed in the parental and mutant RNAs could be accounted for by single base changes.