gebhart/patrepeval huggingface dataset:
Fast Bayesian Matching Pursuit: Model Uncertainty and Parameter Estimation for Sparse Linear Models (2009)

A low-complexity recursive procedure is presented for model selection and minimum mean squared error (MMSE) estimation in linear regression. Emphasis is given to the case of a sparse parameter vector and fewer observations than unknown parameters. A Gaussian mixture is chosen as the prior on the unknown parameter vector. The algorithm returns both a set of high posterior probability models and an approximate MMSE estimate of the parameter vector. Exact ratios of posterior probabilities serve to reveal potential ambiguity among multiple candidate solutions that are ambiguous due to observation noise or correlation among columns in the regressor matrix. Algorithm complexity is O(MNK), with M observations, N coefficients, and K nonzero coefficients. For the case that hyperparameters are unknown, an approximate maximum likelihood estimator is proposed based on the generalized expectation-maximization algorithm. Numerical simulations demonstrate estimation performance and illustrate the distinctions between MMSE estimation and maximum a posteriori probability model selection.
Antisense strategies and therapeutic applications (1996)

The concepts underlying the antisense approach to disease therapy are discussed, and potential applications are examined. Antisense therapeutic agents bind to DNA or RNA sequences, blocking the synthesis of cellular proteins with unparalleled specificity. Transcription and translation are the two processes with which the agents interfere. There are three major classes of antisense agents: antisense sequences, commonly called antisense oligonucleotides; antigene sequences; and ribozymes. Antisense sequences are derivatives of nucleic acids that hybridize cytosolic messenger RNA (mRNA) sense strands through hydrogen bonding to complementary nucleic acid bases. Antigene sequences hybridize double-stranded DNA in the nucleus, forming triple helixes. Ribozymes, rather than inhibiting protein synthesis simply by binding to a single targeted mRNA, combine enzymatic processes with the specificity of antisense base pairing, creating a molecule that can incapacitate multiple targeted mRNAs. Antisense therapeutic agents are being investigated in vitro and in vivo for use in treating human immunodeficiency virus infection, hepatitis B virus infection, herpes simplex virus infection, papillomavirus infection, cancer, restenosis, rheumatoid arthritis, and allergic disorders. Although many results are preliminary, some are promising and have led to clinical trials. A major goal in developing methods of delivering antisense agents is to reduce their susceptibility to nucleases while retaining their ability to bind to targeted sites. Modification of the phosphodiester linkages in oligonucleotides can lend the sequences enzymatic stability without affecting their binding capacities. Carrier systems designed to protect the antisense structure and improve passage through the cell membrane include liposomes, water-soluble polymers, and nanoparticles. The pharmacokinetics of antisense agents are under investigation. Antisense therapeutic agents have the potential to become an integral part of medicinal regimens.
Potent antiviral activity of an antisense oligonucleotide complementary to the intron-exon boundary of human cytomegalovirus genes UL36 and UL37 (1995)

An antisense phosphorothioate oligonucleotide complementary to the intron-exon boundary of human cytomegalovirus genes UL36 and UL37 (UL36ANTI) reduced the yield of infectious virus by 99% and inhibited human cytomegalovirus DNA replication at a concentration of 0.08 microM. In addition, oligonucleotides with base substitutions which resulted in base pair mismatches showed lesser degrees of activity, indicating a sequence-specific antisense mechanism. UL36ANTI was also shown to inhibit DNA replication of ganciclovir-resistant strains and human cytomegalovirus clinical isolates.
Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor (2004)

Flavopiridol (FP) inhibits gene expression and causes apoptosis, and these effects cannot be explained by inhibition of cyclin-dependent kinases that govern cell cycle. The simple and established notion that FP is an inhibitor of transcription predicts its effects. Because Mdm-2 targets p53 for degradation, FP, as predicted, dramatically induced p53 by inhibiting Mdm-2. Once p53 was induced, restoration of transcription (by removal of FP) resulted in superinduction of p21 and Mdm-2. Similarly, low concentrations of FP (50 nm) induced p21 and Mdm-2 because of their initial down-regulation. A sustained decrease of Mdm-2/p21 expression and accumulation of p53 coincided with near-maximal cytotoxicity of FP at concentrations >100 nm. Induction of p53 was a marker, not a cause, of cytotoxicity. FP caused rapid apoptosis (caspase-dependent cell death) in p53-null leukemia cells. In these cells, FP-induced apoptosis was converted to growth arrest by inhibitors of caspases. In apoptosis-reluctant A549 and PC3M cancer cells, FP inhibited cell proliferation but did not cause apoptosis. Like typical inhibitors of transcription, FP sensitized cells to apoptotic stimuli, allowing tumor necrosis factor to cause rapid and massive apoptosis in otherwise apoptosis-reluctant cells. We discuss that, as a reversible inhibitor of transcription, FP can be used clinically in novel rational drug combinations.
Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis (2008)

The mechanisms underlying the susceptibility of individuals with caspase recruitment domain 15 (CARD15) mutations and corresponding abnormalities of nucleotide-binding oligomerization domain 2 (NOD2) protein to Crohn disease are still poorly understood. One possibility is based on previous studies showing that muramyl dipeptide (MDP) activation of NOD2 negatively regulates TLR2 responses and that absence of such regulation leads to heightened Th1 responses. We now report that administration of MDP protects mice from the development of experimental colitis by downregulating multiple TLR responses, not just TLR2. The basis of these in vivo findings was suggested by in vitro studies of DCs, in which we showed that prestimulation of cells with MDP reduces cytokine responses to multiple TLR ligands and this reduction is dependent on enhanced IFN regulatory factor 4 (IRF4) activity. Further studies of mouse models of colitis showed that this inhibitory role of IRF4 does in fact apply to MDP-mediated protection from colitis, since neither IRF4-deficient mice nor mice treated with siRNA specific for IRF4 were protected. These findings indicate that MDP activation of NOD2 regulates innate responses to intestinal microflora by downregulating multiple TLR responses and suggest that the absence of such regulation leads to increased susceptibility to Crohn disease.
A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1 (2003)

Antibody conjugates directed against intercellular adhesion molecule (ICAM-1) or platelet-endothelial cell adhesion molecule (PECAM-1) have formed the basis for drug delivery vehicles that are specifically recognized and internalized by endothelial cells. There is increasing evidence that ICAM-1 and PECAM-1 may also play a role in cell scavenger functions and pathogen entry. To define the mechanisms that regulate ICAM-1 and PECAM-1 internalization, we examined the uptake of anti-PECAM-1 and anti-ICAM-1 conjugates by endothelial cells. We found that the conjugates must be multimeric, because monomeric anti-ICAM-1 and anti-PECAM-1 are not internalized. Newly internalized anti-ICAM-1 and anti-PECAM-1 conjugates did not colocalize with either clathrin or caveolin, and immunoconjugate internalization was not reduced by inhibitors of clathrin-mediated or caveolar endocytosis, suggesting that this is a novel endocytic pathway. Amiloride and protein kinase C (PKC) inhibitors, agents known to inhibit macropinocytosis, reduced the internalization of clustered ICAM-1 and PECAM-1. However, expression of dominant-negative dynamin-2 constructs inhibited uptake of clustered ICAM-1. Binding of anti-ICAM-1 conjugates stimulated the formation of actin stress fibers by human umbilical vein endothelial cells (HUVEC). Latrunculin, radicicol and Y27632 also inhibited internalization of clustered ICAM-1, suggesting that actin rearrangements requiring Src kinase and Rho kinase (ROCK) were required for internalization. Interestingly, these kinases are part of the signal transduction pathways that are activated when circulating leukocytes engage endothelial cell adhesion molecules, suggesting the possibility that CAM-mediated endocytosis is regulated using comparable signaling pathways.
Distracted Driving and Risk of Road Crashes among Novice and Experienced Drivers (2014)

The risk of a crash or near-crash among novice drivers increased with the performance of many secondary tasks, including texting and dialing cell phones. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Highway Traffic Safety Administration.).
The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. (1997)

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (</= 7 d) events of warm and in situ perfused cold ischemia of native kidneys in uninephrectomized rats were examined. mRNA expression of the early adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated in parallel. T cells and macrophages entered the injured kidney by 2-5 d; the associated upregulation of MHC class II antigen expression suggested increased immunogenicity of the organ. Th1 products (IL-2, TNFalpha, IFNgamma) and macrophage-associated products (IL-1, IL-6, TGFbeta) remained highly expressed after 2 d. To examine directly the effects of selectins in I/R injury, a soluble P-selectin glycoprotein ligand (sPSGL) was used. Ischemic kidneys were perfused in situ with 5 microg of sPSGL in UW solution; 50 microg was administered intravenously 3 h after reperfusion. E-selectin mRNA remained at baseline, leukocytes did not infiltrate the injured organs throughout the 7-d period, and their associated products were markedly inhibited. Class II expression did not increase. No renal dysfunction secondary to I/R occurred. The early changes of I/R injury may be prevented by treatment with soluble P- and E-selectin ligand. This may reduce subsequent host inflammatory responses after transplantation.
Hardware-efficient Quantum Optimizer for Small Molecules and Quantum Magnets (2017)

Quantum computers can be used to address molecular structure, materials science and condensed matter physics problems, which currently stretch the limits of existing high-performance computing resources. Finding exact numerical solutions to these interacting fermion problems has exponential cost, while Monte Carlo methods are plagued by the fermionic sign problem. These limitations of classical computational methods have made even few-atom molecular structures problems of practical interest for medium-sized quantum computers. Yet, thus far experimental implementations have been restricted to molecules involving only Period I elements. Here, we demonstrate the experimental optimization of up to six-qubit Hamiltonian problems with over a hundred Pauli terms, determining the ground state energy for molecules of increasing size, up to BeH2. This is enabled by a hardware-efficient variational quantum eigensolver with trial states specifically tailored to the available interactions in our quantum processor, combined with a compact encoding of fermionic Hamiltonians and a robust stochastic optimization routine. We further demonstrate the flexibility of our approach by applying the technique to a problem of quantum magnetism. Across all studied problems, we find agreement between experiment and numerical simulations with a noisy model of the device. These results help elucidate the requirements for scaling the method to larger systems, and aim at bridging the gap between problems at the forefront of high-performance computing and their implementation on quantum hardware.
Data Integration and Data Exchange: It's Really About Time. (2013)

With the deluge in the amount and variety of data in the world, it is rare for data that describes an entity to be completely contained and managed by a single data source. As a consequence, there is often great value in combining data about an entity from multiple sources, and also from versions of data reported by the same source over time. Data integration in which multiple dimensions of time may be expressed explicitly (e.g., as part of the data itself) or implicitly (e.g., the publication date of a data source), must be performed with great care. This is because each data source contains only partial (time-specific) knowledge about an entity, and thus their collective knowledge about the entity may contain conflicts that need to be resolved. In this paper, we call for a formal framework for data integration and data exchange across time that would facilitate the creation of consistent and integrated longitudinal knowledge about entities. We call such longitudinal knowledge of an entity its whenprovenance, which intuitively corresponds to when one knows what one knows about the entity. We believe that the vision and research directions described in this paper will serve to instigate the research and development of the next generation data integration and data exchange system, where both data and time can be reasoned on equal footing. 1.
Mild Traumatic Brain Injury in U.S. Soldiers Returning from Iraq (2008)

Mild traumatic brain injury (i.e., concussion) occurring among soldiers deployed in Iraq is strongly associated with PTSD and physical health problems 3 to 4 months after the soldiers return home. PTSD and depression are important mediators of the relationship between mild traumatic brain injury and physical health problems.
The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma (2012)

Endometrial cancer is the most common malignancy of the female genital tract, and the incidence and mortality rates from this disease are increasing. Although endometrial carcinoma has been regarded as a tissue-specific disease mediated by female sex steroid pathways, considerable evidence implicates a role for an inflammatory response in the development and propagation of endometrial cancer. We hypothesized that if specific patterns of cytokine expression were found to be predictive of adverse outcome, then selective receptor targeting may be a therapeutic option. This study was therefore undertaken to determine the relationship between cytokine production in primary cell culture and clinical outcome in endometrial adenocarcinoma. Fresh endometrial tissues were fractionated into epithelial and stromal fractions and cultured. After 6-7 days, supernatants were collected and cells enumerated. Batched aliquots were assayed using ELISA kits specific for CSF-1, GMCSF, G-CSF, TNF-α, IL-6, IL-8, and VEGF. Data were compared using ANOVA, Fisher's exact, and log rank tests. Increased epithelial VEGF production was observed more often in tumors with Type 2 variants (p = 0.039) and when GPR30 receptor expression was high (p = 0.038). Although increased stromal VEGF production was detected more often in grade 3 endometrioid tumors (p = 0.050), when EGFR expression was high (p = 0.003), and/or when ER/PR expression was low (p = 0.048), VEGF production did not correlated with overall survival (OS). Increased epithelial CSF-1 and TNF-α production, respectively, were observed more often in tumors with deep myometrial invasion (p = 0.014) and advanced stage (p = 0.018). Increased CSF-1 (89.5% vs. 42.9%, p = 0.032), TNF-α (88.9% vs. 42.9%, p = 0.032, and IL-6 (92.3% vs. 61.5%, p = 0.052) also correlated with low OS. In Cox multivariate models, CSF-1 was an independent predictor of low survival when stratified by grade (p = 0.046) and histology (p = 0.050), and TNF-α, when stratified by histology (p = 0.037). In this study, high CSF-1, TNF-α, and IL-6 production rates identified patients at greatest risk for death, and may signify patients likely to benefit from receptor-specific therapy.
Motility and growth of human bone-marrow mesenchymal stem cells during ex vivo expansion in autologous serum (2005)

Human bone-marrow mesenchymal stem cells have an important role in the repair of musculoskeletal tissues by migrating from the bone marrow into the injured site and undergoing differentiation. We investigated the use of autologous human serum as a substitute for fetal bovine serum in the ex vivo expansion medium to avoid the transmission of dangerous transfectants during clinical reconstruction procedures. Autologous human serum was as effective in stimulating growth of bone-marrow stem cells as fetal bovine serum. Furthermore, medium supplemented with autologous human serum was more effective in promoting motility than medium with fetal bovine serum in all cases. Addition of B-fibroblast growth factor to medium with human serum stimulated growth, but not motility. Our results suggest that autologous human serum may provide sufficient ex vivo expansion of human bone-marrow mesenchymal stem cells possessing multidifferentiation potential and may be better than fetal bovine serum in preserving high motility.
MECHANISMS IN PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (2004)

The symptoms of CP/CPPS appear to result from an interplay between psychological factors and dysfunction in the immune, neurological and endocrine systems.
Early Expression of Angiogenesis Factors in Acute Myocardial Ischemia and Infarction (2000)

An increase in the level of HIF-1alpha is an early response to myocardial ischemia or infarction. This response defines, at a molecular level, one of the first adaptations of human myocardium to a deprivation of blood. HIF-1alpha is a useful temporal marker of acutely jeopardized myocardium.
Bacterial infection as assessed by in vivo gene expression (1997)

In vivo expression technology (IVET) has been used to identify > 100 Salmonella typhimurium genes that are specifically expressed during infection of BALB/c mice and/or murine cultured macrophages. Induction of these genes is shown to be required for survival in the animal under conditions of the IVET selection. One class of in vivo induced (ivi) genes, iviVI-A and iviVI-B, constitute an operon that resides in a region of the Salmonella genome with low G+C content and presumably has been acquired by horizontal transfer. These ivi genes encode predicted proteins that are similar to adhesins and invasins from prokaryotic and eukaryotic pathogens (Escherichia coli [tia], Plasmodium falciparum [PfEMP1]) and have coopted the PhoPQ regulatory circuitry of Salmonella virulence genes. Examination of the in vivo induction profile indicates (i) many ivi genes encode regulatory functions (e.g., phoPQ and pmrAB) that serve to enhance the sensitivity and amplitude of virulence gene expression (e.g., spvB); (ii) the biochemical function of many metabolic genes may not represent their sole contribution to virulence; (iii) the host ecology can be inferred from the biochemical functions of ivi genes; and (iv) nutrient limitation plays a dual signaling role in pathogenesis: to induce metabolic functions that complement host nutritional deficiencies and to induce virulence functions required for immediate survival and spread to subsequent host sites.
Intratracheal Inhalation vs Intratracheal Instillation: Differences in Particle Effects (1997)

Our laboratory has developed a method of intratracheal inhalation whereby rats can be exposed to high aerosol concentrations, resulting in high lung particle burdens in a short time period with deposition occurring directly in the lower respiratory tract, thus avoiding many drawbacks of larger nose-only or whole body inhalation systems. In this report, we compare the response of rats exposed by intratracheal inhalation to "fine"(˜210 nm) and "ultrafine" (˜21 nm) titanium dioxide particles with rats exposed to similar doses by intratracheal instillation. Animals receiving particles through inhalation showed a decreased pulmonary response, measured by bronchoalveolar lavage parameters, in both severity and persistence, when compared with those receiving particles through instillation. These results demonstrate a difference in pulmonary response to an inhaled vs an instilled dose, which may be due to differences in dose rate, particle distribution, or altered clearance between the two methods.
Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases (2002)

Intracytoplasmic inclusions composed of alpha-synuclein (alpha-syn) are characteristic of neurodegenerative Lewy body disorders. Using novel monoclonal antibodies raised against altered alpha-syn, we uncovered an unprecedented and extensive burden of alpha-syn pathology in the striatum of Lewy body disorders. The highest density of striatal pathology was observed in patients with a combination of Alzheimer's disease and dementia with Lewy bodies or pure dementia with Lewy bodies, and these alpha-syn aggregates may contribute to the parkinsonism seen in these disorders.
Cation and sugar selectivity determinants in a novel family of transport proteins (1996)

A new family of homologous membrane proteins that transport galactosides-pentoses-hexuronides (GPH) is described. By analysing the aligned amino acid sequences of the GPH family, and by exploiting their different specificities for cations and sugars, we have designed mutations that yield novel insights into the nature of ligand binding sites in membrane proteins. Mutants have been isolated/constructed in the melibiose transport proteins of Escherichia coli, Klebsiella pneumoniae and Salmonella typhimurium, and the lactose transport protein of Streptococcus thermophilus which facilitate uncoupled transport or have an altered cation and/or substrate specificity. Most of the mutations map in the amino-terminal region, in or near amphipathic alpha-helices II and IV, or in interhelix-loop 10-11 of the transport proteins. On the basis of the kinetic properties of these mutants, and the primary and secondary structure analyses presented here, we speculate on the cation binding pocket of this family of transporters. The regulation of the transporters through interaction with, or phosphorylation by, components of the phosphoenolpyruvate:sugar phosphotransferase system is also discussed.