gebhart/patrepeval huggingface dataset:
SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages (1989)

We have reported that SV40-transformed human lung fibroblasts secrete a 92-kDa metalloprotease which is not detectable in the parental cell line IMR-90. We now present the complete structure of this enzyme along with the evidence that it is identical to the 92-kDa metalloprotease secreted by normal human alveolar macrophages, phorbol ester-differentiated monocytic leukemia U937 cells, fibrosarcoma HT1080 cells, and cultured human keratinocytes. A similar, perhaps identical, enzyme can be released by polymorphonuclear cells. The preproenzyme is synthesized as a polypeptide of predicted Mr 78,426 containing a 19 amino-acid-long signal peptide and secreted as a single 92,000 glycosylated proenzyme. The purified proenzyme complexes noncovalently with the tissue inhibitor of metalloproteases (TIMP) and can be activated by organomercurials. Activation with phenylmercuric chloride results in removal of 73 amino acids from the NH2 terminus of the proenzyme, yielding an active form capable of digesting native types IV and V collagen. The in vitro substrate specificity of the enzyme using these substrates was indistinguishable from that of the 72-kDa type IV collagenase. The 92-kDa type IV collagenase consists of five domains; the amino-terminal and zinc-binding domains shared by all members of the secreted metalloprotease gene family, the collagen-binding fibronectin-like domain also present in the 72-kDa type IV collagenase, a carboxyl-terminal hemopexin-like domain shared by all known enzymes of this family with the exception of PUMP-1, and a unique 54-amino-acid-long proline-rich domain homologous to the alpha 2 chain of type V collagen.
Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules (2002)

The envelope glycoprotein (Env) of HIV-1 is incorporated into virions that bud from the cell surface of infected T cells. With immunofluorescence microscopy and subcellular membrane fractionation techniques, the intracellular fate of Env in the secretory pathway of HIV-1-infected T cells was evaluated. Rather than trafficking constitutively from the Golgi to the cell surface, Env is directed to intracellular CTLA-4-containing granules, whose recruitment to the cell surface is regulated. The use of the regulated pathway for intracellular Env storage before virion assembly holds implications for the staging of Env exposure at the cell surface of infected cells and of coordinating HIV virion assembly.
Development of Beta-Amyloid-induced Neurodegeneration in Alzheimer's Disease and Novel Neuroprotective Strategies (2005)

Alzheimer's disease (AD) is a form of dementia in which people develop rapid neurodegeneration, complete loss of cognitive abilities, and are likely to die prematurely. At present, no treatment for AD is known. One of the hallmarks in the development of AD is the aggregation of amyloid protein fragments in the brain, and much evidence points towards beta-amyloid fragments being one of the main causes of the neurodegenerative processes. This review summarises the present concepts and theories on how AD develops, and lists the evidence that supports them. A cascade of biochemical events is initiated that ultimately leads to neuronal death involving an imbalance of intracellular calcium homeostasis via activation of calcium channels, intracellular calcium stores, and subsequent production of free radicals by calcium-sensitive enzymes. Secondary processes include inflammatory responses that produce more free radicals and the induction of apoptosis. Recently, several new strategies have been proposed to try to ameliorate the neurodegenerative developments associated with AD. These include the activation of neuronal growth factor receptors and insulin-like receptors, both of which have neuroprotective properties. Furthermore, the role of cholesterol and potential protective properties of cholesterol-lowering drugs are under intense investigation. Other promising strategies include the inhibition of beta- and gamma-secretases which produce beta-amyloid, activation of proteases that degrade beta-amyloid, glutamate receptor selective drugs, antioxidants, and metal chelating agents, all of which prevent formation of plaques. Novel drugs that act at different levels of the neurodegenerative processes show great promise to reduce neurodegeneration. They could help to prolong the time of unimpaired cognitive abilities of people who develop AD, allowing them to lead an independent life.
REM Sleep and the Early Development of Posttraumatic Stress Disorder (2002)

OBJECTIVE: The potential for chronicity and treatment resistance once posttraumatic stress disorder (PTSD) has become established has stimulated interest in understanding the early pathogenesis of the disorder. Arousal regulation and memory consolidation appear to be important in determining the development of PTSD; both are functions of sleep. Sleep findings from patients with chronic PTSD are complex and somewhat contradictory, and data from the acute phase are quite limited. The aim of the present study was to obtain polysomnographic recordings during an acute period after life-threatening experiences and injury and to relate measures of sleep duration and maintenance and the timing, intensity, and continuity of REM sleep to the early development of PTSD. METHOD: Twenty-one injured subjects meeting study criteria received at least one polysomnographic recording close to the time of medical/surgical stabilization and within a month of injury. PTSD symptoms were assessed concurrently and 6 weeks later. Sleep measures were compared among injured subjects with and without significant PTSD symptoms at follow-up and 10 noninjured comparison subjects and were also correlated with PTSD severity. RESULTS: There was more wake time after the onset of sleep in injured, trauma-exposed patients than in noninjured comparison subjects. Development of PTSD symptoms was associated with shorter average duration of REM sleep before a stage change and more periods of REM sleep. CONCLUSIONS: The development of PTSD symptoms after traumatic injury is associated with a more fragmented pattern of REM sleep.
A Probabilistic Analysis of the Rocchio Algorithm with TFIDF for Text Categorization (1997)

A probabilistic analysis of the Rocchio relevance feedback algorithm, one of the most popular learning methods from information retrieval, is presented in a text categorization framework. The analysis results in a probabilistic version of the Rocchio classifier and offers an explanation for the TFIDF word weighting heuristic. The Rocchio classifier, its probabilistic variant and a standard naive Bayes classifier are compared on three text categorization tasks. The results suggest that the probabilistic algorithms are preferable to the heuristic Rocchio classifier. This research is sponsored by the Wright Laboratory, Aeronautical Systems Center, Air Force Materiel Command, USAF, and the Advanced Research Projects Agency (ARPA) under grant F33615-93-1-1330. The US Government is authorized to reproduce and distribute reprints for Government purposes, notwithstanding any copyright notation thereon. Views and conclusions contained in this document are those of the authors and should not be ...
The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis (2015)

Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer.
Synthesis and evaluation of two new bifunctional carboxymethylated tetraazamacrocyclic chelating agents for protein labeling with indium-111 (1990)

The synthesis of two new N- and C-functionalized tetraazamacrocyclic ligands intended to be covalently linked to biomolecules like monoclonal antibodies and to bind the gamma-emitting isotope indium-111 in a thermodynamically and/or kinetically inert way is described. 12-(p-Nitrobenzyl)-1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraa cetic acid (L1) was synthesized by means of bimolecular cyclization with the appropriate malonic acid diethyl ester and triethylenetetraamine, followed by reduction with diborane and alkylation of the cyclic tetraamine with bromoacetic acid. The corresponding triscarboxymethylated ligand L2 was made by statistical alkylation of the tetraamine. Both ligands fulfill the criteria for antibody labeling using the bifunctional chelate approach, namely fast chelate formation, high radiochemical yield, and high stability under physiological conditions. Surprisingly the heptadentate ligand L2 confers higher stability to In3+ and exhibits faster complex formation than octadentate L1. 13C NMR spectra in solution indicate that the difference in stability is not due to incomplete coordination of all four carboxylate groups in In-L1.
Store Vulnerability Window (SVW): Re-Execution Filtering for Enhanced Load Optimization (2005)

The load-store unit is a performance critical component of a dynamically-scheduled processor. It is also a complex and non-scalable component. Several recently proposed techniques use some form of speculation to simplify the load-store unit and check this speculation by re-executing some of the loads prior to commit. We call such techniques load optimizations. One recent load optimization improves load queue (LQ) scalability by using re-execution rather than associative search to check speculative intra- and inter- thread memory ordering. A second technique improves store queue (SQ) scalability by speculatively filtering some load accesses and some store entries from it and re-executing loads to check that speculation. A third technique speculatively removes redundant loads from the execution engine; re-execution detects false eliminations. Unfortunately, the benefits of a load optimization are often mitigated by re-execution itself Re-execution contends for cache bandwidth with store commit, and serializes load re-execution with subsequent store com-mit. If a given load optimization requires a sufficient number of load re-executions, the aggregate re-execution cost may overwhelm the benefits of the technique entirely and even cause drastic slowdowns. Store vulnerability window (SVW) is a new mechanism that significantly reduces the re-execution requirements of a given load optimization. SVW is based on monotonic store sequence numbering and an adaptation of Bloom filtering. The cost of a typical SVW implementation is a 1KB buffer and a 16-bit field per LQ entry. Across the three optimizations we study, SVW reduces re-executions by an average of 85%. This reduction relieves cache port contention and removes many of the dynamic serialization events that contribute the bulk of re-execution's cost, allows these load optimizations to perform up to their full potential. For the speculative SQ, this means the chance to perform at all, as without SVW it posts significant slowdowns.
Cryptosporidium Parvum-Induced Inflammatory Bowel Disease of TCR-b- x TCR-d-Deficient Mice (1999)

Experimental inoculation of neonatal immunocompetent strains of mice with Cryptosporidium parvum results in a transient, noninflammatory enteric infection. In the present study, we show that inoculation of mice deficient in alphabeta and gammadelta T cells (TCR-beta- x TCR-delta-deficient mice) with C. parvum results in persistent infection and severe inflammatory bowel disease-like lesions. The most severe lesions in these mice were in the cecum with similar yet less severe lesions in the ileum and proximal colon. The most notable aspect of the histopathology was glandular hyperplasia with abscess formation, extensive fibrosis of the lamina propria with infiltrates of predominately polymorphonuclear cells and macrophages, and a few small aggregates of B cells. Persistently infected mice also developed extensive hepatic periportal fibrosis in association with C. parvum colonization of bile ducts. Lesions observed in TCR-beta- x TCR-delta-deficient mice were markedly different than previously described lesions detected in C. parvum-infected TCR-alpha-deficient mice. Cryptosporidium parvum-infected TCR-alpha-deficient mice have extensive infiltrations of B cells, whereas TCR-beta- x TCR-delta-deficient mice had only a few small aggregates of B cells. These findings indicate that although gammadelta T cells are not necessary for induction of intestinal inflammation in C. parvum-infected alphabeta T-cell-deficient mice, their presence does alter the morphology of the ensuing lesion.
Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine (2009)

Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted.
Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy (2005)

Stem cells represent natural units of embryonic development and tissue regeneration. Embryonic stem (ES) cells, in particular, possess a nearly unlimited self-renewal capacity and developmental potential to differentiate into virtually any cell type of an organism. Mouse ES cells, which are established as permanent cell lines from early embryos, can be regarded as a versatile biological system that has led to major advances in cell and developmental biology. Human ES cell lines, which have recently been derived, may additionally serve as an unlimited source of cells for regenerative medicine. Before therapeutic applications can be realized, important problems must be resolved. Ethical issues surround the derivation of human ES cells from in vitro fertilized blastocysts. Current techniques for directed differentiation into somatic cell populations remain inefficient and yield heterogeneous cell populations. Transplanted ES cell progeny may not function normally in organs, might retain tumorigenic potential, and could be rejected immunologically. The number of human ES cell lines available for research may also be insufficient to adequately determine their therapeutic potential. Recent molecular and cellular advances with mouse ES cells, however, portend the successful use of these cells in therapeutics. This review therefore focuses both on mouse and human ES cells with respect to in vitro propagation and differentiation as well as their use in basic cell and developmental biology and toxicology and presents prospects for human ES cells in tissue regeneration and transplantation.
A feedback control scheme for reversing a truck and trailer vehicle (2001)

A control scheme is proposed for stabilization of backward driving along simple paths for a miniaturized vehicle composed of a truck and a two-axle trailer. The paths chosen are straight lines and arcs of circles. When reversing, the truck and trailer under examination can be modeled as an unstable nonlinear system with state and input saturations. The simplified goal of stabilizing along a trajectory (instead of a point) allows us to consider a system with controllable linearization. Still, the combination of instability and saturations makes the task impossible with a single controller. In fact, the system cannot be driven backward from all initial states because of the jack-knife effects between the parts of the multibody vehicle; it is sometimes necessary to drive forward to enter into a specific region of attraction. This leads to the use of hybrid controllers. The scheme has been implemented and successfully used to reverse the radio-controlled vehicle.
Efficient Intracellular Delivery of Nucleic Acid Pharmaceuticals Using Cell-Penetrating Peptides (2011)

Over the last 20 years, researchers have designed or discovered peptides that can permeate membranes and deliver exogenous molecules inside a cell. These peptides, known as cell-penetrating peptides (CPPs), typically consist of 6–30 residues, including HIV TAT peptide, penetratin, oligoarginine, transportan, and TP10. Through chemical conjugation or noncovalent complex formation, these structures successfully deliver bioactive and membrane-impermeable molecules into cells. CPPs have also gained attention as an attractive vehicle for the delivery of nucleic acid pharmaceuticals (NAPs), including genes/plasmids, short oligonucleotides, and small interference RNAs and their analogues, due to their high internalization efficacy, low cytotoxicity, and flexible structural design.In this Account, we survey the potential of CPPs for the design and optimization of NAP delivery systems. First, we describe the impact of the N-terminal stearylation of CPPs. Endocytic pathways make a major contribution to the cellular uptake of NAPs. Stearylation at the N-terminus of CPPs with stearyl-octaarginine (R8), stearyl-(RxR)4, and stearyl-TP10 prompts the formation of a self-assembled core–shell nanoparticle with NAPs, a compact structure that promotes cellular uptake. Researchers have designed modifications such as the addition of trifluoromethylquinoline moieties to lysine residues to destabilize endosomes, as exemplified by PepFect 6, and these changes further improve biological responsiveness. Alternatively, stearylation also allows implantation of CPPs onto the surface of liposomes. This feature facilitates “programmed packaging” to establish multifunctional envelope-type nanodevices (MEND). The R8-MEND showed high transfection efficiency comparable to that of adenovirus in non-dividing cells.Understanding the cellular uptake mechanisms of CPPs will further improve CPP-mediated NAP delivery. The cellular uptake of CPPs and their NAP complex involves various types of endocytosis. Macropinocytosis, a mechanism which is also activated in response to stimuli such as growth factors or viruses, is a primary pathway for arginine-rich CPPs because high cationic charge density promotes this endocytic pathway. The use of larger endosomes (known as macropinosomes) rather than clathrin- or caveolae-mediated endocytosis has been reported in macropinocytosis which would also facilitate the endocytosis of NAP nanoparticles into cells.
Adeno-associated virus vectors transduce primary cells much less efficiently than immortalized cells (1995)

Immortalized cell lines have been used to study infection and replication of adeno-associated virus (AAV) in culture, but primary cells presumably provide a better model for AAV behavior in animals. Here, we have evaluated the ability of AAV vectors to transduce primary and immortalized strains of human epithelial cells and fibroblasts. Two AAV vectors were used, one that transduced an alkaline phosphatase gene (AAV-LAPSN), and one that transduced a beta-galactosidase/neomycin phosphotransferase fusion gene (AAV-L beta geo). The transduction efficiency of the AAV-LAPSN vector, quantitated by measurement of alkaline phosphatase-positive cell foci following infection, was 10 to 60 times greater in immortalized human cells than in primary cells, and total alkaline phosphatase activity in cell lysates was 40 to 50 times greater in immortalized cells. The AAV-L beta geo vector gave similar results. In contrast, the transduction efficiency of a retrovirus vector encoding alkaline phosphatase was equivalent in primary and immortalized cells. Analysis of the quantity and state of the AAV vector genomes in cells showed that primary and immortalized cells contained comparable numbers of vector copies per cell and that the vast majority of vector DNA was not integrated into the cell genome. Additionally, the level of AAV vector-derived message paralleled the transduction efficiency. These results indicate that the block to functional transduction in primary cells occurred after virus entry and limited the abundance of vector-derived message. Data from AAV transduction in cultures of human cells containing immortalizing genes suggest that cellular changes secondary to the introduction of immortalizing genes increased permissiveness for transduction by AAV vectors. In summary, our data demonstrate that AAV vectors transduce primary human cells much less efficiently than immortalized cells and indicate the importance of using primary cells to evaluate AAV vectors for gene therapy applications.