gebhart/patrepeval huggingface dataset:
Importance of Trehalose Biosynthesis for Sinorhizobium meliloti Osmotolerance and Nodulation of Alfalfa Roots (2009)

The disaccharide trehalose is a well-known osmoprotectant, and trehalose accumulation through de novo biosynthesis is a common response of bacteria to abiotic stress. In this study, we have investigated the role of endogenous trehalose synthesis in the osmotolerance of Sinorhizobium meliloti. Genes coding for three possible trehalose synthesis pathways are present in the genome of S. meliloti 1021: OtsA, TreYZ, and TreS. Among these, OtsA has a major role in trehalose accumulation under all of the conditions tested and is the main system involved in osmoadaptation. Nevertheless, the other two systems are also important for growth in hyperosmotic medium. Genes for the three pathways are transcriptionally responsive to osmotic stress. The presence of at least one functional trehalose biosynthesis pathway is required for optimal competitiveness of S. meliloti to nodulate alfalfa roots.
Preferential Transduction of Human Hepatocytes with Lentiviral Vectors Pseudotyped by Sendai Virus F Protein (2002)

One of the major challenges facing gene therapy is the development of vectors targeting specific cell types. Restricting gene delivery to the relevant cell type leads to reduced T-cell responses to transgene products and prolonged gene expression. In this study, we demonstrate that vectors derived from human immunodeficiency virus (HIV) can be pseudotyped with Sendai virus fusion protein F. Such vectors transduced human hepatoma cells and primary human hepatocytes efficiently, but not non-liver cells. Several different approaches were also taken to significantly increase the titer of the pseudotyped vector. These studies may facilitate HIV vector-mediated gene delivery into liver in vivo.
Intracellular delivery of RNA therapeutics with lipid nanoparticles (2017)

Therapeutic RNA molecules such as siRNAs and antisense oligonucleotides have great potential to be used as future medicines in human patients, because they allow the modulation of virtually any protein in the body. Unfortunately, their application is hampered by their physicochemical properties that do not make them very ‘drug-like’. For example, these molecules are 10-25 times higher in molecular weight than conventional small molecule drugs and are highly negatively charged, which prevents their access to the intracellular site of action. Furthermore, they cannot be administered via the oral route because they would be degraded in the gastro-intestinal tract, but also after intravenous administration they are vulnerable to degradation in the bloodstream or rapidly excreted via the kidneys. All these factors together have made the application in human patients a significant challenge whereas in pre-clinical research and biomedical science in general, siRNAs and related molecules have made a huge impact. To also enable this technology for therapeutic applications, intracellular delivery systems have to be developed. In this PhD thesis, lipid nanoparticles (LNPs) have been investigated for this purpose. These LNPs consist of lipid-like molecules that form small vesicles of approximately 100 nanometer in diameter, that encapsulate the RNA therapeutics in their core. This protects the RNA cargo against degradation by nucleases in the bloodstream and prevents rapid excretion. The goal of this research project was to improve lipid nanoparticles for intracellular delivery of RNA therapeutics after intravenous administration. Part of this work involved the modification of the surface of the LNPs with peptides that improve the therapeutic index of the LNPs, for example to improve their interaction with, and uptake by their target cells. Another example is the application of peptides that increase the fraction of the dose that eventually reaches the part within the cell where the drugs needs to exert its function. To this end, different types of coupling chemistries were explored, including the first ever report of copper-free click chemistry on the surface of a liposome and a novel type or pH-responsive conjugation that reacts to a spatiotemporal trigger inside the cell. Furthermore, variations in the composition of the lipid nanoparticles were investigated and how this could influence their ability to deliver therapeutic RNA molecules to different target tissues and after different routes of administration. Finally, the CRISPR-Cas9 gene editing system was described, which could have even greater therapeutic impact than RNA editing/silencing systems, but seems to suffer from the same limitations as its counterparts. The lessons learned from the delivery of RNA therapeutics could also be applied to the delivery of CRISPR-Cas9, as it has already become clear that it cannot be translated to the clinic without a sophisticated delivery system and lipid nanoparticles could also play an important role here.
Pericardial Processing: Challenges, Outcomes and Future Prospects (2011)

The pericardium is a biological tissue widely used as a biomaterial for tissue engineering applications, including the construction of a variety of bioprostheses such as vascular grafts, patches for abdominal or vaginal wall reparation and, more frequently, heart valves. However, despite significant advances, some drawbacks have been found in these bioprostheses such as biological matrix deterioration and tissue degeneration associated with calcifications, even though xenopericardium or glutaraldehyde-treated autologous pericardium were used. In non-autologous pericardial processing, the pericardium must be decellularized in order to remove cellular antigens and procalcific remnants while preserving extracellular matrix integrity. A large variety of decellularization protocols exist, such as chemical, physical or enzymatic methods. Additional cross-linking processing must be carried out to render the tissue non-antigenic and mechanically strong. So far, almost all bioprosthetic materials made of pericardium, and used in clinical practice, are glutaraldehyde-treated bovine or porcine xenopericardium. However, long-term reports are raising issues concerning their durability, especially highlighting the high risk of calcification. Regarding heart valves, calcification currently represents the major drawback leading to potential failure of the bioprosthesis. The aim of this review is to present current issues, challenges, outcomes and future prospects of pericardial processing, including decellularization and cross-linking steps. Understanding current issues and improving pericardial processing will allow refining bioprosthesis conception and patients’ safety.
Effect of Overcoating with Dielectric Films on the Superconductive Properties of the High-Tc Y-Ba-Cu-O Films (1988)

The high- T c Y-Ba-Cu-O superconductive thin films were coated with dielectric films of Nb 2 O 5 and Al 2 O 3 using an rf-magnetron sputtering technique. The coating with dielectric films lowered the zero-resistance temperature of the Y-Ba-Cu-O films. The Auger analyses for these overcoated Y-Ba-Cu-O films suggested that internal diffusion appeared between the Y-Ba-Cu-O films and the dielectric films. It was also found that the crystallinity of the Y-Ba-Cu-O films was degraded due to the overcoating of the dielectric films.
Preparation of Aryl- and Heteroaryltrimethylsilanes (1979)

This review presents a comprehensive survey of the synthetic methods for aryl- and heteroaryltrimethylsilanes. Their preparation can result from direct silicon-carbon coupling reactions, from cycloaddition reactions, or through modification of silylaromatic or -heteroaromatic compounds by incorporation of further functional groups or by conversion of substituents already present. 1. Introduction 2. Direct Introduction of Trimethylsilyl Groups into Aromatic and Heteroaromatic Compounds 2.1. Radical Silylation of Aromatic and Heteroaromatic Compounds 2.2. Nucleophilic Silylation of Aromatic and Heteroaromatic Compounds 2.3. Electrophilic Silylation of Aromatic and Heteroaromatic Compounds 3. Synthesis of Aryl- and Heteroaryltrimethylsilanes via Cycloaddition Reactions 3.1. Aryltrimethylsilanes via [2+2+2]Cycloaddition Reactions 3.2. Aryl- and Heteroaryltrimethylsilanes via [4+2]Cycloaddition Reactions 3.3. Heteroaryltrimethylsilanes via [2+3]Cycloaddition Reactions 4. Introduction of Substituents into the Nucleus of Aryl- and Heteroaryltrimethylsilanes 4.1. Halogenation 4.2. Introduction of Sulfur Functions 4.3. Introduction of Nitrogen Functions 4.4. Introduction of Phosphorus Functions 4.5. Alkylation and Hydroxyalkylation 4.6. Acylation 4.7. Carboxylation 4.8. Silylation 4.9. Protonation 5. Transformation of Substituents in Aryl- and Heteroaryltrimethylsilanes 5.1. Nucleophilic Exchange of Halides 5.2. Functionalization of Carboxylic Acid Derivatives 5.3. Functionalization of Hydroxy and Amino Groups 5.4. Condensation Reactions 5.5. Oxidation Reactions 5.6. Reduction Reactions 5.7. Metal Complexes of Aryl- and Heteroaryltrimethylsilanes 5.8. Miscellaneous 6. Conclusions
Clinical Consequences of Acquired Transfusional Iron Overload in Adults (1981)

We assessed the clinical sequelae of transfusional iron overload in 15 nonthalassemic adults (40 to 71 years of age) with anemias requiring transfusions. Iron loading had been present for less than four years in 14 patients. The number of units of blood transfused ranged from 60 to 210 (mean, 120). Liver-biopsy specimens in 10 patients contained seven to 26 times the normal amount of iron and typically showed focal portal fibrosis. Left ventricular cardiac function was impaired in only the most heavily transfused patients or in those with coexisting coronary-artery disease, All patients had glucose intolerance associated with significantly reduced insulin output, compared with controls (P < 0.01). Pituitary reserve of ACTH was limited in 10 of 12 patients, and that of gonadotropin in five of 13. We conclude that widespread subclinical organ dysfunction can result from transfusional iron overload developing in adulthood. The pattern of organ involvement resembles that encountered in idiopathic hemochromatosis.
Cortical Brain Biopsy in Long-Term Prognostication of 468 Patients with Possible Normal Pressure Hydrocephalus (2012)

Normal pressure hydrocephalus (NPH) can be alleviated by cerebrospinal fluid shunting but the differential diagnosis and patient selection are challenging. Intraventricular intracranial pressure monitoring as part of the diagnostic workup as well as shunting enable to obtain cortical brain biopsies to detect amyloid-β (Aβ) and hyperphosphorylated tau (HPτ), the hallmark lesions of Alzheimer's disease (AD). In possible NPH, Aβ alone indicates an increased risk of AD and when present with HPτ probable AD, but the effect of those brain lesions on survival is not known. The aim of this study was to evaluate the predictive value of brain biopsy for the long-term outcome of possible NPH. Between 1991 and 2006, the Neurosurgery Department of the Kuopio University Hospital evaluated 468 patients for possible NPH by intraventricular intracranial pressure monitoring and frontal cortical brain biopsy immunostained against Aβ and HPτ. All patients were followed up until the end of 2008 (n = 201) or death (n = 267) with a median follow-up of 4.6 years (range 0-17). Logistic regression analysis with Cox models was applied. Out of the 468 cases, Aβ was detected in 197 (42%) cortical biopsies, and together with HPτ in 44 (9%). Aβ alone indicated increased risk of AD and with HPτ probable AD, but it did not affect survival. Vascular aetiology was the most frequent cause of death. Cortical biopsy findings indicate that NPH is at present a heterogeneous syndrome and has notable overlapping with AD. Brain biopsy did not predict survival but may open a novel research window to study the pathobiology of neurodegeneration.
Replication of bovine papillomavirus type 1 origin-containing DNA in crude extracts and with purified proteins. (1994)

The in vitro replication of DNA containing the bovine papillomavirus (BPV-1) origin has been carried out with cell-free extracts from mouse FM3A and human HeLa cells. DNA synthesis required the E1 protein, the minimal origin of replication (nucleotides 7911-22 of the BPV-1 genome), and, at low levels of FM3A extract, the addition of the human single-stranded DNA-binding protein (also called RP-A or RF-A). The E2 protein was not absolutely required, but could stimulate DNA synthesis at low levels of E1. DNA synthesis was also reconstituted using purified proteins from HeLa cells. These protein factors included human single-stranded DNA-binding protein, topoisomerase I, and DNA polymerase (pol) alpha-primase complex. At low concentrations of pol alpha-primase complex, the formation of high molecular weight products was dependent on the addition of DNA polymerase delta holoenzyme containing proliferating cell nuclear antigen and activator 1, also called RF-C. We have overexpressed and isolated the E1 protein from bacteria. This protein also supported BPV DNA synthesis, both in crude extracts and with purified proteins suggesting that E1 phosphorylation is not required for BPV DNA replication in vitro.
An Induced Proximity Model for Caspase-8 Activation (1998)

The assembly of the CD-95 (Fas/Apo-1) receptor death-inducing signaling complex occurs in a hierarchical manner; the death domain of CD-95 binds to the corresponding domain in the adapter molecule Fas-associated death domain (FADD) Mort-1, which in turn recruits the zymogen form of the death protease caspase-8 (FLICE/Mach-1) by a homophilic interaction involving the death effector domains. Immediately after recruitment, the single polypeptide FLICE zymogen is proteolytically processed to the active dimeric species composed of large and small catalytic subunits. Since all caspases cleave their substrates after Asp residues and are themselves processed from the single-chain zymogen to the two-chain active enzyme by cleavage at internal Asp residues, it follows that an upstream caspase can process a downstream zymogen. However, since FLICE represents the most apical caspase in the Fas pathway, its mode of activation has been enigmatic. We hypothesized that the FLICE zymogen possesses intrinsic enzymatic activity such that when approximated, it autoprocesses to the active protease. Support for this was provided by (i) the synthesis of chimeric Fpk3FLICE molecules that can be oligomerized in vivo by the synthetic cell-permeable dimerizer FK1012H2. Cells transfected with Fpk3FLICE underwent apoptosis after exposure to FK1012H2; (ii) the creation of a nonprocessable zymogen form of FLICE that retained low but detectable protease activity.
Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. The Women???s Health Initiative Memory Study: A Randomized, Controlled Trial (2003)

Shumaker, Sally A.; Legault, Claudine; Rapp, Stephen R.; Thal, Leon; Wallace, Robert B.; Ockene, Judith K.; Hendrix, Susan L.; Jones, Beverly N. III; Assaf, Annnlouise R.; Jackson, Rebecca D.; Kotchen, Jane Morley; Wassertheil-Smoller, Sylvia Jean Wactawski-Wende for the WHIMS Investigators
Somatic LKB1 Mutations Promote Cervical Cancer Progression (2009)

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence.
Glucose-sensing and -signalling mechanisms in yeast (2002)

Glucose has dramatic effects on the regulation of carbon metabolism and on many other properties of yeast cells. Several sensing and signalling pathways are involved. For many years attention has focussed on the main glucose-repression pathway which is responsible for the downregulation of respiration, gluconeogenesis and the transport and catabolic capacity of alternative sugars during growth on glucose. The hexokinase 2- dependent glucose-sensing mechanism of this pathway is not well understood but the downstream part of the pathway has been elucidated in great detail. Two putative glucose sensors, the Snf3 and Rgt2 non-transporting glucose carrier homologs, control the expression of many functional glucose carriers. Recently, several new components of this glucose-induction pathway have been identified. The Ras-cAMP pathway controls a wide variety of cellular properties in correlation with cellular proliferation. Glucose is a potent activator of cAMP synthesis. In this case glucose sensing is carried out by two systems, a G-protein-coupled receptor system and a still elusive glucose-phosphorylation-dependent system. The understanding of glucose sensing and signalling in yeast has made dramatic advances in recent years and has become a strong paradigm for the elucidation of nutrient-sensing mechanisms in other eukaryotic organisms.
Impact of bile acids on the growth of human cholangiocarcinoma via FXR (2011)

The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the effects induced by the bile acids.
The role of donor T cells for target organ injuries in acute and chronic graft‐versus‐host disease (2001)

Donor T cells are crucial for target organ injury in graft-versus-host disease (GVHD). We examined the effects of donor T cells on the target organs using a parent-into-F1 model of acute and chronic GVHD. Donor T cells showed engraftment in the spleen, small intestine and liver of mice with acute GVHD, causing typical GVHD pathology in these organs. Interferon-gamma and Fas ligand expression were up-regulated, and host lymphocytes were depleted in the target organs of these mice. In contrast, donor T cells did not show engraftment in the small intestine of mice with chronic GVHD, and no GVHD pathology was observed in this organ. However, both donor T-cell engraftment and GVHD pathology were observed in the spleen and liver of chronic GVHD mice, along with the up-regulation of interleukin-4 (IL-4) and IL-10 expression plus the expansion of host lymphocytes such as splenic B cells and hepatic natural killer (NK) 1.1+ T cells. Donor anti-host cytotoxic T-lymphocyte activity was observed in spleen cells from mice with acute GVHD, but not in spleen cells from mice with chronic GVHD. Transplantation of Fas ligand-deficient (gld) spleen cells did not induce host lymphocyte depletion in target organs. These results indicate that donor T cells augment type 1 T helper immune responses and deplete the host lymphocytes from target organs mainly by Fas-mediated pathways in acute GVHD, while donor T cells augment type 2 T helper immune responses and expand host splenic B cells and hepatic NK1.1+ T cells in chronic GVHD.
Selective, Tight-Binding Inhibitors of Integrin α4β1 That Inhibit Allergic Airway Responses (1999)

Integrin alpha4beta1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of alpha4beta1, based on the Leu-Asp-Val (LDV) sequence from the alternatively spliced connecting segment-1 (CS-1) peptide of cellular fibronectin, are described that employ a novel N-terminal peptide "cap" strategy. One inhibitor, BIO-1211, was approximately 10(6)-fold more potent than the starting peptide and exhibited tight-binding properties (koff = 1.4 x 10(-4) s-1, KD = 70 pM), a remarkable finding for a noncovalent, small-molecule inhibitor of a protein receptor. BIO-1211 was also 200-fold selective for the activated form of alpha4beta1, and it stimulated expression of ligand-induced epitopes on the integrin beta1 subunit, a property consistent with occupancy of the receptor's ligand-binding site. Pretreatment of allergic sheep with a 3-mg nebulized dose of BIO-1211 inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results show that highly selective and potent small-molecule antagonists can be identified to integrins with primary specificity for peptide domains other than Arg-Gly-Asp (RGD); they confirm the generality of integrins as small molecule targets; and they validate alpha4beta1 as a therapeutic target for asthma.
Large-scale incremental processing using distributed transactions and notifications (2010)

Updating an index of the web as documents are crawled requires continuously transforming a large repository of existing documents as new documents arrive. This task is one example of a class of data processing tasks that transform a large repository of data via small, independent mutations. These tasks lie in a gap between the capabilities of existing infrastructure. Databases do not meet the storage or throughput requirements of these tasks: Google's indexing system stores tens of petabytes of data and processes billions of updates per day on thousands of machines. MapReduce and other batch-processing systems cannot process small updates individually as they rely on creating large batches for efficiency.We have built Percolator, a system for incrementally processing updates to a large data set, and deployed it to create the Google web search index. By replacing a batch-based indexing system with an indexing system based on incremental processing using Percolator, we process the same number of documents per day, while reducing the average age of documents in Google search results by 50%.