gebhart/patrepeval huggingface dataset:
The BEACH Is Hot: A LYST of Emerging Roles for BEACH‐Domain Containing Proteins in Human Disease (2013)

BEACH (named after 'Beige and Chediak-Higashi') is a conserved ∼280 residue domain, present in nine human BEACH domain containing proteins (BDCPs). Most BDCPs are large, containing a PH-like domain for membrane association preceding their BEACH domain, and containing WD40 and other domains for ligand binding. Recent studies found that mutations in individual BDCPs cause several human diseases. BDCP alterations affect lysosome size (LYST and NSMAF), apoptosis (NSMAF), autophagy (LYST, WDFY3, LRBA), granule size (LYST, NBEAL2, NBEA) or synapse formation (NBEA). However, the roles of each BDCP in these membrane events remain controversial. After reviewing studies on individual BDCPs, we propose a unifying hypothesis that BDCPs act as scaffolding proteins that facilitate membrane events, including both fission and fusion, determined by their binding partners. BDCPs may also bind each other, enabling fusion or fission of vesicles that are not necessarily of the same type. Such mechanisms explain why different BDCPs may have roles in autophagy; each BDCP is specific for the cell type or the cargo, but not necessarily specific for attaching to the autophagosome. Further elucidation of these mechanisms, preferably carrying out the same experiment on multiple BDCPs, and possibly using patients' cells, may identify potential targets for therapy.
A metastable liquid precursor phase of calcium carbonate and its interactions with polyaspartate (2012)

Invertebrate organisms that use calcium carbonate extensively in the formation of their hard tissues have the ability to deposit biominerals with control over crystal size, shape, orientation, phase, texture, and location. It has been proposed by our group that charged polyelectrolytes, like acidic proteins, may be employed by organisms to direct crystal growth through an intermediate liquid phase in a process called the polymer-induced liquid-precursor (PILP) process. Recently, it has been proposed that calcium carbonate crystallization, even in the absence of any additives, follows a non-classical, multi-step crystallization process by first associating into a liquid precursor phase before transition into solid amorphous calcium carbonate (ACC) and eventually crystalline calcium carbonates. In order to determine if the PILP process involves the promotion, or stabilization, of a naturally occurring liquid precursor to ACC, we have analyzed the formation of saturated and supersaturated calcium carbonate–bicarbonate solutions using Ca2+ ion selective electrodes, pH electrodes, isothermal titration calorimetry, nanoparticle tracking analysis, 13C T2 relaxation measurements, and 13C PFG-STE diffusion NMR measurements. These studies provide evidence that, in the absences of additives, and at near neutral pH (emulating the conditions of biomineralization and biomimetic model systems), a condensed phase of liquid-like droplets of calcium carbonate forms at a critical concentration, where it is stabilized intrinsically by bicarbonate ions. In experiments with polymer additive, the data suggests that the polymer is kinetically stabilizing this liquid condensed phase in a distinct and pronounced fashion during the so called PILP process. Verification of this precursor phase and the stabilization that polymer additives provide during the PILP process sheds new light on the mechanism through which biological organisms can exercise such control over deposited CaCO3 biominerals, and on the potential means to generate in vitro mineral products with features that resemble biominerals seen in nature.
Preparation of 5‐amino‐4‐imidazole‐N‐succinocarboxamide ribotide, 5‐amino‐4‐imidazole‐N‐succinocarboxamide riboside and succinyladenosine, compounds usable in diagnosis and research of adenylosuccinate lyase deficiency (2004)

The enzyme adenylosuccinate lyase (ADSL) intervenes twice in the biosynthesis of adenine nucleotides. ADSL deficiency is an inherited metabolic disease characterized by various degrees of psychomotor retardation and accumulation of dephosphorylated enzyme substrates 5-amino-4-imidazole-N-succinocarboxamide riboside (SAICAr) and succinyladenosine (SAdo) in body fluids. Severity of symptoms seems to correlate with residual activity of mutant enzyme and with SAdo/SAICAr concentration ratio in cerebrospinal fluid. To better understand the pathogenetic mechanisms of the disease symptoms, studies of catalytic properties of mutant enzymes together with in vitro and in vivo experiments utilizing SAICAr and SAdo must be performed. Such studies require availability of both ADSL substrates, 5-amino-4-imidazole-N-succinocarboxamide ribotide (SAICAR) and succinyladenosine 5'-monophosphate (SAMP) and their dephosphorylated products in sufficient amounts and purity. Except for SAMP, none of these compounds is commercially available and they must therefore be synthesized. SAICAR was prepared by recombinant human ADSL-catalysed reaction of AICAR (5-aminoimidazole-4-carboxamide) with fumarate and isolated by thin-layer chromatography. SAICAr and SAdo were prepared by calf intestine alkaline phosphatase-catalysed dephosphorylation of SAICAR and SAMP and isolated on cation- and anion-exchange resin columns. The procedures described are easily scalable and provide high yields of sufficiently pure products for use in experiments related to studies of pathogenetic mechanisms in ADSL deficiency.
Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications (2001)

The formation of coronary collateral vessels is a compensatory mechanism secondary to repetitive or chronic myocardial ischemia. During the past three decades the functional and prognostic benefit of such collateral vessels has been established. There are large interindividual differences in the number and extent of collateral vessels that may be explained by differences in the anatomic situation or by differences in the individual capacity to develop functional collateral vessels. Diabetes mellitus has recently been identified as one of the first negative predictors of collateral vessel formation. Novel molecular approaches have helped to improve our understanding of the process of collateral vessel formation in recent years. Besides the process of true angiogenesis, i.e. the formation of new capillaries out of preexisting ones, the formation of a collateral circulation is largely based on the growth of preexisting arterioles (collateral vessels or anastomoses) named arteriogenesis. One important feature of arteriogenesis is the infiltration of monocytes into the growing collateral vessel. Our group shows that the ability of monocytes to migrate towards a gradient of VEGF-A is severely impaired in diabetic individuals, and this impaired response seems to be secondary to a signal transduction defect within the monocyte. In this review the pathophysiology of diabetes-related monocyte dysfunction and the potential role of VEGF-A in collateral vessel formation are discussed.
Reversible versus Irreversible Binding of Transferrin to Polystyrene Nanoparticles: Soft and Hard Corona (2012)

Protein adsorption to nanoparticles (NPs) is a key prerequisite to understand NP-cell interactions. While the layer thickness of the protein corona has been well characterized in many cases, the absolute number of bound proteins and their exchange dynamics in body fluids is difficult to assess. Here we measure the number of molecules adsorbed to sulfonate (PSOSO(3)H) and carboxyl-(PSCOOH) polystyrene NPs using fluorescence correlation spectroscopy. We find that the fraction of molecules bound to NPs falls onto a single, universal adsorption curve, if plotted as a function of molar protein-to-NP ratio. The adsorption curve shows the build-up of a strongly bound monolayer up to the point of monolayer saturation (at a geometrically defined protein-to-NP ratio), beyond which a secondary, weakly bound layer is formed. While the first layer is irreversibly bound (hard corona), the secondary layer (soft corona) exhibits dynamic exchange, if competing unlabeled is added. In the presence of plasma proteins, the hard corona is stable, while the soft corona is almost completely removed. The existence of two distinct time scales in the protein off-kinetics, for both NP types studied here, indicates the possibility of an exposure memory effect in the NP corona.
Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion (2015)

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.
Analysis of the Asymmetric 002 X-Ray Line Profiles of γ-Irradiated Polyethylene (1980)

Asymmetric line profiles of 002 X-ray reflection diffracted from polyethylene have been analyzed. It is found that the asymmetry of the line profile is evidence for a specific correlation between the size and the lattice spacing in the crystallites. This means that the asymmetrical profile consists of two symmetrical profiles whose centroid positions and widths differ from each other. Application to γ-irradiated polyethylene reveals that degradation of crystallites occurs from the surface and that smaller crystallites with larger lattice spacing disappear more quickly when degraded by γ-irradiation.
Antisense oligonucleotides as therapeutics for malignant diseases. (1997)

The continued progress in our understanding of the biology of neoplasia and in the identification, cloning, and sequencing of genes critical to tumor cell function permits the exploitation of this information to develop specific agents that may directly modulate the function of these genes or their protein products. Antisense oligonucleotides are being investigated as a potential therapeutic modality that takes direct advantage of molecular sequencing. The antisense approach uses short oligonucleotides designed to hybridize to a target mRNA transcript through Watson-Crick base pairing. The formation of this oligonucleotide: RNA heteroduplex results in mRNA inactivation and consequent inhibition of synthesis of the protein product. A fundamental attraction of the antisense approach is that this method potentially may be applied to any gene product, in theory, for the treatment of malignant and non-malignant diseases. However, this simple and attractive model has proven to be much more complex in practice. A number of important challenges in the preclinical development of antisense oligonucleotides have been identified, including stability, sequence length, cellular uptake, target sequence selection, appropriate negative controls, oligonucleotide: protein interactions, and cost of manufacture. Although the biological activity of an oligonucleotide against its molecular target is theoretically sequence-dependent, the animal pharmacokinetics and toxicology of phosphorothioate analogues directed against vastly disparate gene products appear relatively non-sequence-specific. In oncology, a number of clinical trials have been initiated with antisense oligonucleotides directed against molecular targets including: p53; bcl-2; raf kinase; protein kinase C-alpha; c-myb. The experience gained from these early clinical trials will be applicable to the next generation of antisense agents in development. These may include molecules with novel backbones or other structural modifications, chimeric oligonucleotides, or peptide nucleic acids. Continued progress in this arena will require that many of the preclinical challenges confronting antisense development are satisfactory resolved.
Crypto Users' Handbook: A Guide for Implementors of Cryptographic Protection in Computer Systems (1988)

1. Introduction (P. Mattila). 2. Applications. Confidentiality. Data Authentication. Authentication of Identity. Software Protection (S. Herda). 3. Algorithms. Introduction. Theoretical Security. Stream Ciphers and Block Ciphers. Examples of Attacks. Modes and Comparisons. Crypto Variables. Public Key Systems. Evaluation of Cryptographic Algorithms (K.-O. Widman) 4. Protecting the Protection. Key Management (W. Price). Crypto Environment (S.-A. Ekhall). 5. Encryption and Communication. Communication Principles. Encryption and the Communication Architecture. Practical Examples (P. Christoffersson). 6. Standards for Data Security (W. Price). 7. Encryption Implementations. Hardware. Software. Choosing an Implementation (V. Fak). 8. Glossary and Abbreviations. 9. References. Index.
Ion Exchange and Sorption Processes as Methods of Synthesis of Double Phosphates and Intercalated Compounds (1990)

Abstract Traditional methods of obtaining salts by precipitation from solutions, crystallization from melts and solid-state reactions are often ineffective for the synthesis of double phosphates of mono- and polyvalent metals. The reactions of ion exchange or exchanged interaction are not widely used for this purpose. Only soluble acid salts capable of substituting their protons for cations and having sufficient hydrolytical stability are suitable. Their number is quite limited. Among these are: M(HPO4)·H2O, M = Ti, Zr, Hf, Ge, Sn, Pb; UO2HPO4·4H2O, H2MP3 O10 M = Al, Ga, V, Cr, Mn, Fe (TPM-I). A distinctive feature of these compounds is that all of them have two-dimensional lamellar lattice which is capable of reversible changing of crystallographic parameters during the ion exchange process. This proceeds quite easily, since the interaction of protons with the lattice is weak. No cases of effective ion exchange are reported in the solutions of anhydrous phosphates with three-dimensional structure. The analysis of the available literature data on the structure and other physicochemical properties, as well as our own investigations, have permitted to come to the conclusion that the absence of the above-mentioned properties is primarily caused by the firmness of the bond between protons and the phosphate skeleton and by low proton mobilities.
Oxidation and Acetylation as Determinants of 2-Bromocystein-S-ylhydroquinone-Mediated Nephrotoxicity (1994)

2-Bromodiglutathion-S-ylhydroquinone is a more potent nephrotoxicant than 2-bromomonoglutathion-S-ylhydroquinones. In the present study we examined the activity of enzymes involved in mercapturic acid biosynthesis toward both the glutathione conjugates and their cysteine and N-acetylcysteine metabolites and compared the results to the relative nephrotoxicity of these conjugates. Although differences were observed in the kinetics of the gamma-glutamyl transpeptidase (gamma-GT)-mediated hydrolysis and transpeptidation of the glutathione conjugates, the concentration of this enzyme within the kidney probably precludes it from contributing to their differential toxicity. In contrast, the rate at which the cysteine and corresponding mercapturate conjugates underwent N-deacetylation/N-acetylation cycling correlated with previously reported differences in toxicity. The relative rates of these two reactions are important because electrochemical data suggest that 2-bromodicystein-S-ylhydroquinone is more readily oxidized to the reactive quinone than its corresponding mercapturic acid. In addition, 2-bromodi(N-acetylcystein-S-yl)hydroquinone, which is the most potent of the mercapturic acid conjugates, exhibited the highest N-deacetylation/N-acetylation ratio. In contrast, 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone, which is essentially not toxic in vivo, was not a substrate for the renal cysteine conjugate N-deacetylase. The data suggest that the rate-determining step for the in vivo toxicity of these conjugates is probably the N-acetylation reaction and the availability of the corresponding acetyl-CoA cofactor.
Architecting advanced technologies for 14nm and beyond with 3D FinFET transistors for the future SoC applications (2011)

Industry's extensive knowledge of fabricating bulk CMOS planar transistors has made them the device of choice for the cost sensitive foundry semiconductor sector. On advanced nodes the scaling benefits for SoCs will be based on a set of Key Performance Indicators (KPIs) (Fig.1) quantified by measurable Figures of Merit (FOMs). These KPIs cover a range of requirements from system level performance, power, and die area scaling to manufacturing cost, production risk, reliability limitations, designabilty and technology extension for a broad domain of SoCs. Critical performance FOMs include Fmax, compute density performance at constant power density (MHz/mW/mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> ) and performance vs. power for a given cost (PPC) (MHz/mW/$). The idea is to integrate the transistor and physical scaling benefits to offer a cost sensitive technology platform that provides value for the SoC applications and effectively for the end users. Fig. 1 illustrates the complexity of achieving this task to minimize the risk and TTV/TTM while addressing the difficult technical barriers. Device and circuit co-optimization enhances the SoC values measured by PPC, PPA, and Fmax.
Bacterial Ammeline Metabolism via Guanine Deaminase (2009)

Melamine toxicity in mammals has been attributed to the blockage of kidney tubules by insoluble complexes of melamine with cyanuric acid or uric acid. Bacteria metabolize melamine via three consecutive deamination reactions to generate cyanuric acid. The second deamination reaction, in which ammeline is the substrate, is common to many bacteria, but the genes and enzymes responsible have not been previously identified. Here, we combined bioinformatics and experimental data to identify guanine deaminase as the enzyme responsible for this biotransformation. The ammeline degradation phenotype was demonstrated in wild-type Escherichia coli and Pseudomonas strains, including E. coli K12 and Pseudomonas putida KT2440. Bioinformatics analysis of these and other genomes led to the hypothesis that the ammeline deaminating enzyme was guanine deaminase. An E. coli guanine deaminase deletion mutant was deficient in ammeline deaminase activity, supporting the role of guanine deaminase in this reaction. Two guanine deaminases from disparate sources (Bradyrhizobium japonicum USDA 110 and Homo sapiens) that had available X-ray structures were purified to homogeneity and shown to catalyze ammeline deamination at rates sufficient to support bacterial growth on ammeline as a sole nitrogen source. In silico models of guanine deaminase active sites showed that ammeline could bind to guanine deaminase in a similar orientation to guanine, with a favorable docking score. Other members of the amidohydrolase superfamily that are not guanine deaminases were assayed in vitro, and none had substantial ammeline deaminase activity. The present study indicated that widespread guanine deaminases have a promiscuous activity allowing them to catalyze a key reaction in the bacterial transformation of melamine to cyanuric acid and potentially contribute to the toxicity of melamine.
Mutation-Specific Functional Impairments in Distinct Tau Isoforms of Hereditary FTDP-17 (1998)

Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.
Pharmacokinetics and safety of dihydroartemisinin injectable powder after a single dose administration in healthy subjects (2009)

Objective To study the pharmacokinetics and safety of dihydroartemisinin(DHA) injectable powder after a single dose administration in Chinese healthy subjects.Methods Thirty subjects were randomized into 3 groups and administered by single intravenous infusion of DHA injectable powder 40,80 and 160 mg,respectively.LC/MS/MS method was used for determination of DHA in human plasma.The main pharmacokinetic parameters were calculated with WinNonlin software by noncompartmental methods.Adverse events were nearly monitored during the whole test period.Results After single intravenous infusion of DHA injectable powder 40,80 and 160 mg,the main pharmacokinetic parameters of DHA were as follows:Cmax were(561.5±127.4),(1080±210),(2533±503) ng·mL-1;t1/2 were(1.69±0.52),(1.88±0.66),(1.92±0.53) h;AUC0~t were(575.6±98.7),(1370±289),(2893±649) ng·mL-1·h.The Cmax and AUC0~t increased in proportion to the administered doses.No serious adverse events occurred.Conclusion The pharmacokinetics of DHA fit the linear dynamic feature over the dose range studied,and DHA injectable powder was safe and well tolerated in the dosage range of 40 to 160 mg in healthy Chinese subjects.
Sendai Virus-Mediated Gene Delivery into Hepatocytes via Isolated Hepatic Perfusion (2006)

The recombinant Sendai virus vector is a promising tool for human gene therapy, capable of inducing high-level expression of therapeutic genes in tissue cells in situ. The target tissues include airway epithelium, blood vessels, skeletal muscle, retina and the central nervous system, but application to hepatic tissues has not yet been achieved, because direct intraportal injection of the vector is not feasible. We report an efficient and harmless procedure of gene delivery by recombinant Sendai virus into rat parenchymal hepatocytes, based on isolated hepatic perfusion with controlled inflow. Critical parameters for successful hepatic gene delivery are a brief preperfusion period (25 degrees C, 5 min); appropriate vector concentration in the perfusate (10(7) pfu/ml); moderate portal vein pressure (12 mmHg) and a brief hyperthermic postperfusion period (42 degrees C, 5 min). Under these optimized conditions, marker genes were expressed in most parenchymal hepatocytes without significant damage to hepatic tissues. Furthermore, expression of the marker genes was undetectable in nonhepatic tissues, including the gonads, indicating that this approach strictly targets hepatic tissues and thus offers good clinical potential for human gene therapy.