gebhart/patrepeval huggingface dataset:
Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review (2012)

Genetic epidemiological studies on the prevalence and numbers of individuals with α1-antitrypsin deficiency in each of 97 countries worldwide were used to estimate the numbers in each of the five following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. These 97 countries were then grouped into 10 major geographic regions to make it possible to compare the numbers in each of these five phenotypic classes in immediately adjacent countries. Such groupings also make it possible to review the spread of the PI*S and PI*Z alleles from one major geographic grouping to another in the world as well as the spread of these two deficiency alleles within a major geographic region. The data in the 10 tables on the numbers in each of the five phenotypic classes in the countries in the same geographic region as well as the prevalence of the PI*S and PI*Z alleles in countries in the same geographic region provide a novel database for the identification of large numbers of individuals in a given phenotypic class. The database also provides useful information for the identification of countries with high numbers of PI*ZZ individuals for augmentation therapy within a given geographic region.
Effect of dietary monosodium glutamate on trans fat-induced nonalcoholic fatty liver disease (2008)

The effects of dietary monosodium glutamate (MSG) on trans-fatty acid (TFA)-induced nonalcoholic fatty liver disease (NAFLD) are addressed in an animal model. We used Affymetrix microarray analysis to investigate hepatic gene expression and the contribution of visceral white adipose tissue (WAT) to diet-induced NAFLD. Trans-fat feeding increased serum leptin, FFA, HDL-cholesterol (HDL-C), and total cholesterol (T-CHOL) levels, while robustly elevating the expression of genes involved in hepatic lipogenesis, including the transcription factor sterol-regulatory element binding protein 1c. Histological examination revealed hepatic macrosteatosis in TFA-fed animals. Conversely, dietary MSG at doses similar to human average daily intake caused hepatic microsteatosis and the expression of beta-oxidative genes. Serum triglyceride, FFA, and insulin levels were elevated in MSG-treated animals. The abdominal cavities of TFA- or MSG-treated animals had increased WAT deposition compared with controls. Microarray analysis of WAT gene expression revealed increased lipid biosynthetic gene expression, together with a 50% decrease in the key transcription factor Ppargc1a. A combination of TFA+MSG resulted in the highest levels of serum HDL-C, T-CHOL, and leptin. Microarray analysis of TFA+MSG-treated livers showed elevated expression of markers of hepatic inflammation, lipid storage, cell damage, and cell cycle impairment. TFA+MSG mice also had a high degree of WAT deposition and lipogenic gene expression. Levels of Ppargc1a were further reduced to 25% by TFA+MSG treatment. MSG exacerbates TFA-induced NAFLD.
Critical Role of Virion-Associated Cholesterol and Sphingolipid in Hepatitis C Virus Infection (2008)

In this study, we establish that cholesterol and sphingolipid associated with hepatitis C virus (HCV) particles are important for virion maturation and infectivity. In a recently developed culture system enabling study of the complete life cycle of HCV, mature virions were enriched with cholesterol as assessed by the molar ratio of cholesterol to phospholipid in virion and cell membranes. Depletion of cholesterol from the virus or hydrolysis of virion-associated sphingomyelin almost completely abolished HCV infectivity. Supplementation of cholesterol-depleted virus with exogenous cholesterol enhanced infectivity to a level equivalent to that of the untreated control. Cholesterol-depleted or sphingomyelin-hydrolyzed virus had markedly defective internalization, but no influence on cell attachment was observed. Significant portions of HCV structural proteins partitioned into cellular detergent-resistant, lipid-raft-like membranes. Combined with the observation that inhibitors of the sphingolipid biosynthetic pathway block virion production, but not RNA accumulation, in a JFH-1 isolate, our findings suggest that alteration of the lipid composition of HCV particles might be a useful approach in the design of anti-HCV therapy.
A quick-release hook for lifeboats and offshore rigging (1982)

A quick-release hook has been developed for applications in which release-under-load capability is essential. The design is an adaptation of a towing block developed at MIT for side trawlers. The new device has been deployed aboard the U.S. Coast Guard Cutter Alert for two years as a part of its rigid hull inflatable rubber boat handling system. The hook has proven successful and judged a key element of the launch/retrieve operation. This paper details the design, fabrication, and operation of the hook and describes the operational environment in which the prototype was deployed. Other marine applications are discussed as well as the advantages over existing hardware.
Synthesis, Isolation, and Characterization of the Adduct Formed in the Reaction of p-Hydroxyphenyl- acetaldehyde with the Amino Headgroup of Phosphatidylethanolamine and Phosphatidylserine (1998)

The adducts that form when aldehydes modify proteins have been implicated in the pathogenesis of vascular disease and aging. Our previous studies indicated that p-hydroxyphenylacetaldehyde (pHA), the major product of l-tyrosine oxidation by the myeloperoxidase/hydrogen peroxide/chloride system of phagocytes, covalently modifies the ε-amino group of lysine residues at sites of inflammation. Here, we report that pHA also reacts with the amino group of synthetic phospholipids and red blood cell model systems. Using fast atom bombardment mass spectrometric analysis of ethanolamine glycerophospholipid or serine glycerophospholipid incubated with pHA and NaBH3CN, we detected products that were consistent with reduced phospholipid Schiff base adducts. We confirmed the reaction of the aldehyde with the amino group through 1H NMR and mass spectrometric analysis of polar headgroups recovered from the modified and reduced parent lipid. When phospholipid model systems and cell membranes were exposed to physiological levels of l-tyrosine and the myeloperoxidase/hydrogen peroxide/chloride system followed by treatment with NaBH3CN, reduced Schiff base adducts of pHA with ethanolamine glycerophospholipid and serine glycerophospholipid (pHA-PE and pHA-PS, respectively) were produced. The reaction required myeloperoxidase, hydrogen peroxide, l-tyrosine, and chloride ion; it was inhibited by catalase or heme poisons, implicating hydrogen peroxide and peroxidase in the pathway. Collectively, these results demonstrate that an aldehyde generated by the myeloperoxidase system of phagocytes can covalently modify the amino groups of phosphatidylethanolamine and phosphatidylserine. Because amino glycerophospholipids are critical components of cell membranes and circulating lipoproteins such as LDL, similar reactions may play important roles in the initiation or progression of disease at sites of inflammation.
Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation (2014)

T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.
Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer. (2003)

We conclude that uPA and MMP-9 are potential prognostic indicators in pancreatic cancer, whereas microvessel density may not be one. This study confirms our previous observation that uPA is made by the tumor cells themselves. Presence of uPA in vessels of tumor stroma suggests that uPA is in circulation, and its measurement and that of MMP-9 in the blood of these patients may aid in prognosis. Patients showing overexpression of uPA and MMP-9 have a trend toward shorter survival time.
Synthetic LXR agonists increase LDL in CETP species (2005)

Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7alpha-hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies. These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism.
A 32-site Neural Recording Probe Fabricated by Double-Sided Deep Reactive Ion Etching of Silicon-on-Insulator Substrates (2001)

A neural probe with a 32-site electrode array was fabricated using an all-dry Si etch based micromachining process. The fork-like probe shafts were formed by double-sided deep reactive ion etching (DRIE) of a silicon-on-insulator (SOI) substrate, with the buried SiO 2 layer acting as an etch stop. The shafts typically had the dimensions 5 mm x 25 m x 20 m and a tip taper of 4. An array of Ir electrodes, each 100 m 2 , and Au conductor traces were formed by e-beam evaporation. SEM studies showed sharply defined probes and probe tips. The function was verified in bench-top measurements in saline. The magnitude of the electrode impedance was in the 1 MW-range @ 1 kHz, which is consistent with neural recordings. 1.
pH Response of Model Diblock and Triblock Copolymer Networks Containing Polystyrene and Poly(2-hydroxyethyl methacrylate-co-2-(dimethylamino)ethyl methacrylate) (2008)

We investigated the swelling behavior of lamella-forming diblock and triblock copolymers of polystyrene, PS, and poly(2-hydroxyethyl methacrylate-co-2-(dimethylamino)ethyl methacrylate), PHD, with varying 2-(dimethylamino)ethyl methacrylate (DMAEMA) content. In phosphate buffer solutions of varying pH’s, these model networks swell like cationic hydrogels; their swelling characteristics are tunable through the DMAEMA content within the PHD block. While glassy PS domains within PS/PHD/PS can serve as physical cross-links in triblock copolymer networks, the PS domains are not effective anchors in diblock copolymer networks. PS/PHD with high DMAEMA content thus macroscopically disintegrate upon protonation of DMAEMA. The lamellar microdomains within these networks, however, continue to swell with decreasing pH. By reducing the DMAEMA content in PS/PHD, we have been able to create a diblock copolymer network that is macroscopically stable upon protonation of DMAEMA, as its water uptake cannot induce sufficient osmotic pressure to break up the sample. The swelling characteristics of this particular network mirror those of physically cross-linked PS/PHD/PS networks with comparable DMAEMA content.
Instant ray tracing: the bounding interval hierarchy (2006)

We introduce a new ray tracing algorithm that exploits the best of previous methods: Similar to bounding volume hierarchies the memory of the acceleration data structure is linear in the number of objects to be ray traced and can be predicted prior to construction, while the traversal of the hierarchy is as efficient as the one of kd-trees. The construction algorithm can be considered a variant of quicksort and for the first time is based on a global space partitioning heuristic, which is much cheaper to evaluate than the classic surface area heuristic. Compared to spatial partitioning schemes only a fraction of the memory is used and a higher numerical precision is intrinsic. The new method is simple to implement and its high performance is demonstrated by extensive measurements including massive as well as dynamic scenes, where we focus on the total time to image including the construction cost rather than on only frames per second.
A Compendium of Potential Biomarkers of Pancreatic Cancer (2009)

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Cellular Redox Modulator, ortho Mn(III) meso-tetrakis(N-n-Hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ in the Treatment of Brain Tumors (2011)

Despite intensive efforts to improve multimodal treatment of brain tumor, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, mangnese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+). It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compound among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP(5+) mimics our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP(5+) crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP(5+) as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP(5+) caused a significant (P ≤ 0.001) growth delay in D 245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP(5+) increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; p≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, <0.001). The beneficial effects of MnTnHex-2-PyP(5+) are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP(5+), is a promising approach for brain tumor therapy.
Importance of hydrogen-bonding interactions involving the side chain of Asp158 in the catalytic mechanism of papain (1991)

In a previous study, it was shown that replacing Asp158 in papain by Asn had little effect on activity and that the negatively charged carboxylate of Asp158 does not significantly stabilize the active site thiolate-imidazolium ion pair of papain (Ménard et al., 1990). In this paper, we report the kinetic characterization of three more mutants at this position: Asp158Gly, Asp158Ala, and Asp158Glu. From the pH-activity profiles of these and other mutants of papain, it has been possible to develop a model that enables us to dissect out the contribution of the various mutations toward (i) intrinsic activity, (ii) ion pair stability, and (iii) the electrostatic potential at the active site. Results obtained with mutants that place either Gly or Ala at position 158 indicate that the hydrogen bonds involving the side chain of Asp158 in wild-type papain are indirectly important for enzyme activity. When CBZ-Phe-Arg-MCA is used as a substrate, the (kcat/KM)obs values at pH 6.5 are 3650 and 494 M-1 s-1 for Asp158Gly and Asp158Ala, respectively, as compared to 119,000 M-1 s-1 for papain. Results with the Asp158Glu mutant suggest that the side chain of Glu moves closer to the active site and cannot form hydrogen bonds similar to those involving Asp158 in papain. From the four mutations introduced at position 158 in papain, we can conclude that it is not the charge but the hydrogen-bonding interactions involving the side chain of Asp158 that contribute the most to the stabilization of the thiolate-imidazolium ion pair in papain. However, the charge and the hydrogen bonds of Asp158 both contribute to the intrinsic activity of the enzyme.
Efficient method for regioselective isoprenylation of cysteine thiols in unprotected peptides (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEfficient method for regioselective isoprenylation of cysteine thiols in unprotected peptidesChi Ching Yang, Charles K. Marlowe, and Robert KaniaCite this: J. Am. Chem. Soc. 1991, 113, 8, 3177–3178Publication Date (Print):April 1, 1991Publication History Published online1 May 2002Published inissue 1 April 1991https://doi.org/10.1021/ja00008a059RIGHTS & PERMISSIONSArticle Views235Altmetric-Citations31LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (300 KB) Get e-Alerts Get e-Alerts
Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos (2007)

We have adapted a novel multicistronic gene expression system involving viral peptides to the zebrafish. The viral 2A peptide allows production of multiple protein products from a single transgene. Based on highly inefficient peptide bond formation between glycine and proline residues within the 2A peptide, placement of 2A peptide sequence as a linker region between tandem cDNA's allows the stoichiometric translation of multiple unfused protein products. To test this system in zebrafish, we generated two different tandem reporter constructs employing eGFP and mCherry, separated by 2A peptide sequence. Using this system, we produced transgenic zebrafish in which fluorophores were produced as independent proteins from a single transcript. The successful application of this technology in zebrafish will be valuable for visually marking transgenic embryos and transgene-expressing cells, or in any situation where reliable expression of multiple transgenes is desired.
Bypassing immunization: optimized design of "designer T cells" against carcinoembryonic antigen (CEA)-expressing tumors, and lack of suppression by soluble CEA. (1999)

Tumor-associated antigens are typically nonimmunogenic in cancer patients, "immune surveillance" having manifestly failed. The fact that most tumor antigens are normal human proteins presents significant obstacles to current cancer immunization approaches that researchers are presently striving to overcome. An alternative strategy bypasses immunization altogether by direct genetic alteration of autologous patient T cells, to create "designer T cells" specific to a particular antigen. Chimeric immunoglobulin-T cell receptors (IgTCR) with a specificity for carcinoembryonic antigen (CEA) were created to evaluate the optimal IgTCR structure for cancer therapy. Antigen-binding domains of a humanized antibody were combined with TCR signaling chains to yield four different chimeric IgTCR: single chain Fv fragment (sFv)-zeta, fragment antigen-binding (Fab)-zeta, sFv-epsilon, and Fab-epsilon. All of the IgTCR were well expressed on T cells, and all showed specific binding and activation, as demonstrated by IL-2 production on contact with immobilized or cellular CEA, excepting sFv-epsilon alone which was inert solely against cellular targets for steric reasons unique to this construct. In contrast to prior studies of isolated TCR chains that related increased tyrosine-based activation motifs in zeta as a reason for superior signaling potency, these tests are the first to show that epsilon and zeta are indistinguishable for T cell signaling when assayed in the context of the intact TCR complex. Further, Fab was equivalent to sFv as an IgTCR component for expression and antigen binding, establishing an important alternative for IgTCR antigen recognition because sFvs may often lose antigen affinity. When IgTCR was expressed on normal human T cells, cytotoxic potency was demonstrated at low E:T ratios, with T cell recycling and progressive tumor cell destruction. Contrary to recent speculations, these observations prove that high affinity TCR interactions are not an impediment to serial target engagement and disengagement by cytotoxic T cells. The multivalent intercellular interactions of target cell binding, activation, and cytotoxicity were resistant to inhibition by soluble CEA. These studies establish a potentially important new immunotherapeutic modality for the treatment of CEA-expressing tumors.