gebhart/patrepeval huggingface dataset:
Mechanism of Sorting Proopiomelanocortin and Proenkephalin to the Regulated Secretory Pathway of Neuroendocrine Cells (2002)

Proopiomelanocortin (POMC) and proenkephalin (PE) are synthesized at the endoplasmic reticulum and transported to the trans-Golgi network (TGN) where they are sorted and packaged into dense-core granules of the regulated secretory pathway (RSP). The mechanism of sorting POMC and PE to the RSP in neuroendocrine cells was investigated. Consensus sorting signals comprising two acidic residues and two hydrophobic residues exposed on the surface of N-POMC(1-26) and N-PE(1-32) were identified and shown to be sufficient and necessary for targeting POMC and PE to the RSP in PC12, Neuro2a, and AtT-20 cells. The acidic residues of these sorting signals bind specifically to basic residues on the sorting receptor membrane, carboxypeptidase E (CPE), to effect sorting to the RSP. Analysis of POMC and PE sorting in Neuro2a cells depleted of CPE by CPE antisense RNA, and Cpe(fat/fat) mouse pituitary cells lacking CPE showed missorting of both these molecules to the constitutive pathway in vivo. Thus, POMC and PE are sorted to the RSP at the TGN by a mechanism involving the interaction of a specific sorting signal on these molecules with the sorting receptor, CPE.
Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. (1995)

Earlier work has identified a cell population that replicates HIV-1 in the absence of standard T cell stimuli. The system consists of dendritic cells and memory T lymphocytes that emigrate from organ cultures of human skin and together support a productive infection with HIV-1. These emigrants resemble cells that can be found in mucous membranes and that normally traffic in afferent lymph. Here, we report that a low level of infection in the dendritic cell can initiate extensive HIV-1 replication in cocultures with T cells. First we extended our earlier work to larger skin specimens from cadavers. As long as the organ cultures were set up within 36 h of death, the emigrant leukocytes were comparable to cells from fresh surgical specimens in number, phenotype, and function. These mixtures of dendritic cells and T cells provided the milieu for a productive infection with several virus isolates. When purified dendritic cells were separately pulsed with virus and then mixed with T cells that had not been pulsed with HIV-1, active infection ensued. The infectivity of HIV-pulsed dendritic cells persisted for at least 1.5 d in culture, but was blocked if AZT was added during that time to block reverse transcription in the dendritic cells. The number of copies of proviral DNA in the dendritic cells corresponded to < 100 copies per 5 X 10(4) cells, but upon mixing with T cells, > 10(4) copies were found 5-7 d later. By contacting syngeneic T cells, extralymphoid depots of dendritic cells--even with a low viral burden as has been reported in vivo--may contribute to chronic HIV-1 replication in infected individuals.
The Role of Corepressors in Transcriptional Regulation by Nuclear Hormone Receptors (2004)

Nuclear receptors (also known as nuclear hormone receptors) are hormone-regulated transcription factors that control many important physiological and developmental processes in animals and humans. Defects in receptor function result in disease. The diverse biological roles of these receptors reflect their surprisingly versatile transcriptional properties, with many receptors possessing the ability to both repress and activate target gene expression. These bipolar transcriptional properties are mediated through the interactions of the receptors with two distinct classes of auxiliary proteins: corepressors and coactivators. This review focuses on how corepressors work together with nuclear receptors to repress gene transcription in the normal organism and on the aberrations in this process that lead to neoplasia and endocrine disorders. The actions of coactivators and the contributions of the same corepressors to the functions of nonreceptor transcription factors are also touched on.
Identification, Characterization, and Functional Analysis of a Gene Encoding the Ferric Uptake Regulation Protein in Bartonella Species (2001)

Environmental iron concentrations coordinately regulate transcription of genes involved in iron acquisition and virulence via the ferric uptake regulation (fur) system. We identified and sequenced the fur gene and flanking regions of three Bartonella species. The most notable difference between Bartonella Fur and other Fur proteins was a substantially higher predicted isoelectric point. No promoter activity or Fur autoregulation was detected using a gfp reporter gene fused to the 204 nucleotides immediately upstream of the Bartonella fur gene. Bartonella henselae fur gene expression complemented a Vibrio cholerae fur mutant.
Diet‐induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease (2004)

Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.
Circadian expression of the dnaK gene in the cyanobacterium Synechocystis sp. strain PCC 6803 (1995)

The expression of the dnaK gene in the cyanobacterium Synechocystis sp. strain PCC 6803 was continuously monitored as bioluminescence by an automated monitoring system, using the bacterial luciferase genes (luxAB) of Vibrio harveyi as a reporter of promoter activity. A dnaK-reporting bioluminescent Synechocystis strain was constructed by fusing a promoterless segment of the luxAB gene set downstream of the promoter region of the Synechocystis dnaK gene and introduction of this gene fusion into a BglII site downstream of the ndhB gene in the Synechocystis chromosome. Bioluminescence from this strain was continuously monitored and oscillated with a period of about 22 h for at least 5 days in continuous light. The phase of the rhythm was reset by the timing of the 12-h dark period administered prior to the continuous light. The period of the rhythm was temperature compensated between 25 and 35 degrees C. Thus, the bioluminescence rhythm satisfied the three criteria of circadian rhythms. Furthermore, the abundance of dnaK mRNA also oscillated with a period of about 1 day for at least 2 days in continuous light conditions, indicating circadian control of dnaK gene expression in Synechocystis sp. strain PCC 6803.
Emerging drugs for migraine prophylaxis and treatment. (2006)

Migraine is a chronic neurologic disorder with heterogeneous characteristics resulting in a range of symptom profiles, burden, and disability. Migraine affects nearly 12% of the adult population in occidental countries, imposing considerable economic and social losses. The pharmacologic treatment of migraine includes preventive and acute strategies. A better understanding of the migraine pathophysiology along with the discovery of novel molecular targets has lead to a growing number of upcoming therapeutic proposals. This review focuses on new and emerging agents for the treatment of migraine.
(Dihydro)ceramide Synthase 1–Regulated Sensitivity to Cisplatin Is Associated with the Activation of p38 Mitogen-Activated Protein Kinase and Is Abrogated by Sphingosine Kinase 1 (2007)

Resistance to chemotherapeutic drugs often limits their clinical efficacy. Previous studies have implicated the bioactive sphingolipid sphingosine-1-phosphate (S-1-P) in regulating sensitivity to cisplatin [cis-diamminedichloroplatinum(II)] and showed that modulating the S-1-P lyase can alter cisplatin sensitivity. Here, we show that the members of the sphingosine kinase (SphK1 and SphK2) and dihydroceramide synthase (LASS1/CerS1, LASS4/CerS4, and LASS5/CerS5) enzyme families each have a unique role in regulating sensitivity to cisplatin and other drugs. Thus, expression of SphK1 decreases sensitivity to cisplatin, carboplatin, doxorubicin, and vincristine, whereas expression of SphK2 increases sensitivity. Expression of LASS1/CerS1 increases the sensitivity to all the drugs tested, whereas LASS5/CerS5 only increases sensitivity to doxorubicin and vincristine. LASS4/CerS4 expression has no effect on the sensitivity to any drug tested. Reflecting this, we show that the activation of the p38 mitogen-activated protein (MAP) kinase is increased only by LASS1/CerS1, and not by LASS4/CerS4 or LASS5/CerS5. Cisplatin was shown to cause a specific translocation of LASS1/CerS1, but not LASS4/CerS4 or LASS5/CerS5, from the endoplasmic reticulum (ER) to the Golgi apparatus. Supporting the hypothesis that this translocation is mechanistically involved in the response to cisplatin, we showed that expression of SphK1, but not SphK2, abrogates both the increased cisplatin sensitivity in cells stably expressing LASS1/CerS and the translocation of the LASS1/CerS1. The data suggest that the enzymes of the sphingolipid metabolic pathway can be manipulated to improve sensitivity to the widely used drug cisplatin.
Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases (2014)

The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
Protection against FatalPseudomonas aeruginosaPneumonia in Mice after Nasal Immunization with a Live, AttenuatedaroADeletion Mutant (2003)

Studies of immunity to Pseudomonas aeruginosa have indicated that a variety of potential immunogens can elicit protection in animal models, utilizing both antibody- and cell-mediated immune effectors for protection. To attempt to optimize delivery of multiple protective antigens and elicit a broad range of immune effectors, we produced an aroA deletion mutant of the P. aeruginosa serogroup O2/O5 strain PAO1, designated PAO1deltaaroA. Previously, we reported that this strain elicits high levels of opsonic antibody directed against many serogroup O2/O5 strains after nasal immunization of mice and rabbits. Here, we assessed the protective efficacy of immunization with PAO1deltaaroA against acute fatal pneumonia in mice. After active immunization, high levels of protection were achieved against an ExoU-expressing cytotoxic variant of the parental strain PAO1 at doses up to 1,000-fold greater than the 50% lethal dose. Significant protection against PAO1 and two of four other serogroup O2/O5 strains was also found, but there was no protection against serogroup-heterologous strains. The serogroup O2/O5 strains not protected against were killed in opsonophagocytic assays as efficiently as the strains with which protection was seen, indicating a lack of correlation of protection and opsonic killing within the serogroup. In passive immunization experiments using challenge with wild-type PAO1 or other noncytotoxic members of the O2/O5 serogroup, there was no protection despite the presence of high levels of opsonic antibody in the mouse sera. However, passive immunization did prevent mortality from pneumonia due to the cytotoxic PAO1 variant at low-challenge doses. These data suggest that a combination of humoral and cellular immunity is required for protection against P. aeruginosa lung infections, that such immunity can be elicited by using aroA deletion mutants, and that a multivalent P. aeruginosa vaccine composed of aroA deletion mutants of multiple serogroups holds significant promise.
Semantics and Verification of UML Activity Diagrams for Workflow Modelling (2002)

Semantics and Verification of UML Activity Diagrams for Workfl.ow ModellingAlthough I wrote this thesis, I couldn't have done it without the help of several people.First of all, l thank my promotor Roel Wieringa, who managed to find time to read my ohscmc manuscripts, and more importantly provided usd\11 f<~edback to improve tliP111.Hoel gave me the freedom to pursue my own research i11terests and helped lll<' to phrase the results in an understandable way.I thank the other members of my promotion committee, Wil va11 dcr Aalst.Gregor Engds.Ed lhinksma, l\Iaarten Fokkinga, and Paul Grcfc11. for tl1eir useful cornrnc11ts 011 a previous version of this thesis.Besides Hoel.several other people influenced the contents of this thesis.Paul Grefen and \\'ij11a11d Derks were always willing to have a good discussion on workfiow moclclli11g.Wil Yan der Aalst and Jorg Desel provided helpful crii icism on a paper that forms 1 he basis of Chapter 8. \Vorking with .Juforne Dehn<'rt c:011froutecl me 1Yith a Petri net \ie1Y on workfiow modelling.1Yhich has been very illmni11ating for me ..\Int hcmai icians :\Iaarten Fokkinga and DaYid .J anscn managed to increase the precision of 111y statements.In 2001, I attC'ndecl the FASE conference, part of ETAPS. to pr<'sent a paper on the rcq11ircrrnnts-lcvcl semantics.In a keynote talk at this confc1T11n'.Bran Selic rejected what he called 'platonic abstractions' like the perfect synchrony hypothesis.because they are. in his opinion, unrealistic and unimpkm<'ntable.Even though I disagree with him, his talk triggered me to define a low-level implementation-level semantics that does not satisfy perfect sy11chrony.and to prove that th<~ two semantics have similar behaviour.Room mates David Jansen and Wijnand Derks, as well as the rest of the IS and DB group, provided a pleasant atmosphere to work in.Secretaries Sandra Westhoff, Susc Engbers and Els Bosch managed my travels by plane awl train.Maarte11 Fokkinga and Rick van Rein guided the research I did for my Master's thesis in sucl1 a stimulating way that it made me think of doing a PhD.Last but 1101 least, I'd like to thank my friends and family.Orndat dit de afsluiting van mij11 onclcrwijscarriere is, wil ik graag twee personcn in
Massachusetts agriculture 1980 (2016)

Dear friends of Massachusetts agriculture, For the agricultural community in our state, 1987 was marked by meeting challenges, but always finding new ones waiting to be addressed.We are buoyed by the Massachusetts farmer's record of adaptive ingenuity -finding a way to succeed in a difficult climate of intense development pressure.Massachusetts agriculture has a proud history.Our state is home to the oldest continuously operating cattle farm in America -Appleton Farms in Ipswich -which marks its 350th year in 1988.We have 38 other farms that have operated 200 or more years.In an effort to preserve this heritage, we remain firmly committed to the Agricultural Preservation Restriction program.We plan to use judiciously the $35 million allocated under the 1987 Open Space bill to add to the 20,000 acres on 225 farms already under APR.As farmers fight the lure of developers' offers, this program becomes ever more critical.Despite the odds, some segments of our agribusiness sector are thriving.The so-called "green industry" is doing well as scores of families discover the pleasures of home gardening.Farmers across the state have enjoyed great gains through direct marketing at their own retail outlets.The Massachusetts food-processing industry is enjoying robust health, with $3 billion in goods produced in 1987, doubling the output of 10 years ago.1987 also saw the expansion of the Farmers Market Coupon program, under which low-income mothers and the elderly receive coupons redeemable for fresh produce at farmers markets.About $90,000 in coupons was redeemed.We plan to expand the program in 1988.While many segments of our farm-and-food industry are at least holding their own, the situation is quite different for dairy farmers.Unrelenting attrition has dropped our dairies below the 500 mark.We plan to do all we can to keep the dairy farmers we still have.Price continues to be the biggest problem for them and we continue to seek more equitable national price structures.In addition, we have several programs already in place designed to help the dairy industry, including a new $3 million grant program for agri-composting.We look forward to meeting this challenge and others as we build upon past successes in our common quest to see that the business of growing in Massachusetts keeps growing.
Characterization of an anti‐thrombospondin monoclonal antibody (P8) that inhibits human blood platelet functions (1988)

Stimulated human blood platelets release thrombospondin, an alpha-granule glycoprotein of 450 kDa. The aim of this work was to characterize an anti-thrombospondin monoclonal antibody (P8) in order to study the role of thrombospondin in platelet functions. The presence of thrombospondin receptor sites on resting and thrombin-stimulated platelets of three Glanzmann's thrombasthenia patients and normal donors was investigated using the P8 monoclonal antibody. Monoclonal antibody P8 was extensively characterized using ELISA, immunoprecipitation, immunoadsorbent affinity chromatography combined with tryptic peptide map analysis and crossed immunoelectrophoretic techniques. Labelled P8 bound strongly to thrombin-stimulated normal platelets (n = 14917 +/- 420, mean +/- SD) (Kd = 9.2 +/- 3.0 nM) and poorly to resting platelets (n = 2697 +/- 1278) (Kd = 24.8 +/- 18.6 nM). Moreover, the number of binding sites for P8 on thrombin-stimulated platelets from three Glanzmann's thrombasthenia patients, lacking the IIb-IIIa glycoprotein complex, were found similar to normal samples. F(ab')2 fragments of P8 inhibited aggregation of, and reduced secretion from, washed platelets stimulated by low concentrations of thrombin (0.05-0.06 U/ml) and collagen (0.5-0.6 microgram/ml). F(ab')2 fragments of P8 inhibited thrombin-induced platelet aggregation, but did not reduce fibrinogen binding (n) nor affect its dissociation constant (Kd). Inhibition of platelet aggregation by P8 suggests that thrombospondin plays an active role in promoting platelet aggregation, at low concentrations of thrombin and collagen. Normal binding of P8 to thrombin-stimulated Glanzmann thrombasthenic platelets indicates the presence of a thrombospondin receptor on the platelet surface distinct from the GPIIb-IIIa complex.
Stem Cells, Self-Renewal, and Differentiation in the Intestinal Epithelium (2008)

The mammalian intestine is covered by a single layer of epithelial cells that is renewed every 4-5 days. This high cell turnover makes it a very attractive and comprehensive adult organ system for the study of cell proliferation and differentiation. The intestine is composed of proliferative crypts, which contain intestinal stem cells, and villi, which contain differentiated specialized cell types. Through the recent identification of Lgr5, an intestinal stem cell marker, it is now possible to visualize stem cells and study their behavior and differentiation in a much broader context. In this review we describe the identification of intestinal stem cells. We also discuss genetic studies that have helped to elucidate those signals important for progenitor cells to differentiate into one of the specialized intestinal epithelial cell types. These studies describe a genetic hierarchy responsible for cell fate commitment in normal gut physiology. Where relevant we also mention aberrant deregulation of these molecular pathways that results in colon cancer.
Micropattern Formation in Supported Lipid Membranes (2002)

Phospholipid vesicles exhibit a natural tendency to fuse and assemble into a continuous single bilayer membrane on silica and several other substrate materials. The resulting supported membrane maintains many of the physical and biological characteristics of free membranes, including lateral fluidity. Recent advances, building on the supported membrane configuration, have created a wealth of opportunities for the manipulation, control, and analysis of membranes and the reaction environments they provide. The work reviewed in this Account, which can be broadly characterized as the science and technology of membrane patterning, contains three basic components: lateral diffusion control (barriers), membrane deposition techniques (microarrays), and electric field-induced lateral reorganization. Collectively, these preparative and analytical patterned membrane techniques offer a broad experimental platform for the study and utilization of lipid membranes.
Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection (1999)

Contains fulltext : 224165.pdf (Publisher’s version ) (Open Access)
Fault tolerance of quantum low-density parity check codes with sublinear distance scaling (2013)

We study the fault tolerance of quantum low-density parity check (LDPC) codes, such as generalized toric codes with a finite rate suggested by Tillich and Z\'emor [in ISIT 2009: IEEE International Symposium on Information Theory (IEEE, New York, 2009)]. We show that any family of quantum LDPC codes where each syndrome measurement involves a limited number of qubits and each qubit is involved in a limited number of measurements (as well as any similarly limited family of classical LDPC codes), in which distance scales as a positive power $\ensuremath{\alpha}$ of the number of physical qubits ($\ensuremath{\alpha}&lt;1$ for ``bad'' codes), has a finite error probability threshold. We conclude that for sufficiently large quantum computers, quantum LDPC codes can offer an advantage over the toric codes.