gebhart/patrepeval huggingface dataset:
Processing of alpha4 integrin by the proprotein convertases: histidine at position P6 regulates cleavage (2003)

The proprotein convertases (PCs) participate in the limited proteolysis of integrin alpha4 subunit at the H(592)VISKR(597) downward arrow ST site (where underlined residues indicate positively charged amino acids important for PC-mediated cleavage and downward arrow indicates the cleavage site), since this cleavage is inhibited by the serpin alpha1-PDX (alpha1-antitrypsin Portland). Co-expression of alpha4 with each convertase in LoVo (furin-deficient human colon carcinoma) cells revealed that furin and proprotein convertase 5A (PC5A) are the best pro-alpha4 convertases. In agreement, processing of endogenous pro-alpha4 in human lymphoblastoid CEM-T4 cells was enhanced greatly in stable transfectants overexpressing either enzyme. In many leucocyte cell lines, the expression of furin closely correlated with the endogenous processing efficacy, suggesting that furin is a candidate pro-alpha4 convertase. Mutational analysis showed that replacement of P1 Arg(597) with alanine (R597A) abrogated cleavage, whereas the P6 mutant H592R is even better processed by the endogenous convertases of Chinese-hamster ovary CHO-K1 cells. In vitro kinetic studies using synthetic peptides confirmed the importance of a positively charged residue at P6 and showed that wild-type alpha4 processing is performed best by furin and PC5A at acidic and neutral pHs, respectively. Biosynthetic analysis of pro-alpha4 and its H592R and H592K mutants in the presence or absence of the weak base, NH(4)Cl, revealed that the P6 histidine residue renders its processing by furin sensitive to cellular pH. This suggests that pro-alpha4 cleavage occurs preferentially in acidic compartments. In conclusion, although the accepted furin processing motif is Arg-Xaa-(Lys/Arg)-Arg downward arrow, our data further extend it to include a regulatory histidine residue at P6 in precursors that lack a basic residue at P4.
Dosage-Sensitive Function of RETINOBLASTOMA RELATED and Convergent Epigenetic Control Are Required during the Arabidopsis Life Cycle (2010)

The plant life cycle alternates between two distinct multi-cellular generations, the reduced gametophytes and the dominant sporophyte. Little is known about how generation-specific cell fate, differentiation, and development are controlled by the core regulators of the cell cycle. In Arabidopsis, RETINOBLASTOMA RELATED (RBR), an evolutionarily ancient cell cycle regulator, controls cell proliferation, differentiation, and regulation of a subset of Polycomb Repressive Complex 2 (PRC2) genes and METHYLTRANSFERASE 1 (MET1) in the male and female gametophytes, as well as cell fate establishment in the male gametophyte. Here we demonstrate that RBR is also essential for cell fate determination in the female gametophyte, as revealed by loss of cell-specific marker expression in all the gametophytic cells that lack RBR. Maintenance of genome integrity also requires RBR, because diploid plants heterozygous for rbr (rbr/RBR) produce an abnormal portion of triploid offspring, likely due to gametic genome duplication. While the sporophyte of the diploid mutant plants phenocopied wild type due to the haplosufficiency of RBR, genetic analysis of tetraploid plants triplex for rbr (rbr/rbr/rbr/RBR) revealed that RBR has a dosage-dependent pleiotropic effect on sporophytic development, trichome differentiation, and regulation of PRC2 subunit genes CURLY LEAF (CLF) and VERNALIZATION 2 (VRN2), and MET1 in leaves. There were, however, no obvious cell cycle and cell proliferation defects in these plant tissues, suggesting that a single functional RBR copy in tetraploids is capable of maintaining normal cell division but is not sufficient for distinct differentiation and developmental processes. Conversely, in leaves of mutants in sporophytic PRC2 subunits, trichome differentiation was also affected and expression of RBR and MET1 was reduced, providing evidence for a RBR-PRC2-MET1 regulatory feedback loop involved in sporophyte development. Together, dosage-sensitive RBR function and its genetic interaction with PRC2 genes and MET1 must have been recruited during plant evolution to control distinct generation-specific cell fate, differentiation, and development.
Clozapine-induced hypersalivation and the alpha2 adrenoceptor (1995)

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The Drugstore Shoppers (1988)

In recent years the drugstore industry has become increasingly competitive largely due to a set of new discount oriented competitors. To maintain or increase their competitiveness in this market, drugstores must respond by better understanding the needs of the consumer. Based upon a national survey of drugstore shoppers, this article assists the industry by providing a comprehensive description of drugstore shoppers and their experience. Included are a demographc profile of the shopper, consumer evaluation of their drugstore shopping experience, and a summary of how these shoppers spend their money. Examples of how this information can be used by management are also included.
Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients (2012)

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (∼1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients.
Targeting Antigen in Mature Dendritic Cells for Simultaneous Stimulation of CD4+ and CD8+ T Cells (2001)

Due to their potent immunostimulatory capacity, dendritic cells (DC) have become the centerpiece of many vaccine regimens. Immature DC (DCimm) capture, process, and present Ags to CD4(+) lymphocytes, which reciprocally activate DCimm through CD40, and the resulting mature DC (DCmat) loose phagocytic capacity, but acquire the ability to efficiently stimulate CD8(+) lymphocytes. Recombinant vaccinia viruses (rVV) provide a rapid, easy, and efficient method to introduce Ags into DC, but we observed that rVV infection of DCimm results in blockade of DC maturation in response to all activation signals, including CD40L, monocyte-conditioned medium, LPS, TNF-alpha, and poly(I:C), and failure to induce a CD8(+) response. By contrast, DCmat can be infected with rVV and induce a CD8(+) response, but, having lost phagocytic activity, fail to process the Ag via the exogenous class II pathway. To overcome these limitations, we used the CMV protein pp65 as a model Ag and designed a gene containing the lysosomal-associated membrane protein 1 targeting sequence (Sig-pp65-LAMP1) to target pp65 to the class II compartment. DCmat infected with rVV-Sig-pp65-LAMP1 induced proliferation of pp65-specific CD4(+) clones and efficiently induced a pp65-specific CD4(+) response, suggesting that after DC maturation the intracellular processing machinery for class II remains intact for at least 16 h. Moreover, infection of DCmat with rVV-Sig-pp65-LAMP1 resulted in at least equivalent presentation to CD8(+) cells as infection with rVV-pp65. These results demonstrate that despite rVV interference with DCimm maturation, a single targeting vector can deliver Ags to DCmat for the effective simultaneous stimulation of both CD4(+) and CD8(+) cells.
FER kinase promotes breast cancer metastasis by regulating α6- and β1-integrin-dependent cell adhesion and anoikis resistance (2013)

Metastatic breast cancer cannot be treated successfully. Currently, the targeted therapies for metastatic disease are limited to human epidermal growth factor receptor 2 and hormone receptor antagonists. Understanding the mechanisms of breast cancer growth and metastasis is therefore crucial for the development of new intervention strategies. Here, we show that FER kinase (FER) controls migration and metastasis of invasive human breast cancer cell lines by regulating α6- and β1-integrin-dependent adhesion. Conversely, the overexpression of FER in non-metastatic breast cancer cells induces pro-invasive features. FER drives anoikis resistance, regulates tumour growth and is necessary for metastasis in a mouse model of human breast cancer. In human invasive breast cancer, high FER expression is an independent prognostic factor that correlates with high-grade basal/triple-negative tumours and worse overall survival, especially in lymph node-negative patients. These findings establish FER as a promising target for the prevention and inhibition of metastatic breast cancer.
Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus (2001)

Type 2 diabetes mellitus is a severe disease with large economic consequences, which is significantly under-diagnosed and incompletely treated in the general population. Control of blood glucose levels is a key objective in treating diabetic patients, who are most often prescribed one or more oral hypoglycaemic agents in addition to diet and exercise modification as well as insulin. In spite of the availability of different classes of hypoglycaemic drugs, treatment regimens are often unable to achieve an intensive degree of glucose control known to most effectively reduce the incidence and severity of diabetic complications. Hepatic glucose output is elevated in type 2 diabetic patients and current evidence indicates that glycogenolysis (release of monomeric glucose from the glycogen polymer storage form) is an important contributor to the abnormally high production of glucose by the liver. Glycogen phosphorylase is the enzyme that catalyses this release and recent advances in new inhibitors of this structurally and kinetically well studied enzyme have enabled work which further delineate the pharmacological and physiological consequences of inhibiting glucose production by this pathway. Most notably, these agents lower glucose in diabetic animal models, both acutely and chronically, appear to affect both gluconeogenic and glycogenolytic pathways and demonstrate potential for a beneficial effect on cardiovascular risk factors. Cumulatively, this information has bolstered interest and promise in glycogen phosphorylase inhibitors (GPIs) as potential new hypoglycaemic agents for treatment of type 2 diabetes mellitus.
Discrimination of Two Phycoerythrin-Pigment Types of Synechococcus and Their Seasonal Succession in the Uwa Sea (2004)

We identified phycoerythrin-pigment phenotypes of Synechococcus strains in samples obtained from the Uwa Sea, and investigated the seasonal changes in the pigment-type composition of the Synechococcus community in this sea from January 2001 to March 2002. Two Synechococcus strains (UT01 and UT02) with different flow cytometric signatures were isolated by sorting and subsequent culturing. Excitation spectra showed that these two strains possessed different ratios of phycourobilin (PUB) to phycoerythrobilin (PEB). Flow cytometric signatures of the two types were also different; UT01 showed a higher green to red fluorescence ratio than UT02. The ranges of green to red fluorescence intensity of the strains did not overlap, though the strains were cultured under various light intensities (7-160 μE m-2 s-1). In seawater samples, we could divide Synechococcus into lower-and higher-PUB types based on the ratio. There were two peaks of total Synechococcus abundance in June (2.8×105 cells ml-1) and August (1.6×105 cells ml-1) in the upper layer at a depth of 0 to 15 m. Major types during these two peaks were different; the higher-PUB type contributed 75.6% to the total Synechococcus community in June, and the lower-PUB type, 58.6% in August. This is the first report which describes the seasonal succession of two phycoerythrin-pigment types of Synechococcus in a coastal sea.
Clinical Gene Transfer Studies for Hemophilia B (2004)

Hemophilia B, a deficiency of functional factor IX (FIX), has been extensively explored as a model for gene transfer. Two U.S. Food and Drug Administration-approved clinical studies for hemophilia B have been undertaken, both using adeno-associated viral vectors (AAV). AAV vectors have tropism for liver, muscle, central nervous system, and the respiratory tract; both skeletal muscle and liver have been used as target tissues in the hemophilia B studies. In both studies, proof of principle was first established in the hemophilia B dog model, with long-term expression of canine FIX at therapeutic levels achieved before clinical studies were initiated. In the AAV-FIX muscle trial, vector was introduced into skeletal muscle of the upper and lower extremities of eight human patients by direct intramuscular injection. Muscle biopsies taken 2 to 10 months postinjection demonstrated gene transfer and expression (by Southern blot and immunofluorescence, respectively) in all patients, but circulating FIX levels were generally not >1%, and escalation of dose to levels that proved therapeutic in animals was thwarted by feasibility issues regarding the number of injections required. Nevertheless, the study demonstrated that parenteral injection of AAV-FIX was safe at the doses tested, and could result in long-term expression of the transgene. Moreover, the general characteristics of transduction of human muscle were similar to those observed in other animal models. The safety and efficacy data established in the first trial formed the basis for a second trial in which AAV-FIX is administered systemically to target the liver. The liver study is currently ongoing, with six patients enrolled to date.
Applications of Neural Networks in Video Signal Processing (1990)

Although color TV is an established technology, there are a number of longstanding problems for which neural networks may be suited. Impulse noise is such a problem, and a modular neural network approach is presented in this paper. The training and analysis was done on conventional computers, while real-time simulations were performed on a massively parallel computer called the Princeton Engine. The network approach was compared to a conventional alternative, a median filter. Real-time simulations and quantitative analysis demonstrated the technical superiority of the neural system. Ongoing work is investigating the complexity and cost of implementing this system in hardware.
Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents (2015)

We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome.
Flavour science : recent developments (1996)

Flavour of Biological Origin Biotechnological Production of Flavour Chirality and Flavour Thermally Generated Flavour Novel Methods of Flavour Analysis Sensory Methods in Flavour Flavour Binding and Flavour Release Workshops.
Injectable Lipid-Based Depot Formulations: Where Do We Stand? (2020)

The remarkable number of new molecular entities approved per year as parenteral drugs, such as biologics and complex active pharmaceutical ingredients, calls for innovative and tunable drug delivery systems. Besides making these classes of drugs available in the body, injectable depot formulations offer the unique advantage in the parenteral world of reducing the number of required injections, thus increasing effectiveness as well as patient compliance. To date, a plethora of excipients has been proposed to formulate depot systems, and among those, lipids stand out due to their unique biocompatibility properties and safety profile. Looking at the several long-acting drug delivery systems based on lipids designed so far, a legitimate question may arise: How far away are we from an ideal depot formulation? Here, we review sustained release lipid-based platforms developed in the last 5 years, namely oil-based solutions, liposomal systems, in situ forming systems, solid particles, and implants, and we critically discuss the requirements for an ideal depot formulation with respect to the used excipients, biocompatibility, and the challenges presented by the manufacturing process. Finally, we delve into lights and shadows originating from the current setups of in vitro release assays developed with the aim of assessing the translational potential of depot injectables.
'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations (2001)

Cystic fibrosis is a genetic disease that is associated with abnormal sweat electrolytes, sino-pulmonary disease, exocrine pancreatic insufficiency, and male infertility. Insights into genotype/phenotype relations have recently been gained in this disorder. The strongest relationship exists between 'severe' mutations in the gene that encodes the cystic fibrosis transmembrane regulator (CFTR) and pancreatic insufficiency. The relationship between 'mild' mutations, associated with residual CFTR function, and expression of disease is less precise. Atypical 'mild' mutations in the CFTR gene have been linked to late-onset pulmonary disease, congenital bilateral absence of the vas deferens, and idiopathic pancreatitis. Less commonly, sinusitis, allergic bronchopulmonary aspergillosis, and possibly even asthma may also be associated with mutations in the CFTR gene, but those syndromes predominantly reflect non-CFTR gene modifiers and environmental influences.
Embossing technique for fabricating integrated optical components in hard inorganic waveguiding materials (1983)

We describe a novel embossing technique for fabricating integrated optical components in hard and resistant inorganic waveguiding materials of good optical quality. The desired structure is embossed into a dip-coated deformable gel film prepared from organometallic solutions. Subsequent heat treatment transforms it into inorganic hard oxide material. We have successfully fabricated surface-relief gratings with 1200 lines/mm on SiO(2)-TiO(2) waveguides (with refractive index n(F) approximately 1.8, thickness d(F) approximately 120 nm, and loss <1 dB/cm). The embossed gratings served as input and output grating couplers and as Bragg reflectors. We propose to fabricate other integrated optical components, for example, channel waveguides, with this method.
Lipoprotein lipase enhances the interaction of low density lipoproteins with artery-derived extracellular matrix proteoglycans (1993)

The association of plasma low density lipoproteins (LDL) with arterial proteoglycans (PG) is of key importance in LDL retention and modification in the artery wall. Lipoprotein lipase (LpL), the rate-limiting enzyme for hydrolysis of lipoprotein triglyceride, is known to bind both LDL and arterial PG. In the presence of LpL, cellular internalization and degradation of LDL is enhanced by a pathway initiated by interaction of LDL with a cell surface heparan sulfate proteoglycan. To determine whether LpL enhances the binding of LDL to arterial chondroitin sulfate (CS)PG and dermatan sulfate (DS)PG, the major extracellular PG of the artery wall, a microtiter plate assay was used to study LpL-PG-LDL interactions. Binding of LDL to both CSPG and DSPG was increased in the presence of LpL but differential effects were seen for the two PG. LpL enhanced the binding of LDL to CSPG a maximum of 20% and to DSPG a maximum of 40%. Heparin displacement of PG binding suggested a greater binding strength for DSPG-LpL-LDL with 0.25 micrograms heparin required to displace 50% of DSPG compared to 0.01 micrograms to displace 50% of CSPG. The greater enhancement of DSPG-LDL interaction by LpL is of particular interest since increases in DSPG correlate with the accumulation of aortic cholesterol. These data suggest that lipoprotein lipase may enhance the interaction of plasma low density lipoprotein with arterial chondroitin sulfate proteoglycan and dermatan sulfate proteoglycan and thus facilitate low density lipoprotein retention in the artery wall.
Degradable Conjugates from Oxanorbornadiene Reagents (2012)

Oxanorbornadienedicarboxylate (OND) reagents were explored for purposes of binding and releasing drugs from serum albumins as representative macromolecular carriers. Being highly reactive Michael acceptors, ONDs form adducts with thiols and amines, which then undergo retro-Diels-Alder fragmentation. A study of more than 30 model adducts revealed a number of modifications that can be used to influence adduct stability. For the most reactive OND linkers, the labeling of the single available bovine serum albumin (BSA) cysteine residue was complete within minutes at a mid-micromolar concentration of reactants. While a selectivity of greater than 1000-fold for thiol over amine was observed with model amino acids, the labeling of protein amines with ONDs is fast enough to be practical, as demonstrated by the reaction with thiol-depleted BSA. The OND-amine adducts were found to be up to 15 times more stable than OND-thiol adducts, and to be sensitive to acid by virtue of a stereochemically dependent acceleration of cycloreversion. The release rate of fluorescent cargo from serum albumins was tuned by selecting the coupling partners: the available half-lives ranged from 40 min to 7 days at 37 °C. Such versatility of release profiles from protein carriers, controlled by the nature of the OND linkage, is a useful addition to the drug delivery toolbox.
Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury (2011)

MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach.