gebhart/patrepeval huggingface dataset:
Retinoids and their receptors in differentiation, embryogenesis, and neoplasia (1991)

The crucial role of retinoids in controlling differentiation processes has become evident from studies conducted in a variety of in vivo and in vitro systems. Most striking is the role of retinoic acid as a morphogenic substance in vertebrate limb development, but equally important is its role in the maintenance of epithelial integrity in most superficial linings of the body. The similarity of the mode of action of retinoids to that of the steroid and thyroid hormones has recently been demonstrated with the discovery of the nuclear receptors for retinoic acid, which belong to the steroid/thyroid hormone receptor superfamily. These receptors act as transcriptional activators by binding as heterodimers to specific nucleotide sequences in the response elements of target genes. Response elements for retinoic acid have so far been identified for the rat growth hormone and phosphoenolpyruvate carboxykinase, the mouse complement H and laminin B1, the human and mouse retinoic acid receptor beta, the human osteocalcin, and the human alcohol dehydrogenase genes. The retinoic acid response element (RARE) for the rat growth hormone gene is also a thyroid hormone response element (TRE), and the AP-1 binding site of the human osteocalcin promoter is also a vitamin D response element (VDRE) and a RARE. Both these elements are palindromic. Other RAREs have a direct repeat configuration of the half-site motif AGGTCA separated by five nucleotides (AGGTCA xxxxx AGGTCA). The direct repeat arrangement of the same core motif AGGTCA separated by three or four nucleotides becomes a VDRE or TRE, respectively. A point mutation has been identified in the RAR alpha gene of embryonal carcinoma cells resistant to retinoic acid. In addition to the three retinoic acid receptors (alpha, beta, gamma) belonging to the steroid/thyroid hormone receptor superfamily, a second class of retinoid receptors (RXR) alpha, beta, gamma has also been characterized and its relatedness to a gene, XR2C, of the locus ultraspiracle required for pattern formation in Drosophila has been established. That would suggest that both vertebrates and invertebrates may require similar transcriptional activators during morphogenesis. An RXRE has been identified in the CRBPII gene promoter and it contains five repeats of the canonical sequence AGGTCA separated by one nucleotide. The importance of retinoids, both as chemopreventive agents of tumorigenesis and potent differentiation inducers of neoplastic cells, can only be emphasized by the recent finding that the t(15;17) (q21- q11-22) translocation, specifically associated with acute promyelocytic leukemia, also causes translocation of the retinoic acid receptor alpha gene and its fusion with with a new locus, myl, of unknown function.(ABSTRACT TRUNCATED AT 250 WORDS)
Specific Intermediates in the Folding Reactions of Small Proteins and the Mechanism of Protein Folding (1982)

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More
Localized Inhibition of Protein Phosphatase 1 by NUAK1 Promotes Spliceosome Activity and Reveals a MYC-Sensitive Feedback Control of Transcription (2020)

Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes.
Evidence for ADP-ribosylation factor (ARF) as a regulator of in vitro endosome-endosome fusion. (1992)

We have used an in vitro endosome fusion assay, recombinant ARF, synthetic peptides, and guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) to study the role of ARF during endocytosis. Previous work has shown that GTP gamma S stimulates in vitro endosome fusion in dilute cytosol (less than 0.5 mg/ml) but inhibits fusion in concentrated cytosol (greater than 1.0 mg/ml). Two peptides corresponding to the NH2-terminal 16 amino acids of human ARF1 and ARF4 blocked GTP gamma S stimulation of fusion in dilute cytosol and reversed GTP gamma S inhibition of fusion in concentrated cytosol. The addition of recombinant human ARF1 to endosomes in dilute or concentrated cytosol resulted in GTP gamma S-dependent inhibition of fusion. Only the myristoylated form of ARF inhibited fusion. The NH2-terminal ARF1 peptide reversed inhibition by recombinant ARF1. Preincubation experiments showed that endosomes could form an ARF-resistant intermediate during the fusion process. Western blot analysis revealed clathrin-coated vesicles extracted with detergent retained ARF. The results suggest that ARF is involved in both the stimulatory and inhibitory effects of GTP gamma S in dilute and concentrated cytosol, respectively. Furthermore, myristoylation, the NH2-terminal domain, and binding to GTP appear to be critical for ARF activity during an early prefusion step required for endocytosis.
A simple laterally tapered waveguide for low-loss coupling to single-mode fibers (1993)

Low-loss coupling between semiconductor photonic devices and single-mode fibers is achieved using a simple InP/InGaAsP tapered waveguide. The proposed simple structure has a small and nearly square guiding core at its output facet. In this structure, the output field has a non-Gaussian profile, but low-pass filter coupling can be achieved by optimizing the design of the guiding core sizes. The waveguide is composed of a laterally tapered InGaAsP guiding layer and an InP cladding region on an InP substrate, facilitating integration of the waveguide with active devices using conventional processes. The waveguide is shown to have a total insertion loss of 2.6 dB, including a coupling loss of 0.9 dB and large +or-2.5- mu m misalignment tolerance in lateral and vertical directions with single-mode filters.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Differential coupling of G‐protein‐linked receptors to Ca2+ mobilization through inositol(1,4,5)trisphosphate or ryanodine receptors in cerebellar granule cells in primary culture (1999)

Rat cerebellar granule cells in primary culture possess muscarinic, metabotropic glutamatergic, histaminergic and alpha-adrenergic receptors which couple to phosphoinositide-specific phospholipase C. We have determined the ability of these receptors to elevate inositol(1,4,5)trisphosphate and to release intracellular calcium, in order to establish the correlation between these two responses. In resting cerebellar granule cells, only the muscarinic agonist carbachol evoked significant increases in both inositol(1,4, 5)trisphosphate and cytoplasmic free Ca2+. Mild depolarization (20 mM KCl) enhanced inositol(1,4,5)trisphosphate elevation by carbachol and histamine, but not by noradrenaline or the metabotropic glutamate agonist 1S,3R ACPD. In contrast, Ca2+-release responses were modified differently by 20 mM KCl-depolarization: the responses to carbachol, histamine and 1S,3R ACPD, but not the responses to noradrenaline, were markedly enhanced. The contribution of ryanodine-sensitive Ca2+-release channels (ryanodine receptors) to the calcium release signal in depolarized cells was determined. Ryanodine (10 microM) inhibited most effectively the cytoplasmic Ca2+ elevation evoked by 1S,3R ACPD (> 90%), while Ca2+ release upon stimulation by carbachol and histamine was only inhibited by approximately 60% and remained larger than in the absence of KCl. Our data are consistent with a specific coupling between metabotropic glutamate receptors and ryanodine-sensitive Ca2+-release channels which may not require generation of inositol(1, 4,5)trisphosphate.
Angular distribution of particles sputtered from metals and alloys (1988)

The angular distributions of atoms sputtered from pure Cu and Be as well as Cu98Be2, Cu71Zn29, Co3Au, and WSi2.3 were investigated for bombardment with Ar+ ions of 250 eV and 2 keV under normal incidence. Between polar emission angles θ=0° and 60°, for the higher bombarding energy all observed angular distributions look very much alike and follow essentially a cos3 θ law. For the low bombarding energy, however, significant differences between the angular distributions of the alloy constituents are found. The effect, which is most pronounced for CuBe, seems to scale with the atomic mass in the way that the lower mass particles are sputtered preferentially along the surface normal.
Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein (1987)

We have genetically replaced the diphtheria toxin receptor binding domain with a synthetic gene encoding interleukin-2 (IL-2) and a translational stop signal. The diphtheria toxin-related T-cell growth factor fusion gene encodes a 70 586-d polypeptide, pro-IL-2-toxin. The mature form of IL-2-toxin has a deduced mol. wt of 68,086 and is shown to be exported to the periplasmic compartment of Escherichia coli (pABI508), and contain immunologic determinants intrinsic to both its diphtheria toxin and IL-2 components. IL-2-toxin has been purified from periplasmic extracts of recombinant strains of E. coli (pABI508) by immunoaffinity chromatography using immobilized anti-IL-2. The purified chimeric toxin is shown to selectively inhibit protein synthesis in IL-2 receptor bearing targeted cells, whereas cell lines which do not express the IL-2 receptor are resistant to IL-2-toxin action.
Blood‐brain barrier transport using a high affinity, brain‐selective VNAR antibody targeting transferrin receptor 1 (2020)

Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. We established a functional selection method to identify high affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB. A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used for in vitro selection against recombinant human TfR1 ectodomain (rh-TfR1-ECD) followed by in vivo selection in mouse for brain parenchyma penetrating antibodies. TXB2 VNAR was identified as a high affinity, species cross-reactive VNAR antibody against TfR1-ECD that does not compete with transferrin or ferritin for receptor binding. IV dosing of TXB2 when fused to human Fc domain (TXB2-hFc) at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1-positive neurons. Likewise, IV dosing of TXB2-hFc fused with neurotensin (TXB2-hFc-NT) at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2-hFc did not elicit any acute adverse reactions, bind, or deplete circulating reticulocytes or reduce BBB-expressed endogenous TfR1 in mice. There was no evidence of target-mediated clearance or accumulation in peripheral organs except lung. In conclusion, TXB2 is a high affinity, species cross-reactive, and brain-selective VNAR antibody to TfR1 that rapidly crosses the BBB and exhibits a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.
Microfluidic-Enabled Intracellular Delivery of Membrane Impermeable Inhibitors to Study Target Engagement in Human Primary Cells (2017)

Biochemical screening is a major source of lead generation for novel targets. However, during the process of small molecule lead optimization, compounds with excellent biochemical activity may show poor cellular potency, making structure-activity relationships difficult to decipher. This may be due to low membrane permeability of the molecule, resulting in insufficient intracellular drug concentration. The Cell Squeeze platform increases permeability regardless of compound structure by mechanically disrupting the membrane, which can overcome permeability limitations and bridge the gap between biochemical and cellular studies. In this study, we show that poorly permeable Janus kinase (JAK) inhibitors are delivered into primary cells using Cell Squeeze, inhibiting up to 90% of the JAK pathway, while incubation of JAK inhibitors with or without electroporation had no significant effect. We believe this robust intracellular delivery approach could enable more effective lead optimization and deepen our understanding of target engagement by small molecules and functional probes.
Expression of bovine vitamin K-dependent carboxylase activity in baculovirus-infected insect cells. (1993)

A vitamin K-dependent carboxylase has recently been purified from bovine liver microsomes and candidate cDNA clones have been isolated. Definitive identification of the carboxylase remains circumstantial since expression of candidate carboxylase cDNAs in mammalian cells is confounded by the presence of endogenous carboxylase activity. To overcome this problem, a recombinant strain of baculovirus (Autographa california nuclear polyhedrosis virus, AcMNPV) encoding a putative carboxylase (vbCbx/AcMNPV) was used to infect Sf9 insect cells, which we demonstrate have no endogenous carboxylase activity. Infection with vbCbx/AcMNPV conferred vitamin K-dependent carboxylase activity to Sf9 insect cells. Carboxylase activity was demonstrated to peak 2-3 days after infection with vbCbx/AcMNPV. Metabolic radiolabeling with L-[35S]methionine revealed that the 90-kDa recombinant protein is the major protein synthesized at the time of peak activity after infection. An anti-peptide antibody directed against residues 86-99 reacted with bovine liver carboxylase on Western blot analysis and immunoprecipitated recombinant carboxylase from infected Sf9 microsomal protein preparations. Since Sf9 insect cells lack endogenous vitamin K-dependent carboxylase activity, expression of carboxylase activity in Sf9 insect cells with recombinant baculovirus demonstrates that the protein encoded by this cDNA is a vitamin K-dependent gamma-glutamyl carboxylase.
The protection given by pilus and whole cell vaccines of Bacteroides nodosus strain 198 against ovine foot‐rot induced by strains of different serogroups (1985)

A highly purified pilus vaccine prepared from cells of Bacteroides nodosus strain 198 provided a high level of protection against homologous challenge and small, not statistically significant, levels of protection against challenge with 4 other strains each from different serogroups. In a second experiment, a partially purified pilus vaccine from strain 198 induced significant immunity to 1 of 4 heterologous strains which were different from those used in the first experiment. In a third experiment a strain 198 whole cell vaccine produced significant immunity against 3 of 6 heterologous strains used in the first 2 experiments. There was no obvious relationship between the colony type, degree of piliation and level of cross-protection obtained against a particular strain. The results provide further evidence that immunogens associated with, but distinct from, the pilus are involved in cross-protection and that cross-protective antigens are common to some, but not all, strains.
Probabilistic character disambiguation for reduced keyboards using small text samples (1992)

Reduced keyboards are text typing keyboards which contain fewer than 26 alphabetic keys, and which may therefore be accessed and used by certain physically disabled persons more easily than a conventional “QWERTY” typing keyboard. Automatic character disambiguation systems enable text to be typed upon a reduced keyboard with a keying efficiency approaching one key/character, despite the fact that each key represents more than one alphabetic character. Existing disambiguation systems typically use probabilistic models of character sequences (n-grams) from representative text samples to predict the next character, and hence disambiguate among the different characters on each key. N-grams for such disambiguation models have been extracted previously from large (1 million word) text corpora. The research reported here shows that a much smaller corpus of limited domain can be used with similar results, thus facilitating development of disambiguation systems by eliminating the need for a large corpus. Four reduced keyboard layouts are compared, three of which were used in earlier research on character disambiguation in the Dutch and English languages, and a fourth based on character frequency, which achieves similar efficiency to the first three. Models of different order are compared (the “order” of the model being determined by the length of the longest n-grams in it), the principal result being that, while higher-order models (containing long n-grams) give better performance than lower-order models (which contain only short n-grams), lower-order n-grams can contribute significantly to the disambiguation performance of a higher-order model, and should therefore be included in order to maximize disambiguation efficiency.
Top Ten Challenges for the Planning Minister for 2007 (2007)

PIA members were asked to state immediate, short-term issues and two most important long-term issues affecting planning in Victoria that needs to be attended to by the new Minister for Planning. The need to achieve an effective and efficient planning of development in Victoria based on good governance and economic, social and environmental sustainability seems to be the top priority.
Starch deposition in storage organs and the importance of nutrients and external factors (1998)

Abstract Starch is an important agricultural product deposited in vegetative and reproductive storage organs (sinks) of various crop species. Starch yield may in some cases be limited by photosynthesis, i.e. source‐limited. This is particularly true for starch synthesized in potato tubers. Here, the physiological sink is characterized by a symplastic phloem unloading path. In reproductive storage tissues (seeds), however, photosynthates must pass the apoplast on their path from phloem unloading to the storage cell. In cereal grains, phloem unloading of sucrose and poslunloading processes rather than photosynthesis may thus control starch synthesis (sink‐limited). Various limiting steps along the path of photosynthate movement from the phloem to the storage cells are considered. The primary organic carbon for starch synthesis is sucrose. Sucrose delivered to the storage cell is metabolized to UDPglucose and fructose by means of sucrose synthase activity. Concerning sucrose breakdown the role of cell‐wall bound invertase is not well defined. Competition for UDPglucose consumed for growth or storage may be a crucial process in photosynthate partitioning. High starch yields of crops require an undisturbed growth of the sink organ and an optimal filling of sink amyloplasts with starch. The most important form of organic carbon imported into amyloplasts of storage organs (cereal grain and potato tuber) and used for starch synthesis is glucose 1‐phosphate. It is still to be clarified whether the rate of glucose 1‐phosphate absorption has a direct impact on starch yield. In cereals, the total amount of starch accumulated depends significantly on the duration of grain filling. Ample nutrient and water supply at the post‐anthesis stage prolongs the period of grain filling and hence favours starch production. High temperature reduces the activity of soluble starch synthase with negative consequences for starch accumulation. The biochemical and physiological implications of these stress factors are discussed. Recently, successful transgenic manipulations of starch synthesis in crop plants have increased starch yield.
Gene targeting in the mouse (1994)

Mice with alterations to specific endogenous genes can be produced by gene targeting in embryonic stem cells. The field has developed rapidly over the past decade, so that large numbers of mice with different gene deficiencies have been generated. Knockout mice provide an ideal opportunity to analyse the function of individual mammalian genes and to model a range of human inherited disorders. This powerful approach has also identified numerous examples of gene redundancy and has highlighted the need to consider metabolic differences between man and mouse in disease modelling. More sophisticated gene-targeting methods are now being used to introduce subtle gene alterations. In the future, more refined genetic analysis and genome, rather than individual gene, alterations will be achieved by incorporating site-specific recombination into targeting strategies. Gene targeting could also make a contribution to improved protocols for gene therapy.
Automated control in cloud computing (2009)

With advances in virtualization technology, virtual machine services offered by cloud utility providers are becoming increasingly powerful, anchoring the ecosystem of cloud services. Virtual computing services are attractive in part because they enable customers to acquire and release computing resources for guest applications adaptively in response to load surges and other dynamic behaviors. ``Elastic'' cloud computing APIs present a natural opportunity for feedback controllers to automate this adaptive resource provisioning, and many recent works have explored feedback control policies for a variety of network services under various assumptions.
Cubic nonlinear optical effects in deoxyribonucleic acid (DNA) based materials containing chromophores (2007)

Third-order nonlinear optical properties were investigated for the system incorporating the Disperse Red 1 dye and the deoxyribonucleic acid - cetyltrimethylammonium complex (DNA-CTMA). The interaction of the dye with the DNA chains does not lead to major changes of the nonlinear optical effects due to the DR1 dye. Polarization dependences of the nonlinear absorption in this system reveal, however, some indications that the interactions may lead to ordering of the dye molecules against the DNA chains.