gebhart/patrepeval huggingface dataset:
Design of [R-(Z)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere (1997)

Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
Photocatalytic reduction of CO2: a brief review on product analysis and systematic methods (2012)

Photocatalytic reduction of CO2 for fuels production by using solar energy is an attractive process to address both energy and environmental issues. Currently, it is still a great challenge to control the CO2 reduction pathways. As a result, many possible chemicals could be present in the reaction products, ranging from CO, CH4 to higher alkanes in the gas phase, and oxygenates in the liquid phase such as alcohols, aldehydes and carboxylic acids. A thorough and accurate determination of products is of critical importance for the evaluation of photocatalyst performance. However to date, only very few studies have paid attention to the screening of reduction products, and more comprehensive and standard analysis methods are not yet reported in the literature. In this review, different analysis methods reported so far are summarized. At the same time, we also developed one set of techniques involving (1) the design of a two-channel-three-detector gas chromatography system for gaseous product analysis in the presence of a high concentration of CO2 and alcohols analysis in the liquid phase, and (2) a high performance liquid chromatography system for the analysis of aldehydes and carboxylic acids in the liquid phase. The effect of commonly used organic additives as well as alkaline conditions on liquid phase analysis was also investigated for the first time.
A nuclear export signal is essential for the cytosolic localization of the Ran binding protein, RanBP1. (1996)

RanBP1 is a Ran/TC4 binding protein that can promote the interaction between Ran and beta-importin /beta-karyopherin, a component of the docking complex for nuclear protein cargo. This interaction occurs through a Ran binding domain (RBD). Here we show that RanBP1 is primarily cytoplasmic, but the isolated RBD accumulates in the nucleus. A region COOH-terminal to the RBD is responsible for this cytoplasmic localization. This domain acts heterologously, localizing a nuclear cyclin B1 mutant to the cytoplasm. The domain contains a nuclear export signal that is necessary but not sufficient for the nuclear export of a functional RBD In transiently transfected cells, epitope-tagged RanBP1 promotes dexamethasone-dependent nuclear accumulation of a glucocorticoid receptor-green fluorescent protein fusion, but the isolated RBD potently inhibits this accumulation. The cytosolic location of RanBP1 may therefore be important for nuclear protein import. RanBP1 may provide a key link between the nuclear import and export pathways.
Long‐term synaptic enhancement and short‐term potentiation in rat fascia dentata act through different mechanisms (1982)

1. The component processes contributing to post-activation change in synaptic efficacy in the perforant pathway to the fascia dentata were studied in rats under sodium pentobarbitone anaesthesia.2. With low stimulus strength, which activated only a relatively small number of perforant path fibres, repetitive stimulation led to effects which had very similar characteristics to those observed at neuromuscular synapses under similar conditions. Paired shocks resulted in a short ( approximately 100 ms) facilitation superimposed on a depression, possibly due to depletion of available transmitter, which recovered more slowly ( approximately 4 s). Short trains of stimuli at 125-250 Hz led to a longer lasting increase in synaptic strength which decayed to control levels with a double exponential time course. The two exponential components behaved like augmentation and potentiation at neuromuscular synapses, with time constants at 33 degrees C of about 5 s and about 90 s respectively.3. High-intensity stimulus trains of identical frequency and duration led to an enhancement of synaptic strength which lasted for longer than 30 min.4. The paired shock depletion effect was increased in direct proportion to the amount of augmentation and potentiation present following low-intensity stimulus trains. Following high-intensity trains the paired shock depletion effect was increased by the same amount, and recovered with the same time course as following low-intensity stimulus trains, even though there remained a significant enhancement of the synaptic response.5. The results are interpreted as indicating that augmentation and potentiation are due to an increase in the probability of transmitter release whereas long-term enhancement acts through some other, as yet undetermined, mechanism. Following high-intensity stimulation all three processes are activated.
Reasoning With Neural Tensor Networks for Knowledge Base Completion (2013)

Knowledge bases are an important resource for question answering and other tasks but often suffer from incompleteness and lack of ability to reason over their dis-crete entities and relationships. In this paper we introduce an expressive neu-ral tensor network suitable for reasoning over relationships between two entities. Previous work represented entities as either discrete atomic units or with a single entity vector representation. We show that performance can be improved when en-tities are represented as an average of their constituting word vectors. This allows sharing of statistical strength between, for instance, facts involving the “Sumatran tiger ” and “Bengal tiger. ” Lastly, we demonstrate that all models improve when these word vectors are initialized with vectors learned from unsupervised large corpora. We assess the model by considering the problem of predicting additional true relations between entities given a subset of the knowledge base. Our model outperforms previous models and can classify unseen relationships in WordNet and FreeBase with an accuracy of 86.2 % and 90.0%, respectively. 1
Do Alterations in Intercellular Coupling Play a Role in Cardiac Contractile Dysfunction? (1998)

yocardial stunning 1 and hibernation 2 have been subjects of intense laboratory and clinical investigations to elucidate mechanisms responsible for contractile dysfunction after transient ischemia or chronic hypoperfusion. Considerable evidence has implicated the generation of oxygen-derived free radicals and derangements in myocardial energy metabolism and excitation-contraction coupling as major contributors to the pathogenesis of myocardial stunning and hibernation. Despite enormous progress in this area, however, our understanding of the cellular pathophysiology of contractile dysfunction in ischemic heart disease remains incomplete.
Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer (2010)

At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
Up-regulated cytoplasmic expression, with reduced membranous distribution, of thesrc substrate p120ctn in gastric carcinoma (1999)

p120(ctn) is a substrate of the tyrosine kinase pp60 src. Tyrosine kinases such as src localize to the adherens junctions and phosphorylate junctional proteins in both normal and transformed cells.(1) p120(ctn) forms a complex with E-cadherin at the adherens junction and is phosphorylated by ligands such as epidermal growth factor receptor as well as pp60 src. Phosphorylation of p120(ctn) has been shown to correlate with cell transformation. The aim of this study was to investigate in vivo expression of p120(ctn) in gastric carcinoma and to examine any relationship to pathological characteristics and patient survival. Immunohistochemical staining for p120(ctn) was performed in 68 gastric carcinoma specimens (19 diffuse, 49 intestinal type), in 22 lymph node metastases, and in gastric mucosal biopsies from 16 patients with gastric dysplasia and ten healthy controls. Up-regulation of p120(ctn) cytoplasmic staining was seen in six (37 per cent) of the gastric dysplasia cases and in 45 (66 per cent) tumours (89 per cent of diffuse and 57 per cent of intestinal tumours). Loss of membranous distribution of staining for p120(ctn) was seen in 22 (32 per cent) tumours (52 per cent of diffuse and 24 per cent of intestinal tumours). The staining pattern in the primary tumour showed no correlation with tumour type, grade, or stage, or patient survival. Of 22 lymph node metastases examined, 13 (60 per cent) showed loss of membranous staining. In conclusion, staining for p120(ctn) in gastric carcinoma and dysplasia revealed marked up-regulation of cytoplasmic staining, sometimes associated with reduced membranous expression. Up-regulation of expression of p120(ctn) has not previously been described in human epithelial malignancy. The significance of these findings is uncertain, but they may reflect a change in tyrosine kinase signal transduction pathways, and a role for p120(ctn) in ligand-induced mitogenic signalling and cell transformation.
A pervasive system for real-time blood pressure monitoring (2013)

Tese de Mestrado Integrado. Engenharia Electrotecnica e de Computadores. Faculdade de Engenharia. Universidade do Porto. 2013
The space cost of lazy reference counting (2004)

Reference counting memory management is often advocated as a technique for reducing or avoiding the pauses associated with tracing garbage collection. We present some measurements to remind the reader that classic reference count implementations may in fact exhibit longer pauses than tracing collectors.We then analyze reference counting with lazy deletion, the standard technique for avoiding long pauses by deferring deletions and associated reference count decrements, usually to allocation time. Our principal result is that if each reference count operation is constrained to take constant time, then the overall space requirements can be increased by a factor of Ω(R) in the worst case, where R is the ratio between the size of the largest and smallest allocated object. This bound is achievable, but probably large enough to render this design point useless for most real-time applications.We show that this space cost can largely be avoided if allocating an $n$ byte object is allowed to additionally perform O(n) reference counting work.
Passive Transfer of Antibodies Protects Immunocompetent and Immunodeficient Mice against Lethal Ebola Virus Infection without Complete Inhibition of Viral Replication (2001)

Ebola hemorrhagic fever is a severe, usually fatal illness caused by Ebola virus, a member of the filovirus family. The use of nonhomologous immune serum in animal studies and blood from survivors in two anecdotal reports of Ebola hemorrhagic fever in humans has shown promise, but the efficacy of these treatments has not been demonstrated definitively. We have evaluated the protective efficacy of polyclonal immune serum in a mouse model of Ebola virus infection. Our results demonstrate that mice infected subcutaneously with live Ebola virus survive infection and generate high levels of anti-Ebola virus immunoglobulin G (IgG). Passive transfer of immune serum from these mice before challenge protected upto 100% of naive mice against lethal Ebola virus infection. Protection correlated with the level of anti-Ebola virus IgG titers, and passive treatment with high-titer antiserum was associated with a delay in the peak of viral replication. Transfer of immune serum to SCID mice resulted in 100% survival after lethal challenge with Ebola virus, indicating that antibodies alone can protect from lethal disease. Thus antibodies suppress or delay viral growth, provide protection against lethal Ebola virus infection, and may not require participation of other immune components for protection.
The cryopreservation of human embryonic stem cells (2005)

hES (human embryonic stem) cells hold tremendous potential in the newly emerging field of regenerative medicine, in addition to being a useful tool in basic scientific research and for pharmacological and cytotoxicity screening. However, an essential prerequisite for the future widespread application of hES cells are the development of efficient cryopreservation protocols to facilitate their storage and transportation. This review summarizes the current state of progress in the field of hES cell cryopreservation, by critically examining and comparing the various cryopreservation protocols that have been developed. These can be classified into two categories: (1) conventional slow-cooling protocols and (2) vitrification protocols. Previously, the application of slow-cooling cryopreservation protocols to freely-suspended hES cell clumps yielded extremely dismal results. However, a recent study demonstrated that post-thaw survivability was markedly improved when slow-cooling protocols were applied instead to adherent hES colonies. Vitrification protocols have been shown to be much better than the standard slow-cooling protocol for the cryopreservation of freely suspended hES cell clumps. However, no study has yet attempted to apply vitrification protocols to adherent hES colonies. It must be noted that vitrification protocols are extremely labour-intensive and tedious to perform manually. Additionally, the use of cryostraws in vitrification protocols is unsuited for handling bulk quantities of hES cells, in addition to posing serious technical difficulties in developing machine automation for cryopreservation. These are some of the major challenges that have to be overcome if further progress is to be made in this field.
Incidence of weight loss in head and neck cancer patients on commencing radiotherapy treatment at a regional oncology centre (1999)

The aim of this prospective study was to investigate the incidence of weight loss in head and neck cancer patients on commencing radiotherapy treatment at a regional oncology centre. Of the 100 patients included in the study, 33% presented with carcinoma of the larynx. Fifty-seven per cent of patients had lost weight on commencing treatment. A mean weight loss of 6.5 kg, equating to approximately 10% of body weight, was reported. A significant number of patients experienced a dry and/or sore mouth, had difficulty masticating and swallowing food, had altered taste perception, were missing meals or had symptoms of uncontrollable nausea and constipation. Since radiotherapy treatment may further limit oral intake, it is essential that dietetic intervention is addressed for all head and neck cancer patients and incorporated into the treatment plan on diagnosis before definitive management commences.
Analysis of the expression profiles of cytokines and cytokine-related genes during the progression of breast cancer growth in mice (2009)

Cytokines are a protein family of regulatory factors derived from tumors and their environmental components that contribute to the growth, invasion and metastasis of breast cancer. However, the way in which tumor progression and cytokines regulate each other is not well understood. In this study, we used an oligoDNA microarray to assess the kinetic expression profile of cytokine genes in tumor tissues and lymph nodes during the progression of tumor growth in mice that had been subcutaneously challenged with breast adenocarcinoma SB5b cells. Our results demonstrated that IL-15, IL-17, IL-18 and IL-18 binding protein (IL-18bp), which are associated with inflammation, were increased in tumor tissues. Conversely, chemokines and their receptors, including CXCR4/CXCL12, CCR7/CCL21, CCL9, CXCL9 and CCL12, were overexpressed in lymph nodes during tumor growth. Furthermore, RT-PCR and Western blot analysis revealed that IL-18, a pro-angiogenic factor in tumors, was up-regulated in tumor tissues. Interestingly, CCR3, IL-1R2, SOCS and IL-20 were up-regulated in tumor tissues, but down-regulated in lymph nodes during tumor growth. This result suggests that the expression of cytokines and cytokine-related genes was differentially regulated, which resulted in a beneficial effect for tumor progression.
Temporal phase unwrapping: application to surface profiling of discontinuous objects (1997)

The recently proposed technique of temporal phase unwrapping has been used to analyze the phase maps from a projected-fringe phase-shifting surface profilometer. A sequence of maps is acquired while the fringe pitch is changed; the phase at each pixel is then unwrapped over time independently of the other pixels in the image to provide an absolute measure of surface height. The main advantage is that objects containing height discontinuities are profiled as easily as smooth ones. This contrasts with the conventional spatial phase-unwrapping approach for which the phase jump across a height discontinuity is indeterminate to an integral multiple of 2pi. The error in height is shown to decrease inversely with the number of phase maps used.
Macrocyclization equilibria in polycycloolefins (1988)

Abstract Macrocyclization equilibrium data from metathesis reactions of cycloolefins (cyclobutene, cyclooctene, and cyclododecene) are compared with predictions of a novel, simple rotational isomeric state (RIS) scheme for polyalkenes with at least three single bonds between adjacent double bonds. The predictions agree with experiment within the combined experimental errors, supporting the conformational models and confirming that macrocyclization equilibrium has indeed been established in the metathesis reactions.
Developmental and Growth Temperature Regulation of Two Different Microsomal [omega]-6 Desaturase Genes in Soybeans (1996)

The polyunsaturated fatty acid content is one of the major factors influencing the quality of vegetable oils. Edible oils rich in monounsaturated fatty acid provide improved oil stability, flavor, and nutrition for human and animal consumption. In plants, the microsomal omega-6 desaturase-catalyzed pathway is the primary route of production of polyunsaturated lipids. We report the isolation of two different cDNA sequences, FAD2-1 and FAD2-2, encoding microsomal omega-6 desaturase in soybeans and the characterization of their developmental and temperature regulation. The FAD2-1 gene is strongly expressed in developing seeds, whereas the FAD2-2 gene is constitutively expressed in both vegetative tissues and developing seeds. Thus, the FAD2-2 gene-encoded omega-6 desaturase appears to be responsible for production of polyunsaturated fatty acids within membrane lipids in both vegetative tissues and developing seeds. The seed-specifically expressed FAD2-1 gene is likely to play a major role in controlling conversion of oleic acid to linoleic acid within storage lipids during seed development. In both soybean seed and leaf tissues, linoleic acid and linolenic acid levels gradually increase as temperature decreases. However, the levels of transcripts for FAD2-1, FAD2-2, and the plastidial omega-6 desaturase gene (FAD 6) do not increase at low temperature. These results suggest that the elevated polyunsaturated fatty acid levels in developing soybean seeds grown at low temperature are not due to the enhanced expression of omega-6 desaturase genes.
Methionine Aminopeptidase 2 Inhibition Is an Effective Treatment Strategy for Neuroblastoma in Preclinical Models (2005)

Tumor vascularity is correlated with an aggressive disease phenotype in neuroblastoma, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. We previously showed that the antiangiogenic compound TNP-470, an irreversible methionine aminopeptidase 2 (MetAP2) inhibitor, suppressed local and disseminated human neuroblastoma growth rates in murine models but had significant associated toxicity at the effective dose. We have recently shown that a novel, reversible MetAP2 inhibitor, A-357300, significantly inhibits CHP-134-derived neuroblastoma s.c. xenograft growth rate with a treatment-to-control (T/C) ratio at day 24 of 0.19 (P < 0.001) without toxicity. We now show that the combination of A-357300 with cyclophosphamide at the maximal tolerated dose sustained tumor regression with a T/C at day 48 of 0.16 (P < 0.001) in the CHP-134 xenograft model. A-357300 also significantly inhibited establishment and growth rate of hematogenous metastatic deposits following tail vein inoculation of CHP-134 cells and increased overall survival (P = 0.021). Lastly, A-357300 caused regression of established tumors in a genetically engineered murine model with progression-free survival in five of eight mice (P < 0.0001). There was no evidence of toxicity. These data show that MetAP2 may be an important molecular target for high-risk human neuroblastomas. We speculate that the growth inhibition may be through both tumor cell intrinsic and extrinsic (antiangiogenic) mechanisms. The potential for a wide therapeutic index may allow for treatment strategies that integrate MetAP2 inhibition with conventional cytotoxic compounds.
Exosome Targeting of Tumor Antigens Expressed by Cancer Vaccines Can Improve Antigen Immunogenicity and Therapeutic Efficacy (2011)

MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans.