gebhart/patrepeval huggingface dataset:
Relaxin as a New Hormone* (1982)

RELAXIN was described as a hormone some 55 years ago but despite some persistent pioneering work, passed into relative obscurity for a long period of time. The present status of relaxin is such that it directly impinges on reproductive endocrinology and perhaps on those endocrinologists who appreciate that connective tissue metabolism is controlled by hormones and who wish to share in the task of refurbishing a hormone long left on the shelf. There is no question but that work on relaxin was at a low ebb for 40 years after its initial discovery by Frederick Hisaw in 1926. Certainly part of the resurgence of work on relaxin in the early 1970s is identified with initiatives of Dr. Steinetz, and there is now a sufficient body of knowledge to warrant its integration into general endocrinology. A documentation of the reasons for the neglect of relaxin would make an interesting exercise in the history of endocrinology but is outside the scope of this review. I mention my perceptions below because they may become applicable to other fields of endeavor in endocrinology as reductions in Federal funding for research encourage scientists to look to the private sector for support.
Signal Amplification Using “Spot-on-a-Chip” Technology for the Identification of Proteins via MALDI-TOF MS (2000)

The presented "spot-on-a-chip" technology enables easy enrichment of samples in the low nanomolar (1-5 nM) range and provides a fast and reliable automated sample preparation method for performing matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis with high sensitivity and throughput. Through microdispensing, which allows accurate deposition of 60-pL droplets, dilute samples were enriched by making multiple droplet depositions in nanovials. The sample was confined to a defined spot area (300 x 300 microm), and multiple depositions increase the surface density of analyte in the nanovial, thereby providing detection of low attomole levels. The impact of the nanovial geometry with respect to the MALDI-TOF MS resolution for peptides deposited in the microfabricated silicon vials was investigated and the optimal geometry and size were determined. The spot-on-a-chip technology, that is, the combination of microdispensing, micromachined silicon nanovials and on-spot enrichment provides a signal amplification of at least 10-50 times as compared to an ordinary sample preparation. The linearity of the enrichment effect is shown by the analysis of a peptide mixture at the 5 nM level. The signal amplification provided by the spot-on-a-chip enrichment is demonstrated by the analysis of relevant biological samples, interleukin-8 from a spiked cell supernatant, and by successful protein identification of an excised spot from a high-sensitivity silver-stained two-dimensional electrophoresis gel separation.
Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the FcγRII receptor (1995)

The mechanisms by which a stimulatory monoclonal antibody (mAb), called mAb F11, induces granular secretion and aggregation in human platelets have been characterized. Fab fragments of mAb F11, as well as an mAb directed against the platelet Fc gamma RII receptor (mAb IV.3) were found to inhibit mAb F11-induced platelet secretion and aggregation, indicating that the mAb F11 IgG molecule interacts with the Fc gamma RII receptor through its Fc domain and with its own antigen through its Fab domain. The mAb F11 recognized two platelet proteins of 32 and 35 kDa on the platelet membrane surface, as identified by Western blot analysis. We purified both proteins from human platelet membranes using DEAE-Sepharose chromatography followed by mAb F11 affinity chromatography. When added to platelet-rich plasma, the purified proteins dose-dependently inhibited mAb F11-induced platelet aggregation. The purified protein preparation also competitively inhibited the binding of 125I-labelled mAb F11 to intact platelets. The N-terminal 26 amino acid sequences of both the 32 and 35 kDa proteins were identical and contained a single unblocked serine in the N-terminal position. When digested with N-glycanase, the 32 and 35 kDa proteins were converted into a single approximately 29 kDa protein, indicating that these two proteins are derived from the same core protein but differ in their degree of glycosylation. Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. Databank analysis of the N-terminal and internal amino acid sequences of the F11 antigen indicated that the N-terminal sequence exhibited the highest degree of similarity to the variable region of the alpha-chain of human T-cell receptors (TCR). In contrast, the F11 internal sequences did not exhibit any similarity to the TCR. Our results demonstrate that the F11 antigen is a novel platelet membrane surface glycoprotein which becomes cross-linked with the Fc gamma RII receptor when platelets are activated by the stimulatory mAb F11. These mechanisms may be relevant to the production of immune thrombocytopenia by platelet-activating antibodies.
Optimization of Critical Hairpin Features Allows miRNA-based Gene Knockdown Upon Single-copy Transduction (2014)

Gene knockdown using micro RNA (miRNA)-based vector constructs is likely to become a prominent gene therapy approach. It was the aim of this study to improve the efficiency of gene knockdown through optimizing the structure of miRNA mimics. Knockdown of two target genes was analyzed: CCR5 and green fluorescent protein. We describe here a novel and optimized miRNA mimic design called mirGE comprising a lower stem length of 13 base pairs (bp), positioning of the targeting strand on the 5' side of the miRNA, together with nucleotide mismatches in upper stem positions 1 and 12 placed on the passenger strand. Our mirGE proved superior to miR-30 in four aspects: yield of targeting strand incorporation into RNA-induced silencing complex (RISC); incorporation into RISC of correct targeting strand; precision of cleavage by Drosha; and ratio of targeting strand over passenger strand. A triple mirGE hairpin cassette targeting CCR5 was constructed. It allowed CCR5 knockdown with an efficiency of over 90% upon single-copy transduction. Importantly, single-copy expression of this construct rendered transduced target cells, including primary human macrophages, resistant to infection with a CCR5-tropic strain of HIV. Our results provide new insights for a better knockdown efficiency of constructs containing miRNA. Our results also provide the proof-of-principle that cells can be rendered HIV resistant through single-copy vector transduction, rendering this approach more compatible with clinical applications.
In Vitro Killing of Candida albicans by Fatty Acids and Monoglycerides (2001)

The susceptibility of Candida albicans to several fatty acids and their 1-monoglycerides was tested with a short inactivation time, and ultrathin sections were studied by transmission electron microscopy (TEM) after treatment with capric acid. The results show that capric acid, a 10-carbon saturated fatty acid, causes the fastest and most effective killing of all three strains of C. albicans tested, leaving the cytoplasm disorganized and shrunken because of a disrupted or disintegrated plasma membrane. Lauric acid, a 12-carbon saturated fatty acid, was the most active at lower concentrations and after a longer incubation time.
A Novel ets-related Transcription Factor, ERT/ESX/ESE-1, Regulates Expression of the Transforming Growth Factor-β Type II Receptor (1998)

A 2.5-kilobase cDNA clone that encodes a 371-amino acid novel transcription factor was isolated from a human placenta cDNA library using a yeast one-hybrid system. The novel ets-related transcription factor (ERT) showed a homology with the ETS DNA-binding domain. Using constructs of the transforming growth factor-beta (TGF-beta) type II receptor (RII) promoter linked to the luciferase gene, we have demonstrated that ERT activates transcription of the TGF-beta RII gene through the 5'-TTTCCTGTTTCC-3' response element spanning nucleotides +13 to +24 and multiple additional ETS binding sites between -1816 and -82 of the TGF-beta RII promoter. A specific interaction between ERT and the ETS binding sites was also demonstrated using an electrophoretic mobility shift assay. Deletion mapping of ERT protein suggests that the transactivation domain resides in the amino terminus while the DNA-binding domain is localized to the carboxyl-terminal region. Our results suggest that ERT might be a major transcription factor involved in the transcriptional regulation of the TGF-beta RII gene.
Oscillatory modes control using vibration blocking filter (2002)

A vibration blocking filter (VBF) design is proposed for the purpose of canceling poorly damped oscillatory mode of the system to be controlled. It improves precise positioning, eliminates unwanted system vibrations and does not require prohibitively high input and state values. The control structures with VBF have been analyzed and compared to other methods of dealing with undamped system oscillations. The design produces a FIR filter that has minimum "one norm" and requires negligible design and on-line computational effort.
Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan, on non-alcoholic steatohepatitis using FLS-ob/ob male mice (2012)

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a metabolic syndrome characterized by accumulation of hepatic fat, inflammation and varying degrees of fibrosis. Angiotensin (AT)-II has been reported to play a role in the establishment of NASH. This study examined the effects of an AT-II receptor blocker, irbesartan, on NASH using fatty liver Shionogi (FLS)-ob/ob male mice as the closest animal model of human metabolic syndrome-related NASH. Irbesartan (30 mg/kg/day) was orally administered to FLS-ob/ob mice for 12 weeks (irbesartan group). The effects of irbesartan on steatohepatitis were examined using factors including steatosis, fibrosis, inflammation and oxidative stress. The areas of hepatic fibrosis and hepatic hydroxyproline content were significantly lower in the irbesartan group compared to controls. The areas of α-smooth muscle actin-positivity and F4/80-positive cells were significantly decreased in the irbesartan group. The percentage of 8-hydroxy-2-deoxyguanosine (8-OHdG)-positive cells and 8-OHdG DNA content were significantly decreased in the irbesartan group compared to controls. Levels of RNA expression for procollagen I, transforming growth factor β1, tumor necrosis factor-α, sterol regulatory element-binding protein 1c and fatty acid synthase were significantly lower in the irbesartan group compared to controls. In contrast, the gene expression of peroxisome proliferator activated receptor-α was significantly higher in the irbesartan group compared to controls. Irbesartan administration improved hepatic steatosis and attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Kupffer cells and reducing oxidative stress.
Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling (2011)

Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD) and is observed in mutant amyloid precursor protein (APP) transgenic mouse models of familial AD. Melatonin is a potent antioxidant, can prevent toxic aggregation of Alzheimer's beta-amyloid (Aβ) peptide and, when taken long term, can protect against cognitive deficits in APP transgenic mice. To study the effects of melatonin on brain mitochondrial function in an AD model, APP/PS1 transgenic mice were treated for 1 month with melatonin. Analysis of isolated brain mitochondria from mice indicated that melatonin treatment decreased mitochondrial Aβ levels by two- to fourfold in different brain regions. This was accompanied by a near complete restoration of mitochondrial respiratory rates, membrane potential, and ATP levels in isolated mitochondria from the hippocampus, cortex, or striatum. When isolated mitochondria from untreated young mice were given melatonin, a slight increase in respiratory rate was observed. No such effect was observed in mitochondria from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. This restoration was partially blocked by melatonin receptor antagonists indicating melatonin receptor signaling is required for the full effect. Therefore, treatments that stimulate melatonin receptor signaling may be beneficial for restoring mitochondrial function in AD, and preservation of mitochondrial function may an important mechanism by which long term melatonin treatment delays cognitive dysfunction in AD mice.
Primer on Pulsed Electrical Field Ablation (2021)

Pulsed electrical field (PEF) energy is a promising technique for catheter ablation of cardiac arrhythmias. In this article, the key aspects that need to be considered for safe and effective PEF delivery are reviewed, and their impact on clinical feasibility is discussed. The most important benefit of PEF appears to be the ability to kill cells through mechanisms that do not alter stromal proteins, sparing sensitive structures to improve safety, without sacrificing cardiomyocyte ablation efficacy. Many parameters affect PEF treatment outcomes, including pulse intensity, waveform shape, and number of pulses, as well as electrode configuration and geometry. These physical and electrical characteristics must be titrated carefully to balance target tissue effects with collateral implications (muscle contraction, temperature rise, risk of electrical arcing events). It is important to note that any combination of parameters affecting PEF needs to be tested for clinical efficacy and safety. Applying PEF clinically requires knowledge of the fundamentals of this technology to exploit its opportunities and generate viable, durable health improvements for patients.
Effect of n-dodecane on Crypthecodinium cohnii fermentations and DHA production (2006)

The potential use of n-dodecane as an oxygen vector for enhancement of Crypthecodinium cohnii growth and docosahexaenoic acid (DHA) production was studied. The volumetric fraction of oxygen vector influenced the gas-liquid volumetric mass transfer coefficient k (L) a positively. The k (L) a increased almost linearly with the increase of volumetric fraction of n-dodecane up to 1%. The stirring rate showed a higher influence on the k (L) a than the aeration rate. The effects of this hydrocarbon on C. cohnii growth and DHA production were then investigated. A control batch fermentation without n-dodecane addition (CF) and a batch fermentation where n-dodecane 1% (v/v) was added (DF) were carried out simultaneously under the same experimental conditions. It was found that, before 86.7 h of fermentation, the biomass concentration, the specific growth rate, the DHA, and total fatty acids (TFA) production were higher in the CF. After this fermentation time, the biomass concentration, the DHA and TFA production were higher in the DF. The highest DHA content of biomass (6.14%), DHA percentage of TFA (51%), and DHA production volumetric rate r (DHA) (9.75 mg l(-1 )h(-1)) were obtained at the end of the fermentation with n-dodecane (135.2 h). The dissolved oxygen tension (DOT) was always higher in the DF, indicating a better oxygen transfer due to the oxygen vector presence. However, since the other C. cohnii unsaturated fatty acids percentages did not increase with the oxygen availability increase due to the n-dodecane presence, a desaturase oxygen-dependent mechanism involved in the C. cohnii DHA biosynthesis was not considered to explain the DHA production increase. A selective extraction through the n-dodecane was suggested.
An Equilibrium Model for Chloride Removal from Recycled Cooling Water Using the Ultra‐High Lime with Aluminum Process (2005)

Removal of chloride from recycled cooling water is needed to reduce corrosion and prolong equipment life. Laboratory experiments have demonstrated that the ultra-high lime with aluminum (UHLA) process has the ability to achieve high chloride removal efficiency from recycled cooling water. In an effort to further understand the behavior of chloride in the UHLA process, a fundamental model of the chemical processes was developed. The purpose of this paper is to describe this equilibrium model and present values for solubility products of precipitated solids that have not been investigated previously. The model was based on PHREEQC and a new program called INVRS K was integrated with PHREEQC to calculate values of unknown or poorly defined equilibrium or kinetic constants using a Gauss-Newton nonlinear regression routine. Model predictions indicated that the results could be best described by assuming the formation of a solid solution of calcium chloroaluminate (Ca4Al2Cl2OH12), tricalcium hydroxyaluminate (Ca3Al2OH12), and tetracalcium hydroxyaluminate (Ca4Al2OH14).
BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. (2011)

8509 Background: Most agents tested in large phase II trials in patients (pts) with metastatic melanoma have response rates of 10-20%. Approximately 50% of melanomas harbor a V600E activating mutation in the BRAF gene, which can now be targeted with specific inhibitors. In a Phase I study, treatment with vemurafenib (V), an orally available inhibitor of mutant BRAF, led to a high incidence of tumor regressions in BRAF-mutant melanoma (Flaherty et al. NEJM 2010). Here we report the results of BRIM-2, a pivotal Phase II trial of V in previously treated pts with BRAF-mutant melanoma. Methods: The primary endpoint was best overall response rate (BORR), with a target of 30% and a lower boundary of the exact 95% CI of at least 20% by independent review committee (IRC). BRAF mutation status was determined using a PCR-based investigational, companion diagnostic assay (cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems). Pts without active CNS metastasis who had received at least one prior line of therapy for metastatic melanoma received V (960 mg po twice daily) until progressive disease, unacceptable toxicity, or death. Results: 132 pts were enrolled (Oct 2009-Mar 2010), median age 51.5 yr, 54% ECOG PS 1, 61% M1c, 49% elevated LDH, and 49% >1 line of prior therapy. At the time of analysis (Sept 27, 2010, median follow-up 7 mo), BORR was 52.3% (95% CI: 43–61%; 2.3% CR, 50% PR) by IRC, with 29.5% SD and only 13.6% PD. Median duration of response was 6.8 mo (95% CI: 5.6-NR), and median PFS was 6.2 mo (95% CI: 5.6–6.8%). Median OS had not been reached. Most common adverse events (AEs; ≥25% pts, mostly Grade 1-2) were arthralgia, rash, photosensitivity, fatigue, alopecia, pruritis, and skin papilloma. The most common Grade 3 AE was cutaneous squamous cell carcinoma (24.2%), the majority centrally reviewed as keratoacanthoma-type. AEs were generally reversible with dose modification or interruption. 42% of pts required dose reductions, most commonly for rash, arthralgia and LFT abnormalities. Conclusions: BRIM2 met its primary endpoint based on BORR, confirming that V is an active agent in pts with BRAF mutation-positive melanoma who have completed prior first-line therapy.
Using the Nyström Method to Speed Up Kernel Machines (2000)

A major problem for kernel-based predictors (such as Support Vector Machines and Gaussian processes) is that the amount of computation required to find the solution scales as O(n ), where n is the number of training examples. We show that an approximation to the eigendecomposition of the Gram matrix can be computed by the Nyström method (which is used for the numerical solution of eigenproblems). This is achieved by carrying out an eigendecomposition on a smaller system of size m &amp;lt; n, and then expanding the results back up to n dimensions. The computational complexity of a predictor using this approximation is O(m n). We report experiments on the USPS and abalone data sets and show that we can set m n without any significant decrease in the accuracy of the solution.
Targeted Disruption of the BCL9/β-Catenin Complex Inhibits Oncogenic Wnt Signaling (2012)

Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of β-catenin with B cell lymphoma 9 (BCL9), a co-activator for β-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives β-catenin signaling through direct binding mediated by its α-helical homology domain 2. We developed a stabilized α helix of BCL9 (SAH-BCL9), which we show targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-β-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.
Intense High-Energy Proton Beams from Petawatt-Laser Irradiation of Solids (2000)

An intense collimated beam of high-energy protons is emitted normal to the rear surface of thin solid targets irradiated at 1 PW power and peak intensity 3x10(20) W cm(-2). Up to 48 J ( 12%) of the laser energy is transferred to 2x10(13) protons of energy >10 MeV. The energy spectrum exhibits a sharp high-energy cutoff as high as 58 MeV on the axis of the beam which decreases in energy with increasing off axis angle. Proton induced nuclear processes have been observed and used to characterize the beam.
RNA Binding Domain of Telomerase Reverse Transcriptase (2001)

Telomerase is a ribonucleoprotein reverse transcriptase that extends the ends of chromosomes. The two telomerase subunits essential for catalysis in vitro are the telomerase reverse transcriptase (TERT) and the telomerase RNA. Using truncations and site-specific mutations, we identified sequence elements of TERT and telomerase RNA required for catalytic activity and protein-RNA interaction for Tetrahymena thermophila telomerase. We found that the TERT amino and carboxyl termini, although evolutionarily poorly conserved, are nonetheless important for catalytic activity. In contrast, high-affinity telomerase RNA binding requires only a small region in the amino terminus of TERT. Surprisingly, the TERT region necessary and sufficient for telomerase RNA binding is completely separable from the reverse transcriptase motifs. The minimal Tetrahymena TERT RNA binding domain contains two sequence motifs with ciliate-specific conservation and one TERT motif with conservation across all species. With human TERT, we demonstrate that a similar region within the TERT amino terminus is essential for human telomerase RNA binding as well. Finally, we defined the Tetrahymena telomerase RNA sequences that are essential for TERT interaction. We found that a four-nucleotide region 5' of the template is critical for TERT binding and that the 5' end of telomerase RNA is sufficient for TERT binding. Our results reveal at least one evolutionarily conserved molecular mechanism by which the telomerase reverse transcriptase is functionally specialized for obligate use of an internal RNA template.