gebhart/patrepeval huggingface dataset:
A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy (2016)

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.
ChemInform Abstract: NITRENDIPINE: IDENTIFICATION AND SYNTHESIS OF MAIN METABOLITES (1984)

Abstract Von dem Nitren‐ dipin (Ia) werden die Strukturen der Hauptmetaboliten (IIa)‐(IIc) sowie (IIIa) bis (IIIc) durch geeignete Synthesen oder durch spektroskopischen Vergleich mit den Referenzsubstanzen (VII), (VIII) und (Xa) und (Xb) aufgeklärt.
Connective Tissue Growth Factor and Cardiac Fibrosis after Myocardial Infarction (2005)

The temporal and spatial expression of transforming growth factor (TGF)-beta(1) and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-beta(1), CTGF, and procollagen alpha1(I) mRNA were localized by in situ hybridization, and TGF-beta(1) and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-beta(1), CTGF, and collagen after MI. Procollagen alpha1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-beta(1) mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-beta(1) or CTGF. TGF-beta(1) is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.
ALLOGRAFT INFLAMMATORY FACTOR-1 (1996)

Allograft inflammatory factor-1 (AIF-1), a cytokine-responsive macrophage molecule, was originally identified and cloned from rat cardiac allografts with chronic cardiac rejection. We performed the present study to determine whether AIF-1 was also involved in the inflammatory response associated with human cardiac transplant rejection. AIF-1 gene transcripts were identified by the reverse-transcriptase polymerase chain reaction in endomyocardial biopsy specimens from human heart transplants and in macrophage cell lines. In the 441-base pair coding region of the human and rat cDNAs, the nucleotide sequences were 86% identical and the deduced amino acid sequences were 90% identical. Consistent with our studies in the rat. AIF-1 was selectively expressed in human macrophage-like cell lines, and immunostaining in human heart allografts localized the AIF-1 gene product to a subset of CD68+ macrophages in the interstitial and perivascular spaces. The parallels between rat and human AIF-1 expression suggest that AIF-1 may have a common effect on the function of activated macrophages in cardiac allografts.
A Mutant of Arabidopsis thaliana Which Lacks Activation of RuBP Carboxylase In Vivo (1982)

A mutant of Arabidopsis thaliana has been isolated in which ribulose-1,5-bisphosphate carboxylase is present in a nonactivatable form in vivo. The mutation appears to affect carboxylase activation specifically, and not any other enzyme of the photosynthesis or photorespiratory cycles. The effect of the mutation on carboxylase activation is indirect, inasmuch as the properties of ribulose-1,5-bisphosphate carboxylase purified from the mutant are not distinguishable from those of the wild type enzyme. The mutant requires high levels of atmospheric CO(2) for growth because photosynthesis is severely impaired in atmospheres containing normal levels of CO(2), irrespective of the atmospheric O(2) concentration. In this respect, the mutant is distinguished from previously described high-CO(2) requiring mutants of Arabidopsis which have defects in photorespiratory carbon or nitrogen metabolism.
Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes. (1988)

Regulation of tumor necrosis factor (TNF) gene expression was investigated in resting human monocytes and in 12-O-tetradecanoylphorbol-13-acetate (TPA) activated monocytes. TNF transcripts were undetectable in resting monocytes. However, in TPA-activated monocytes, TNF mRNA was first detectable by 3 h and reached maximal levels by 12 h of drug exposure. Using run-on transcription assays, the TNF gene was transcriptionally inactive in resting monocytes, but was rapidly activated after TPA exposure. The protein synthesis inhibitor, cycloheximide (CHX), had no detectable effect on levels of TNF transcripts in resting monocytes, while this agent superinduced the level of TNF mRNA by 50-fold in TPA-activated cells. TPA activated monocytes were also exposed to actinomycin D and/or CHX to determine whether transcriptional or posttranscriptional control of TNF gene expression was responsible for the induction of TNF transcripts. After 1 h of actinomycin D treatment, the amount of TNF transcripts was reduced by 75%. In contrast, no difference in TNF mRNA levels was observed in TPA-activated monocytes exposed to CHX alone or CHX in combination with actinomycin D. These findings indicated that CHX prevented the degradation of TNF mRNA by inhibiting the synthesis of a labile protein. Run-on transcription assays performed on cells exposed to either TPA or the combination of TPA and CHX further indicated that CHX treatment increased transcription of the TNF gene. Thus, TNF gene expression is controlled at the transcriptional level in resting human monocytes, while both transcriptional and posttranscriptional events regulate the level of TNF transcripts in TPA-activated cells.
A subspace identification extension to the phase correlation method (2003)

The phase correlation method (PCM) is known to provide straightforward estimation of rigid translational motion between two images. It is often claimed that the original method is best suited to identify integer pixel displacements, which has prompted the development of numerous subpixel displacement identification methods. However, the fact that the phase correlation matrix is rank one for a noise-free rigid translation model is often overlooked. This property leads to the low complexity subspace identification technique presented here. The combination of non-integer pixel displacement identification without interpolation, robustness to noise, and limited computational complexity make this approach a very attractive extension of the PCM. In addition, this approach is shown to be complementary with other subpixel phase correlation based techniques.
CHIRAL ROUNDUP (2002)

RETURN TO ISSUEPREVNewsNEXTCHIRAL ROUNDUPAs pharmaceutical companies face bleak prospects, their suppliers diligently tend the fertile fields of chiral chemistry in varied waysA. MAUREEN ROUCHIView Author Information C&EN WASHINGTONCite this: Chem. Eng. News 2002, 80, 23, 43–50Publication Date (Print):June 10, 2002Publication History Published online13 November 2010Published inissue 10 June 2002https://pubs.acs.org/doi/10.1021/cen-v080n023.p043https://doi.org/10.1021/cen-v080n023.p043newsACS PublicationsCopyright © 2002 American Chemical SocietyArticle Views19Altmetric-Citations49LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options SUBJECTS:Pharmaceuticals Get e-Alerts
Design Approach to Sealant Selection for the Life of the Well (1999)

Abstract Recent experience in the field has demonstrated that the mechanical properties of the annular sealant are a critical factor in the success of a well. A demanding operational regime such as High Pressure/High Temperature (HP/HT) and well interventions, e.g. pressure testing stimulation, place high demands on the mechanical design of a candidate sealant. The following steps should be followed to determine the required mechanical properties of such well sealant candidates: The stability of the bore hole should be evaluated prior to placing the sealant in the annulus. The stability is affected by the far field stresses, the weight (s.g.) of the drilling fluid and the mechanical properties of the formation. The integrity of the sealant should be investigated for the operational envelope of the well. Finite Element models were used to determine the influence of wellbore stability aspects and the effects of loading on the integrity of the sealant. The mechanical properties of the sealant considered were elasticity, tensile strength, shear strength and bonding strength. In this way it was possible to examine aspects of non-linear material behavior of the sealant. The following factors were investigated in this study: What are the well parameters and its operating envelope? What are the total stresses on the formation and on the sealant under various HP/HT conditions? Which mechanical properties does the sealant have to possess in order to be able to withstand different types of stress? The study indicated that there is a strong interaction between on the one hand the behavior of the sealant and on the other hand the formation in-situ stresses, the formation properties, the well completion parameters and its operating envelope. Depending on these input conditions, the sealant was observed to behave in one of the following manners. The sealant remained intact without any damage. A micro annulus occurred between sealant and casing/formation. The sealant failed because of either tensile or shear deformation. Calculations were performed for various wellbore stability scenarios, well completion characteristics, well loading envelopes and properties of the sealant. Typical oil well cement slurries, latex slurries, foam cements and cement hybrids were investigated. Typical results from the study are discussed and procedures for field application are given.
A Monoclonal Antibody Raised against Human β-factor XIIa which also Recognizes α-factor XIIa but not Factor XII or Complexes of Factor XIIa with C1 Esterase Inhibitor (2000)

A monoclonal antibody (mAb 2/215) against human beta-factor XIIa (beta-FXIIa), was shown by equilibrium binding studies to have a high affinity for alpha-factor XIIa (alpha-FXIIa) (Kd 1.8 nM) and beta-FXIIa (Kd 0.65 nM) but no detectable reaction with FXII zymogen or alpha-FXIIa:C1 esterase inhibitor (C1-INH) complex. Surface plasmon resonance studies showed that the mAb 2/215 bound to immobilized alpha-FXIIa with high affinity (KD 3.93 +/- 1.46 x 10(-11) M). Western blots employing mAb 2/215 indicated that human plasma contained small amounts of alpha-FXIIa but no beta-FXIIa. mAb 2/215 did not inhibit the amidolytic activity of beta-FXIIa and protected beta-FXIIa from inhibition by C1-INH. The recovery by ELISA,employing mAb 2/215 as the capture antibody, of alpha-FXIIa added to plasma was 11.3%, 42% after inhibition of alpha-FXIIa with 3:4dichloroisocoumarin, and 82% when 0.5% Triton-X100 was added to the assay. Gel filtration showed that the majority of plasma alpha-FXIIa existed as a complex (Mr approximately 170,000). This distinctive mAb increases the capacity to study the contact system in health and disease.
Identification of Carboxyl-Terminal Peptide Fragments of Parathyroid Hormone in Human Plasma at Low-Picomolar Levels by Mass Spectrometry (2005)

For decades, researchers have tried to identify the primary structures of circulating carboxyl-terminal parathyroid hormone (C-PTH) peptide fragments that may be present at only picomolar levels in human plasma. Although immunoassays and radiosequencing techniques have provided valuable fragment characterizations, no analysis has successfully determined their exact primary structures. In this work, for the first time, four human C-PTH peptide fragments, hPTH(34−84), hPTH(37−84), hPTH(38−84), and hPTH(45−84), have been identified from human plasma using MS-based methods. C-PTH peptide fragments were isolated from plasma samples by immunoaffinity extraction. The eluate was analyzed by capillary LC fractionation followed by MALDI-TOF-MS or by on-line coupling of nano-LC with ESI-TOF-MS. Both the MALDI- and the ESI-based approaches were capable of detecting C-PTH peptide fragments in human plasma at <10 pmol/L. The MALDI-TOF approach was effective in preliminary searches for C-PTH peptide fragments, but the use of high laser power limited the resolution necessary for accurate C-PTH peptide identification. The high mass resolution (10 000) and accuracy (10 ppm) attained by the ESI-TOF approach enabled unambiguous identification of these peptides. The four C-PTH peptide fragments identified in plasma samples from patients with chronic renal insufficiency were also found in the plasma of healthy women receiving recombinant human PTH either by subcutaneous injection or by intravenous infusion. This newly developed analytical capability should greatly enhance the understanding of PTH metabolism and parathyroid gland function.
New statistical strategy for monitoring safety and efficacy in single-arm clinical trials. (1996)

The proposed monitoring strategy provides a flexible, practical means to continuously monitor both safety and efficacy in single-arm cancer clinical trials. The design strategy can be implemented easily using a freely available menu-driven computer program, and provides a scientifically sound alternative to the use of ad hoc safety monitoring rules.
Identifying syntactic differences between two programs (1991)

Abstract Programmers frequently face the need to identify the differences between two programs, usually two different versions of a program. Text‐based tools such as the UNIXr̀ utility diff often produce unsatisfactory comparisons because they cannot accurately pinpoint the differences and because they sometimes produce irrelevant differences. Since programs have a rigid syntactic structure as described by the grammar of the programming language in which they are written, we develop a comparison algorithm that exploits knowledge of the grammar. The algorithm, which is based on a dynamic programming scheme, can point out the differences between two programs more accurately than previous text comparison tools. Finally, the two programs are pretty‐printed ‘synchronously’ with the differences highlighted so that the differences are easily identified.
Recombinant human parathyroid hormone synthesized in Escherichia coli. Purification and characterization. (1988)

Recombinant human parathyroid hormone (hPTH) was expressed in Escherichia coli harboring a plasmid containing a synthetic human parathyroid hormone gene under the control of the E. coli lac promoter. Three major forms of the hormone were isolated by acid extraction and purified to homogeneity by high performance liquid chromatography. By amino acid analysis and NH2-terminal sequencing, these were identified as hPTH-(1-84), formyl-methionyl-hPTH-(1-84), and hPTH-(8-84). The recombinant hPTH-(1-84) was immunologically indistinguishable from a World Health Organization standard of extracted native hPTH-(1-84). Recombinant hPTH-(1-84) was also bioactive in renal and skeletal adenylate cyclase assays. In the skeletal bioassay performed in UMR 108 osteosarcoma cells its activity was identical to that of an hPTH-(1-84) standard. In this bioassay, formyl-methionyl-hPTH-(1-84) had 10% of the activity of hPTH-(1-84) and hPTH-(8-84) was inactive. The results demonstrate the importance of isolating hPTH-(1-84) from other recombinant forms and metabolites to achieve full hormonal bioactivity and indicate that purified recombinant hPTH-(1-84) can thereby be obtained which should be a useful source of hormone for both basic and clinical studies.
Fusion of Insulin Receptor Ectodomains to Immunoglobulin Constant Domains Reproduces High-affinity Insulin Binding in Vitro (1996)

A unique feature of the insulin receptor is that it is dimeric in the absence of ligand. Dimerization of two adjacent transmembrane domain (TMD) alpha helices has been shown to be critical in receptor kinase activation. Moreover, previous work has suggested that the TMD is involved in stabilizing the high-affinity binding site; soluble receptors expressed after simple truncation at the ectodomain-TMD junction have reduced affinity for insulin. To further examine this issue, we have replaced the TMD and intracellular domain of the soluble human insulin receptor (HIRs) with constant domains from immunoglobulin Fc and lambda subunits (HIRs-Fc and HIRs-lambda). Studies of receptor biosynthesis and binding characteristics were performed following transient transfection of receptor cDNAs into human embryonal kidney 293 cells. Each hybrid receptor was initially synthesized as a single chain proreceptor, followed by cleavage into alpha- and beta-Fc or beta-lambda subunits. The majority of secreted protein appeared in the cell medium as fully processed heterotetramer. Fc fragments released from HIRs-Fc by papain digestion and analyzed by nonreducing SDS-polyacrylamide gel electrophoresis were dimeric. Furthermore, dissociation constants for both chimeras were similar to those for the full-length holoreceptor (wild-type receptor, Kd1 = 200 pM and Kd2 = 2 nM; HIRs-Fc, Kd1 = 200 pM and Kd2 = 40 nM; and HIRs-lambda, Kd1 = 200 pM and Kd2 = 5 nM). These results extend previous observations that dimerization of the membrane-proximal ectodomain is necessary to maintain an intact high-affinity insulin-binding site.
Natural history of Fabry disease in females in the Fabry Outcome Survey (2005)

Background: Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of α-galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females. Aims: This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients. Methods: Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement. Results: The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL. Conclusions: Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.
TMOF‐like factor controls the biosynthesis of serine proteases in the larval gut of Heliothis virescens (2001)

Proteolytic enzyme biosynthesis in the midgut of the 4th instar larva of Heliothis virescens is cyclical. Protease activity increases immediately after the molt from the 3rd to the 4th instar larvae and declines just before the molt into the 5th instar. Characterization of the midgut proteases using soybean tryspin inhibitor (SBTI) Bowman Birk Inhibitor (BBI) 4-(2-aminoethyl)benzensulfonylfluoride (AEBSF) and N-tosyl-L-phenylalanine chloromethylketone (TPCK) indicate that protease activity is mostly trypsinlike (80%) with a small amount of chymotrypsinlike activity (20%). Injections of late 3rd and 4th instar larval hemolymph into H. virescens larvae inhibited tryspin biosynthesis in the larval midgut. Similar results were obtained when highly purified 4th instar larval hemolymph that crossreacted with Aea-TMOF antisurm using ELISA was injected into 2nd instar larvae. Injections of Aea-TMOF and its analogues into 2nd instar, and Aea-TMOF alone into 4th instar larvae stopped trypsin biosynthesis 24 and 48 h after the injections, respectively. Injections of 4th instar H. virescens larval hemolymph into female Aedes aegypti that took a blood meal stopped trypsin biosynthesis and egg development. These results show that the biosynthesis of trypsin-like enzymes in the midgut of a lepidoptera is modulated with a hemolymph circulating TMOF-like factor that is closely related to Aea-TMOF. Arch.