gebhart/patrepeval huggingface dataset:
A bioinformatics analysis of alternative exon usage in human genes coding for extracellular matrix proteins. (2004)

Alternative splicing increases protein diversity through the generation of different mRNA molecules from the same gene. Although alternative splicing seems to be a widespread phenomenon in the human transcriptome, it is possible that different subgroups of genes present different patterns, related to their biological roles. Analysis of a subgroup may enhance common features of its members that would otherwise disappear amidst a heterogeneous population. Extracellular matrix (ECM) proteins are a good set for such analyses since they are structurally and functionally related. This family of proteins is involved in a large variety of functions, probably achieved by the combinatorial use of protein domains through exon shuffling events. To determine if ECM genes have a different pattern of alternative splicing, we compared clusters of expressed sequences of ECM to all other genes regarding features related to the most frequent type of alternative splicing, alternative exon usage (AEU), such as: the number of alternative exon-intron structures per cluster, the number of AEU events per exon-intron structure, the number of exons per event, among others. Although we did not find many differences between the two sets, we observed a higher frequency of AEU events involving entire protein domains in the ECM set, a feature that could be associated with their multi-domain nature. As other subgroups or even the ECM set in different tissues could present distinct patterns of AEU, it may be premature to conclude that alternative splicing is homogeneous among groups of related genes.
Biosynthesis and metabolism of leukotrienes (2007)

Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA4 (leukotriene A4), which is enzymatically converted into either LTB4 (leukotriene B4) by LTA4 hydrolase or LTC4 (leukotriene C4) by LTC4 synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Several other proteins, including cPLA2a (cytosolic phospholipase A2a) and FLAP (5-LO-activating protein) also assemble at the perinuclear region before production of LTA4. LTC4 synthase is an integral membrane protein that is present at the nuclear envelope; however, LTA4 hydrolase remains cytosolic. Biologically active LTB4 is metabolized by w-oxidation carried out by specific cytochrome P450s (CYP4F) followed by b-oxidation from the w-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/15-oxo-prostaglandin-13-reductase that forms a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC4 occurs by sequential peptide cleavage reactions involving a g-glutamyl transpeptidase that forms LTD4 (leukotriene D4) and a membrane-bound dipeptidase that converts LTD4 into LTE4 (leukotriene E4) before w-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease.
Quantitative Comparison between Differential Adhesion Models and Cell Sorting in the Presence and Absence of Fluctuations (1995)

We study the effect of inhibition of cell-membrane ruffling on cell sorting in experiments and simulations. We use aggregates of neural retinal and pigmented retinal cells obtained from chicken embryos and inhibit membrane ruffling by adding the drug cytochalasin B to the culture medium. Simulations using the large- $Q$ Potts model with differential adhesivity, with the simulation temperature controlling the membrane ruffling amplitude, agree quantitatively with the experimental results for both normal and low fluctuation sorting, providing strong support for the validity of the model. In both cases, inhibition of ruffling prevents large scale cell sorting.
Organolead Halide Perovskite: New Horizons in Solar Cell Research (2014)

Organolead-halide-perovskite-based solar cells have recently received significant attention due to their excellent photovoltaic performance and low cost. The general formula of this perovskite light harvester is RPbX3, where R and X stand for a monovalent organic cation and halide anion, respectively. Structures of the perovskite solar cell are designed based on the function of the perovskite. Organolead halide perovskites can be used either as sensitizers or n- or p-type light harvesters. Rapid progress has been made over the past year since the first report on long-term, durable, 9.7% efficiency perovskite solar cells based on CH3NH3PbI3-sensitized TiO2 in 2012. As a result, power conversion efficiencies as high as 16% have been achieved. Further improvement is expected from this material in terms of understanding charge accumulation and transport properties. Organolead halide perovskite is now regarded as a promising solar cell material, opening new horizons in solar cell research.
ChemInform Abstract: Acylphosphonates. Part 7. A New Method for Stereospecific and Stereoselective Generation of Dideoxyribonucleoside Phosphorothioates via the Acylphosphonate Intermediates. (1987)

Abstract The dinucleoside trichloroethoxycarbonyl phosphonates (II) which are prepared using the reagent (I) are converted to the phosphite intermediates (IV) with entire retention of configuration at the phosphorus; subsequent treatment with elemental sulfur provides the phosphorothioates (V) which are deblocked to (VI).
Immunohistochemical analysis of β-tubulin isotypes in human prostate carcinoma and benign prostatic hypertrophy (1997)

The beta II tubulin isotype is a potential marker for prostate adenocarcinoma. The possibility that tumor beta-tubulin isotype composition may effect the response to antimicrotubule drug therapy in prostate cancer and other tumors merit investigation.
Scanning probe with elastomeric (PDMS) tip for scanning probe microcontact printing (SP-CP) (2004)

This paper reports a newly developed scanning probe microcontact printing (SP-/spl mu/CP) method to generate submicron patterns. It uses a scanning probe with an elastomeric tip to transfer chemical or biological materials onto a substrate. SP-/spl mu/CP combines the advantages of microcontact printing and scanning probe microscopy technologists. The design and fabrication of the scanning probe is described in this work. The functioning of the probe is demonstrated by generation of sub-500 nm ODT lines on a gold surface using SP-/spl mu/CP method.
Phase I Study of Immunization with Dendritic Cells Modified with Fowlpox Encoding Carcinoembryonic Antigen and Costimulatory Molecules (2005)

This immunization strategy is safe and activates potent CEA-specific immune responses.
A Computer-Assisted Management Program for Antibiotics and Other Antiinfective Agents (1998)

During the intervention period, all 545 patients admitted were cared for with the aid of the antiinfectives-management program. Measures of processes and outcomes were compared with those for the 1136 patients admitted to the same unit during the two years before the intervention period. The use of the program led to significant reductions in orders for drugs to which the patients had reported allergies (35, vs. 146 during the preintervention period; P<0.01), excess drug dosages (87 vs. 405, P<0.01), and antibiotic-susceptibility mismatches (12 vs. 206, P<0.01). There were also marked reductions in the mean number of days of excessive drug dosage (2.7 vs. 5.9, P<0.002) and in adverse events caused by antiinfective agents (4 vs. 28, P<0.02). In analyses of patients who received antiinfective agents, those treated during the intervention period who always received the regimens recommended by the computer program (n=203) had significant reductions, as compared with those who did not always receive the recommended regimens (n= 195) and those in the preintervention cohort (n = 766), in the cost of antiinfective agents (adjusted mean, $102 vs. $427 and $340, respectively; P<0.001), in total hospital costs (adjusted mean, $26,315 vs. $44,865 and $35,283; P<0.001), and in the length of the hospital stay days (adjusted mean, 10.0 vs. 16.7 and 12.9; P<0.001). CONCLUSIONS; A computerized antiinfectives-management program can improve the quality of patient care and reduce costs.
Fiber Bragg grating pressure sensor with ultrahigh sensitivity and reduced temperature sensitivity (2009)

A fiber Bragg grating (FBG) pressure sensing scheme based on a flat diaphragm and an L-shaped lever is presented. An L-shaped lever transfers the pressure-induced defection of the flat diaphragm to the axial elongation of the FBG. The curve where the L-shaped lever contacts the diaphragm is a segment of an Archimedes spiral, which is used to enhance the responsivity. Because the thermal expansion coefficient of the quartz-glass L-shaped lever and the steel sensor shell is different, the temperature effect is compensated for by optimizing the dimension parameters. Theoretical analysis is presented, and the experimental results show that an ultrahigh pressure responsivity of 244 pm/kPa and a low temperature responsivity of 2.8 pm/°C are achieved.
Degradation of Double-Stranded RNA by Human Pancreatic Ribonuclease:  Crucial Role of Noncatalytic Basic Amino Acid Residues (2003)

Under physiological salt conditions double-stranded (ds) RNA is resistant to the action of most mammalian extracellular ribonucleases (RNases). However, some pancreatic-type RNases are able to degrade dsRNA under conditions in which the activity of bovine RNase A, the prototype of the RNase superfamily, is essentially undetectable. Human pancreatic ribonuclease (HP-RNase) is the most powerful enzyme to degrade dsRNA within the tetrapod RNase superfamily, being 500-fold more active than the orthologous bovine enzyme on this substrate. HP-RNase has basic amino acids at positions where RNase A shows instead neutral residues. We found by modeling that some of these basic charges are located on the periphery of the substrate binding site. To verify the role of these residues in the cleavage of dsRNA, we prepared four variants of HP-RNase: R4A, G38D, K102A, and the triple mutant R4A/G38D/K102A. The overall structure and active site conformation of the variants were not significantly affected by the amino acid substitutions, as deduced from CD spectra and activity on single-stranded RNA substrates. The kinetic parameters of the mutants with double-helical poly(A).poly(U) as a substrate were determined, as well as their helix-destabilizing action on a synthetic DNA substrate. The results obtained indicate that the potent activity of HP-RNase on dsRNA is related to the presence of noncatalytic basic residues which cooperatively contribute to the binding and destabilization of the double-helical RNA molecule. These data and the wide distribution of the enzyme in different organs and body fluids suggest that HP-RNase has evolved to perform both digestive and nondigestive physiological functions.
THE USE OF MULTIPLE MEASUREMENTS IN TAXONOMIC PROBLEMS (1936)

The articles published by the Annals of Eugenics (1925–1954) have been made available online as an historical archive intended for scholarly use. The work of eugenicists was often pervaded by prejudice against racial, ethnic and disabled groups. The online publication of this material for scholarly research purposes is not an endorsement of those views nor a promotion of eugenics in any way.
(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:  A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes (2004)

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Thrombospondin and in vivo angiogenesis induced by basic fibroblast growth factor or lipopolysaccharide. (1993)

In this system, thrombospondin enhanced the in vivo angiogenic process induced by bFGF or LPS. This enhancement appears to be associated with an in vivo activation and chemotactic effect on the polymorphonuclear cells.
Molecular evolution of dengue type 2 virus in Thailand. (1998)

Dengue is a mosquito-borne viral infection that in recent years has become a major international public health concern. Dengue hemorrhagic fever (DHF), first recognized in Southeast Asia in the 1950s, is today a leading cause of childhood death in many countries. The pathogenesis of this illness is poorly understood, mainly because there are no laboratory or animal models of disease. We have studied the genetic relationships of dengue viruses of serotype 2, one of four antigenically distinct dengue virus groups, to determine if viruses obtained from cases of less severe dengue fever (DF) have distinct evolutionary origins from those obtained from DHF cases. A very large number (73) of virus samples from patients with DF or DHF in two locations in Thailand (Bangkok and Kamphaeng Phet) were compared by sequence analysis of 240 nucleotides from the envelope/nonstructural protein 1 (E/NS1) gene junction of the viral genome. Phylogenetic trees generated with these data have been shown to reflect long-term evolutionary relationships among strains. The results suggest that 1) many different virus variants may circulate simultaneously in Thailand, thus reflecting the quasispecies nature of these RNA viruses, in spite of population immunity; 2) viruses belonging to two previously distinct genotypic groups have been isolated from both DF and DHF cases, supporting the view that they arose from a common progenitor and share the potential to cause severe disease; and 3) viruses associated with the potential to cause DHF segregate into what is now one, large genotypic group and they have evolved independently in Southeast Asia for some time.
SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies (2011)

SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: Lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2(6-20)NH2 peptide. (1996)

To determine if nitration of tyrosine residues by peroxynitrite (PN), which can be generated endogenously, can disrupt the phosphorylation of tyrosine residues in proteins involved in cell signaling networks, we studied the effect of PN-promoted nitration of tyrosine residues in a pentadecameric peptide, cdc2(6-20)NH2, on the ability of the peptide to be phosphorylated. cdc2(6-20)NH2 corresponds to the tyrosine phosphorylation site of p34cdc2 kinase, which is phosphorylated by lck kinase (lymphocyte-specific tyrosine kinase, p56lck). PN nitrates both Tyr-15 and Tyr-19 of the peptide in phosphate buffer (pH 7.5) at 37 degrees C. Nitration of Tyr-15. which is the phosphorylated amino acid residue, inhibits completely the phosphorylation of the peptide. The nitration reaction is enhanced by either Fe(III)EDTA or Cu(II)-Zn(II)-superoxide dismutase (Cu,Zn-SOD). The kinetic data are consistent with the view that reactions of Fe(111)EDTA or Cu,Zn-SOD with the cis form of PN yield complexes in which PN decomposes more slowly to form N02+, the nitrating agent. Thus, the nitration efficiency of PN is enhanced. These results are discussed from the point of view that PN-promoted nitration will result in permanent impairment of cyclic cascades that control signal transduction processes and regulate cell cycles.
Sotatercept Improves Anemia, Vascular Calcification, and Bone Loss in Patients With End-Stage Kidney Disease on Hemodialysis (2015)

• In an ongoing study of sotatercept in HD subjects for the correction of anemia, subjects responding to an erythropoietin- stimulating agent (ESA) were washed out of their ESA effect until Hb was 10 g/dL, or both Hb increase ≥1 g/dL and Hb >10 g/dL, or requiring rescue varied in relation to dose for the sotatercept 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg dose groups and the associated placebo-control subjects for which there are available long-term study data (Figure 2). • The sotatercept 0.7/0.4 mg/kg dose group is ongoing and not included in this analysis; however, the mean time to rescue was similar between the 0.7/0.4 mg/kg dose group (4 subjects rescued, 100.3 days) and the 0.7 mg/kg dose group (5 subjects rescued, 99.4 days). Figure 2. Proportions of Subjects With Hb Response or Rescue During the 225-Day Treatment Phase (FAS)* 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Other 0 (0.0) 0 (0.0) • Sotatercept was well tolerated over 225 days (up to eight 28-day dose cycles), with an acceptable safety profile in subjects with ESKD on HD and without increases in home BP. In subjects given sotatercept 0.7/0.4 mg/kg on a 14-day dose cycle, cumulative safety appeared to be consistent with the other dose groups, although data are still accruing. • Sotatercept treatment with 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg doses every 28 days was associated with dose- dependent Hb improvements (achieving target increase ≥1 g/dL and target range 10-12 g/dL) that were generally sustained over multiple dosing cycles. An ongoing dose group with 14-day dosing (0.7/0.4 mg/kg) did not improve Hb efficacy in the first 28 days; however, time to rescue was similar to that in the 0.7 mg/kg dose group. • In this small interim dataset evaluating exploratory QCT data measured at baseline and Day 225 (after up to eight 28-day dose cycles), there was an apparent effect of sotatercept on multiple parameters of CKD-MBD, including slowing progression of VC, increasing femoral neck cortical bone mass, and slowing the increase in lumbar spine bone mass. - Differences between the groups at baseline may have influenced these results. The placebo group exhibited higher baseline serum levels of bone turnover markers and higher Agatston scores indicative of more severe ROD and VC, potentially increasing the chance of observing differences on these measures between the placebo group and the sotatercept groups. • Sotatercept may address significant unmet needs in the treatment of anemia and CKD-MBD in patients with ESKD. - Additional data from the ongoing sotatercept 0.7/0.4 mg/kg dose group are expected to further substantiate the efficacy and safety findings observed in the other dose groups.
Blocking the Myostatin Signal With a Dominant Negative Receptor Improves the Success of Human Myoblast Transplantation in Dystrophic Mice (2010)

Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Myostatin (MSTN) is a negative regulator of skeletal muscle development and responsible for limiting regeneration. It binds with high affinity to the activin type IIB receptor (ActRIIB). Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the MSTN signal with expression of a dominant negative mutant of ActRIIB (dnActRIIB). In vitro, blocking MSTN activity with a lentivirus carrying dnActRIIB increased proliferation and fusion of human myoblasts because MSTN regulates the expression of several myogenic regulatory factors. In vivo, myoblasts infected with the dnActRIIB lentivirus were transplanted in immunodeficient dystrophic mice. Dystrophin immunostaining of tibialis anterior (TA) cross-sections of these mice 1 month post-transplantation revealed more human dystrophin-positive myofibers following the transplantation of dnActRIIB myoblasts than of control myoblasts. Thus, blocking the MSTN signal with dnActRIIB improved the success of myoblast transplantation by increasing the myoblast proliferation and fusion and changed the expression of myogenic regulatory factors.
Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen (2005)

Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degradation of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced experimental allergic encephalomyelitis. Chromatography and zymography data demonstrated that the proteolytic activity of this preparation was exclusively associated with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage determined by mass spectrometry were localized within immunodominant regions of MBP. The abzymes could also cleave recombinant substrates containing encephalytogenic MBP(85-101) peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degradation of MBP suggests a mechanistic explanation of the slow development of neurodegeneration associated with MS.
Effect of Simultaneous Substitution of Alkali Earth Metals and Nb in Li7La3Zr2O12 on Lithium-Ion Conductivity (2013)

Various lithium-ion garnet-like oxides, Li7+X-Y(La3−XAX)(Zr2−YNbY)O12, (where A is an alkali earth metal) were prepared by solid-state reaction, and their lithium-ion conductivities and lattice parameters were determined by AC impedance and X-ray diffraction analysis. The La and Zr sites in these materials were simultaneously substituted, and the extent of substitution was varied to optimize both lattice parameter and lithium content associated with the highest possible lithium-ion conductivity. The optimum lattice parameter at a constant lithium content was determined to be between 12.94 and 12.96 Å. Within this range of lattice parameters, higher lithium-ion conductivities were associated with reduced lithium content.