gebhart/patrepeval huggingface dataset:
Pharmacological management of acromegaly: a current perspective (2010)

Acromegaly is a chronic disorder of enhanced growth hormone (GH) secretion and elevated insulin-like growth factor–I (IGF-I) levels, the most frequent cause of which is a pituitary adenoma. Persistently elevated GH and IGF-I levels lead to substantial morbidity and mortality. Treatment goals include complete removal of the tumor causing the disease, symptomatic relief, reduction of multisystem complications, and control of local mass effect. While transsphenoidal tumor resection is considered first-line treatment of patients in whom a surgical cure can be expected, pharmacological therapy is playing an increased role in the armamentarium against acromegaly in patients unsuitable for or refusing surgery, after failure of surgical treatment (inadequate resection, cavernous sinus invasion, or transcapsular intraarachnoid invasion), or in select cases as primary treatment. Three broad drug classes are available for the treatment of acromegaly: somatostatin analogs, dopamine agonists, and GH receptor antagonists. Somatostatin analogs are considered as the first-line pharmacological treatment of acromegaly, although efficacy varies among the different formulations. Octreotide long-acting release (LAR) appears to be more efficacious than lanreotide sustained release (SR). Lanreotide Autogel (ATG) has been shown to result in similar biological control as octreotide LAR, and there may be a benefit in switching from one to the other in some cases of treatment failure. The novel multireceptor somatostatin analog pasireotide, currently in Phase II clinical trials, also shows promise in the treatment of acromegaly. Dopamine agonists have been the earliest and most widely used agents in the treatment of acromegaly but have been found to be less effective than somatostatin analogs. In this class of drugs, cabergoline has shown greater efficacy and tolerability than bromocriptine. Dopamine agonists have the advantage of oral administration, resulting in increased use in select patient groups. Selective GH receptor antagonists, such as pegvisomant, act by blocking the effects of GH, resulting in decreased IGF-I production despite persistent elevation of GH serum levels. Thus far, tumor growth has not been a concern during pegvisomant therapy. However, combination treatment with somatostatin analogs may counteract these effects. The authors discuss the latest guidelines for biochemical cure and highlight the efficacy of combination therapy. In addition, the effects of pharmacological presurgical treatment on surgical outcome are explored.
LIBSVM (2011)

LIBSVM is a library for Support Vector Machines (SVMs). We have been actively developing this package since the year 2000. The goal is to help users to easily apply SVM to their applications. LIBSVM has gained wide popularity in machine learning and many other areas. In this article, we present all implementation details of LIBSVM. Issues such as solving SVM optimization problems theoretical convergence multiclass classification probability estimates and parameter selection are discussed in detail.
Gene organization of oryzacystatin‐II, a new cystatin superfamily member of plant origin, is closely related to that of oryzacystatin‐I but different from those of animal cystatins (1991)

The gene structure of oryzacystatin-II, a new cystatin superfamily member of rice seed origin, was determined. It spans approximately 2.5 kbp and comprises 3 exons. The number of exons and the intron-breakpoints coincide with those of oryzacystatin-I, the first well-defined plant cystatin. However, no similar sequences were observed between the two oryzacystatin genes in 5'-upstream regulatory regions, even though both are expressed specifically during the ripening stage of rice seeds. The gene organization of these two plant cystatins is generally different from that of animal cystatins.
Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAFV600E Conformation (2016)

The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAF<sup>V600E</sup>) accounts for about 90% of these activating mutations. While BRAF<sup>V600E</sup>-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants. RAF kinases signal as homo- and heterodimers, and another complication associated with small molecule BRAF<sup>V600E</sup> inhibition is drug-induced allosteric activation of a wild-type RAF subunit (BRAF or CRAF) of the kinase dimer, a process called "transactivation" or "paradoxical activation." Here, we used BRAF<sup>V600E</sup> and vemurafenib as a model system to develop chemically linked kinase inhibitors to lock RAF dimers in an inactive conformation that cannot undergo transactivation. This structure-based design effort resulted in the development of Vem-BisAmide-2, a compound containing two vemurafenib molecules connected by a bis amide linker. We show that Vem-BisAmide-2 has comparable inhibitory potency as vemurafenib to BRAF<sup>V600E</sup> both in vitro and in cells but promotes an inactive dimeric BRAF<sup>V600E</sup> conformation unable to undergo transactivation. The crystal structure of a BRAF<sup>V600E</sup>/Vem-BisAmide-2 complex and associated biochemical studies reveal the molecular basis for how Vem-BisAmide-2 mediates selectivity for an inactive over an active dimeric BRAF<sup>V600E</sup> conformation. These studies have implications for targeting BRAF<sup>V600E</sup>/RAF heterodimers and other kinase dimers for therapy.
Lattice code decoder for space-time codes (2000)

We explore the lattice sphere packing representation of a multi-antenna system and the algebraic space-time (ST) codes. We apply the sphere decoding (SD) algorithm to the resulted lattice code. For the uncoded system, SD yields, with small increase in complexity, a huge improvement over the well-known V-BLAST detection algorithm. SD of algebraic ST codes exploits the full diversity of the coded multi-antenna system, and makes the proposed scheme very appealing to take advantage of the richness of the multi-antenna environment. The fact that the SD does not depend on the constellation size, gives rise to systems with very high spectral efficiency, maximum-likelihood performance, and low decoding complexity.
Catalytic Asymmetric Addition of Carbon Dioxide to Propylene Oxide with Unprecedented Enantioselectivity (2006)

New chiral catalyst systems were developed for the reaction of carbon dioxide with propylene oxide (PO) at atmospheric pressure to generate enantiomerically enriched propylene carbonate (PC). The best selectivity was achieved with a Co(III)(salen)-trifluoroacetyl complex and bis(triphenylphosphoranylidene)ammonium fluoride (PPN+F-) as catalysts, affording PC in 40% yield and 83% ee (selectivity factor = 19). In addition, PC was prepared for the first time by kinetic resolution of PO with tetrabutylammonium methyl carbonate (TBAMC, nBu4N+ (-)OOCOMe). With TBAMC as "activated CO2", up to 71% ee was obtained.
Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema. (1991)

Members of two unrelated families with type I hereditary angioneurotic edema (HANE) were found to have elevated levels of C1 inhibitor (C1INH) mRNA. DNA sequence analysis of PCR-amplified monocyte C1INH mRNA revealed normal and mutant transcripts, as expected in this disorder that occurs in heterozygous individuals. Single base mutations near the 3' end of the coding sequence were identified in affected members of each family. One mutation consisted of insertion of an adenosine at position 1304 which created a premature termination codon (TAA), whereas the second consisted of deletion of the thymidine at position 1298 which created a premature termination codon (TGA) 23 nucleotides downstream. These mutations are approximately 250 nucleotides upstream of the natural termination codon. Nuclear run-off experiments in one kindred revealed no difference in transcription rates of the C1INH gene between the patients and normals. C1INH mRNA half-life experiments were not technically feasible because of the prolonged half-life of the normal transcript. Dideoxynucleotide primer extension experiments allowed the differentiation of the normal and mutant transcripts. These studies showed that the mutant transcript was not decreased relative to the normal, and this therefore was at least partially responsible for the C1INH mRNA elevation. This elevation may be due to the decreased catabolism of the mutant transcript.
Nerve growth factor: A key local regulator in the pathogenesis of inflammatory arthritis (2011)

Based on our findings, we propose a model in which NGF secreted by FLS into PsA and RA synovium promotes the survival of activated autoreactive T cells as well as FLS proliferation. Thus, NGF has the potential to sustain the chronic inflammatory cascades of arthritis of autoimmune origin.
‘Sweetening’ Pregnancy: Galectins at the Fetomaternal Interface (2013)

Successful mammalian pregnancy relies upon acceptance of a semi-allogeneic fetus by the maternal immune system. Lessons learned from studies on protective immunity to microbial infections and tumours, prevention of autoimmunity, and allograft rejection have contributed to delineate the mechanisms leading to T-cell tolerance at the fetomaternal interface. Recent observations highlight the contribution of galectins, a family of endogenous glycan-binding proteins, to critical biological events occurring during mammalian gestation, including immune cell tolerance, inflammation, implantation, and angiogenesis. These multifunctional lectins can hierarchically control a cascade of immunoregulatory events including the expansion, recruitment, and function of regulatory T cells, the promotion of tolerogenic dendritic cells, and the execution of T-cell death programs. In addition, galectins can control cell adhesion and signaling events critical for implantation and are involved in fundamental processes linking tissue hypoxia to angiogenesis. In an attempt to integrate the regulatory roles of galectins to immunological and vascular programs operating during pregnancy. Here we outline the regulated expression and function of individual members of the galectin family within the fetoplacental unit and their biological implications for the development and preservation of successful pregnancies.
Chain and conformation stability of solid-state DNA: implications for room temperature storage (2009)

There is currently wide interest in room temperature storage of dehydrated DNA. However, there is insufficient knowledge about its chemical and structural stability. Here, we show that solid-state DNA degradation is greatly affected by atmospheric water and oxygen at room temperature. In these conditions DNA can even be lost by aggregation. These are major concerns since laboratory plastic ware is not airtight. Chain-breaking rates measured between 70 degrees C and 140 degrees C seemed to follow Arrhenius' law. Extrapolation to 25 degrees C gave a degradation rate of about 1-40 cuts/10(5) nucleotides/century. However, these figures are to be taken as very tentative since they depend on the validity of the extrapolation and the positive or negative effect of contaminants, buffers or additives. Regarding the secondary structure, denaturation experiments showed that DNA secondary structure could be preserved or fully restored upon rehydration, except possibly for small fragments. Indeed, below about 500 bp, DNA fragments underwent a very slow evolution (almost suppressed in the presence of trehalose) which could end in an irreversible denaturation. Thus, this work validates using room temperature for storage of DNA if completely protected from water and oxygen.
A numerical study of transcranial focused ultrasound beam propagation at low frequency (2005)

The feasibility of transcranial ultrasound focusing with a non-moving phased array and without skull-specific aberration correction was investigated using computer simulations. Three cadaver skull CT image data sets were incorporated into an acoustic wave transmission model to simulate transskull ultrasound wave propagation. Using a 0.25 MHz hemispherical array (125 mm radius of curvature, 250 mm diameter, 24 255 elements), the simulated beams could be focused and steered with transducer element driving phases and amplitude adjusted for focal beam steering in water (water-path). A total of 82 foci, spanning wide ranges of distance in the three orthogonal dimensions, were simulated to test the focal beam steering capability inside the three skulls. The acoustic pressure distribution in a volume of 20 x 20 x 20 mm(3) centred at each focus was calculated with a 0.5 mm spacing in each axis. Clearly defined foci were retained through the skulls (skull-path) in most cases. The skull-path foci were on average 1.6 +/- 0.8 mm shifted from their intended locations. The -3 dB skull-path beam width and length were on average 4.3 +/- 1.0 mm and 7.7 +/- 1.8 mm, respectively. The skull-path sidelobe levels ranged from 25% to 55% of the peak pressure values. The skull-path peak pressure levels were about 10%-40% of their water-path counterparts. Focusing low-frequency beam through skull without skull-specific aberration correction is possible. This method may be useful for applying ultrasound to disrupt the blood-brain barrier for targeted delivery of therapeutic or diagnostic agents, or to induce microbubbles, or for other uses of ultrasound in brain where the required power levels are low and the sharp focusing is not needed.
γ-secretase directly sheds the survival receptor BCMA from plasma cells (2015)

Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases.
RecA.oligonucleotide filaments bind in the minor groove of double-stranded DNA. (1995)

Escherichia coli RecA protein, in the presence of ATP or its analog adenosine 5'-[gamma-thio]triphosphate, polymerizes on single-stranded DNA to form nucleoprotein filaments that can then bind to homologous sequences on duplex DNA. The three-stranded joint molecule formed as a result of this binding event is a key intermediate in general recombination. We have used affinity cleavage to examine this three-stranded joint by incorporating a single thymidine-EDTA.Fe (T*) into the oligonucleotide part of the filament. Our analysis of the cleavage patterns from the joint molecule reveals that the nucleoprotein filament binds in the minor groove of an extended Watson-Crick duplex.
Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options (2015)

Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions that may complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.
Approximation algorithms for a winner determination problem of single-item multi-unit auctions (2011)

This paper treats a winner determination problem of a Vickrey-Clarke-Groves mechanism based single-item multi-unit auction. For this problem, two simple 2-approximation algorithms are proposed. One is a linear time algorithm using a linear knapsack problem. The other is a greedy type algorithm. In addition, a fully polynomial time approximation algorithm based on a dynamic programming is described. Computational experiments verify availabilities of our algorithms by comparing computational times and approximation ratios.
Emerging Macrolide Resistance in Mycoplasma pneumoniae in Children (2009)

Macrolide-resistant M. pneumoniae can be associated with prolonged severe respiratory infection in children. Real-time PCR offers a rapid method of diagnosing macrolide resistance in community-acquired respiratory infections due to M. pneumoniae.
Divergence of a DNA Replication Gene Cluster in the T4-Related Bacteriophage RB69 (1998)

The genomes of bacteriophages T4 and RB69 are phylogenetically related but diverge in nucleotide sequence at many loci and are incompatible with each other in vivo. We describe here the biological implications of divergence in a genomic segment that encodes four essential DNA replication proteins: gp45 (sliding clamp), gp44/62 complex (clamp loader), and gp46 (a recombination protein). We have cloned, sequenced, and expressed several overlapping segments of the RB69 gene 46-45.2-(rpbA)-45-44-62 cluster and compared its features to those of the homologous gene cluster from T4. The deduced primary structures of all four RB69 replication proteins and gp45.2 from this cluster are very similar (80 to 95% similarity) to those of their respective T4 homologs. In contrast, the rpbA region (which encodes a nonessential protein in T4) is highly diverged (approximately 49% similarity) between the two phage genomes and does not encode protein in RB69. Expression studies and patterns of high divergence of intercistronic nucleotide sequences of this cluster suggest that T4 and RB69 evolved similar transcriptional and translational control strategies for the cistrons contained therein, but with different specificities. In plasmid-phage complementation assays, we show that posttranslationally, RB69 and T4 homologs of gp45 and the gp44/62 complex can be effectively exchanged between the two phage replicase assemblies; however, we also show results which suggest that mixed clamp loader complexes consisting of T4 gp62 and RB69 gp44 subunits are not active for phage DNA replication. Thus, specificity of the gp44-gp62 interaction in the clamp loader marks a point of departure between the T4 and RB69 replication systems.
Physicochemical Determinants of Incompatibility and Instability in Injectable Drug Solutions and Admixtures (1978)

Several physicochemical conditions or phenomena most commonly causing incompatibility, instability or related difficulties in parenteral drug solutions and admixtures are reviewed. The following factors involved in chemical incompatibilities are reviewed: concentration, pH, acid-base character, reduction-oxidation, photolysis, epimerization, temperature, dextrose catalysis and hydrolysis. The following factors involved in visual incompatibilities are discussed: pH, acid-base character, solvent system, color change, complexation, adsorption and adherence, dissolution rate, salting-out and leaching, and foaming. Pharmacists may recognize, predict and avoid parenteral imcompatibilities based on their experience, an understanding of physicochemical principles and reference to pertinent publications.
Nucleotide Excision Repair of DNA by Mammalian Cell Extracts and Purified Proteins (1993)

Nucleotide excision repair of DNA is the main strategy that mammalian cells use to remove the carcinogenic lesions caused by UV light and many other common mutagens. During this process, a multiprotein system locates a lesion and catalyzes enzymatic cleavage of the altered strand. The damaged oligonucleotide and the incision proteins are then displaced, DNA synthesis proceeds to form a short patch using the nonmodified strand as a template, and repair is completed by a DNA ligase.
Chiral Palladium(II) Complexes Possessing a Tridentate N‐Heterocyclic Carbene Amidate Alkoxide Ligand: Access to Oxygen‐Bridging Dimer Structures (2008)

Catalysts with a bite: Chiral PdII complexes were prepared with tridentate N-heterocyclic carbene amidate alkoxide ligands. Dimeric and monomeric forms were mutually convertible by acid or base treatment (see scheme). The catalysts promote asymmetric Heck reactions efficiently, offering high enantioselectivities far superior to those of existing methods. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Discovery of 3-Methyl-N-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘H-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D4 Agonist for the Treatment of Erectile Dysfunction (2006)

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.