gebhart/patrepeval huggingface dataset:
CRISPR/Cas system for yeast genome engineering: advances and applications (2017)

The methods based on the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system have quickly gained popularity for genome editing and transcriptional regulation in many organisms, including yeast. This review aims to provide a comprehensive overview of CRISPR application for different yeast species: from basic principles and genetic design to applications.
A new general approach for the simultaneous chemical synthesis of large numbers of oligonucleotides: segmental solid supports (1983)

A new approach is described which will allow the simultaneous synthesis of large numbers of pre-defined oligonucleotide chains. No machine aid is needed. The simultaneous syntheses can be performed by one person and do not require much more time than is currently needed for the synthesis of just one oligonucleotide in existing strategies. The general idea is the following: One uses noninterchangeable polymeric entities from each of which enough OD units can be isolated after completion of the syntheses. Whenever growing chains on different entities have to be elongated with the same building block these entities are gathered in the same reaction vessel. After such a common reaction cycle the entities are separated and now combined according to the next common building blocks etc. The practicability of this approach is demonstrated by the synthesis of d(T-A-A-T-A-T-T-A) and d(T-A-G-T-A-C-T-A) on cellulose filter disks following the phosphotriester approach.
Analysis of expression sequence tags from Nicotiana sylvestris (2003)

Partially normalized complementary DNA (cDNA) libraries were generated from root and leaf tissues of a diploid tobacco species, Nicotiana sylvestris. Single-pass sequences were obtained from a total of 13, 019 cDNA clones and were assembled into 6, 513 non-redundant cDNA groups. We estimate that these cDNA sequences represent approximately 3, 500 unique tobacco genes. The EST database described here will become a valuable resource for future research using Nicotiana species.(Communicated by Yasuyuki YAMADA, M. J. A., June 10, 2003)
Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene‐related peptide (1995)

1. The dura mater encephali of the rat was exposed and the blood flow around branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Changes in the meningeal blood flow (MBF) following electrical stimulation of the dura mater at a parasagittal site were registered. The effects of human calcitonin gene-related peptide (h-alpha CGRP) and the CGRP antagonist (h-alpha CGRP8-37) on the MBF were tested. 2. Electrical stimulation with rectangular pulses of 0.5 ms, 10-20 V, 5-10 Hz and a duration of 30 s caused an increase of the MBF in 14 out of 16 rats tested. The increases were dependent on stimulus strength and frequency. 3. The increase in MBF was inhibited in a dose-dependent manner by topical application of 0.1 ml of h-alpha CGRP8-37 at concentrations of 10(-7) - 10(-5) M. The highest dose abolished the increase in MBF. 4. Topical administration of 0.1 ml of h-alpha CGRP at a concentration of 10(-4) M increased the basal MBF by 15% on average. 5. It is suggested that the increase in MBF following electrical stimulation of the dura mater is mediated by the release of CGRP. The contribution of the dural afferent and sympathetic and parasympathetic efferent nerve fibres to this response are discussed.
In vivo interleukin 6 gene expression in the tumoral environment in multiple myeloma (1991)

Whether interleukin 6 (IL 6) is an autocrine or paracrine myeloma cell growth factor in vivo remains unresolved. To identify which cells are producing IL 6 in vivo, we have studied the IL 6 gene expression in bone marrow mononuclear cells (BMMC) of 19 patients with multiple myeloma (MM) and in peripheral blood mononuclear cells (PBMC) of 9 patients with plasma cell leukemia (PCL). We found that the IL 6 gene was transcribed by BMMC of most patients with MM (79%). Further, IL 6 mRNA was not produced by purified myeloma cells from patients with either MM (5 patients) or PCL, but by the bone marrow environment, mainly by monocytes and myeloid cells (CD13+CD15+ cells). For 2 patients with PCL, for whom PBMC and BMMC samples were available, IL 6 mRNA could be detected in BMMC but not in PBMC. Finally, no IL 6 mRNA was detected in five freshly established IL 6-dependent myeloma cell lines. The present data give a clear-cut demonstration of the paracrine origin of IL 6 in vivo in human MM.
Molecular characterization of factor X deficiency associated with borderline plasma factor X level. (2004)

Borderline plasma factor X (FX) levels might complicate the diagnosis of FX deficiency. An asymptomatic individual with 73% FX activity was identified to be heterozygous for the Val342Ala mutation. Expression studies suggested that this substitution is responsible for a CRM+ FX variant with normal activation but modestly reduced catalytic function.
Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy (2008)

The SCN5A-encoded Na(v)1.5 Na(+) channel is expressed in interstitial cells of Cajal and smooth muscle in the circular layer of the human intestine. Patients with mutations in SCN5A are more likely to report gastrointestinal symptoms, especially abdominal pain. Twin and family studies of irritable bowel syndrome (IBS) suggest a genetic basis for IBS, but no genes have been identified to date. Therefore, our aims were to evaluate SCN5A as a candidate gene involved in the pathogenesis of IBS and to determine physiological consequences of identified mutations. Mutational analysis was performed on genomic DNA obtained from 49 subjects diagnosed with IBS who reported at least moderately severe abdominal pain. One patient hosted a loss-of-function missense mutation, G298S, that was not observed in >3,000 reference alleles derived from 1,500 healthy control subjects. Na(+) currents were recorded from the four common human SCN5A transcripts in transfected HEK-293 cells. Comparing Na(v)1.5 with G298S-SCN5A versus wild type in HEK cells, Na(+) current density was significantly less by 49-77%, and channel activation time was delayed in backgrounds that also contained the common H558R polymorphism. Single-channel measurements showed no change in Na(v)1.5 conductance. Mechanosensitivity was reduced in the H558/Q1077del transcript but not in the other three backgrounds. In conclusion, the G298S-SCN5A missense mutation caused a marked reduction of whole cell Na(+) current and loss of function of Na(v)1.5, suggesting SCN5A as a candidate gene in the pathophysiology of IBS.
Synthetic Peptide Vaccine Targeting a Cryptic Neutralizing Epitope in Domain 2 ofBacillus anthracisProtective Antigen (2009)

Current evidence suggests that protective antigen (PA)-based anthrax vaccines may elicit a narrow neutralizing antibody repertoire, and this may represent a vulnerability with PA-based vaccines. In an effort to identify neutralizing specificities which may complement those prevalent in PA antiserum, we evaluated whether sequences within the 2beta2-2beta3 loop of PA, which are apparent in the crystal structure of heptameric but not monomeric PA, might represent a target for an epitope-specific vaccine for anthrax and, further, whether antibodies to these sequences are induced in rabbits immunized with monomeric PA. We evaluated the immunogenicity in rabbits of a multiple antigenic peptide (MAP) displaying copies of amino acids (aa) 305 to 319 of this region. Overall, four out of six rabbits vaccinated with the MAP peptide in Freund's adjuvant developed high-titer, high-avidity antibody responses which cross-reacted with the immobilized peptide sequence comprising aa 305 to 319 and with PA, as determined by an enzyme-linked immunosorbent assay, and which displayed potent and durable neutralization of lethal toxin (LeTx) in vitro, with peak titers which were 452%, 100%, 67%, and 41% of the peak neutralization titers observed in positive-control rabbits immunized with PA. Importantly, analysis of sera from multiple cohorts of rabbits with high-titer immunity to PA demonstrated a virtual absence of this potent antibody specificity, and work by others suggests that this specificity may be present at only low levels in primate PA antiserum. These results highlight the potential importance of this immunologically cryptic neutralizing epitope from PA as a target for alternative and adjunctive vaccines for anthrax.
Entropy-constrained trellis coded quantization (2002)

Improved encoding performance is shown by simulation based on trellises generated by rate-1/2 convolutional encoding circuits. The formulation reserves one bit/branch to specify the path through the trellis, and the trellis branch codewords are encoded with a suitable entropy code.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The Epidemiology of Narcolepsy in Olmsted County, Minnesota: A Population-Based Study (2002)

Narcolepsy is not a rare disorder. It appears to be commoner in men. It originates most commonly in the 2nd decade. Narcolepsy without cataplexy is an important subgroup, warranting further study.
High-Fidelity Measurement of Qubits Encoded in Multilevel Superconducting Circuits (2020)

Qubit measurements are central to quantum information processing. In the field of superconducting qubits, standard readout techniques are limited not only by the signal-to-noise ratio, but also by state relaxation during the measurement. In this work, we demonstrate that the limitation due to relaxation can be suppressed by using the many-level Hilbert space of superconducting circuits: In a multilevel encoding, the measurement is corrupted only when multiple errors occur. Employing this technique, we show that we can directly resolve transmon gate errors at the level of one part in 10 3 . Extending this idea, we apply the same principles to the measurement of a logical qubit encoded in a bosonic mode and detected with a transmon ancilla, implementing a proposal by Hann et al. [Phys. Rev. A 98, 022305 (2018)]. Qubit state assignments are made based on a sequence of repeated readouts, further reducing the overall infidelity. This approach is quite general, and several encodings are studied; the codewords are more distinguishable when the distance between them is increased with respect to photon loss. The trade-off between multiple readouts and state relaxation is explored and shown to be consistent with the photon-loss model. We report a logical assignment infidelity of 5.8 10 -5 for a Fock-based encoding and 4.2 10 -3 for a quantum error correction code (the S 2, N 1 binomial code). Our results not only improve the fidelity of quantum information applications, but also enable more precise characterization of process or gate errors.
The IBM System/360 Model 91: Machine Philosophy and Instruction-Handling (1967)

The System/360 Model 91 central processing unit provides internal computational performance one to two orders of magnitude greater than that of the IBM 7090 Data Processing System through a combination of advancements in machine organization, circuit design, and hardware packaging. The circuits employed will switch at speeds of less than 3 nsec, and the circuit environment is such that delay is approximately 5 nsec per circuit level. Organizationally, primary emphasis is placed on (1) alleviating the disparity between storage time and circuit speed, and (2) the development of high speed floating-point arithmetic algorithms. This paper deals mainly with item (1) of the organization. A design is described which improves the ratio of storage bandwidth and access time to cycle time through the use of storage interleaving and CPU buffer registers. It is shown that history recording (the retention of complete instruction loops in the CPU) reduces the need to exercise storage, and that sophisticated employment of buffering techniques has reduced the effective access time. The system is organized so that execution hardware is separated from the instruction unit; the resulting smaller, semiautonomous “packages” improve intra-area communication.
Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin (2010)

Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in diverse physiological and pathological processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore, targeting ATX with small molecule inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compounds inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC(50) = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.
Routes for fructose utilization by Escherichia coli. (2001)

There are three main routes for the utilization of fructose by Escherichia coli. One (Route A) predominates in the growth of wild-type strains. It involves the functioning of the phosphoenolpyruvate:glycose phosphotransferase system (PTS) and a fructose operon, mapping at min. 48.7, containing genes for a membrane-spanning protein (fruA), a 1-phosphofructose kinase (fruK) and a diphosphoryl transfer protein (fruB), under negative regulation by a fruR gene mapping at min. 1.9. A second route (Route B) also involves the PTS and membrane-spanning proteins that recognize a variety of sugars possessing the 3,4,5-D-arabino-hexoseconfiguration but with primary specificity for mannose(manXYZ), mannitol (mtlA) and glucitol (gutA) and which, if over-produced, can transport also fructose. A third route (Route C), functioning in mutants devoid of Routes A and B, does not involve the PTS: fructose diffuses into the cell via an isoform (PtsG-F) of the major glucose permease of the PTS and is then phosphorylated by ATP and a manno(fructo)kinase (Mak+) specified by a normally cryptic 1032 bp ORF (yajF) of hitherto unknown function (Mak-o), mapping at min. 8.8 and corresponding to a peptide of 344 amino acids. Conversion of the Mak-o to the Mak+ phenotypeinvolves an A24D mutation in a putative regulatory region.
Mutational landscape and significance across 12 major cancer types (2013)

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
The role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model. (1999)

In humans, the Fc receptor for IgG, FcgammaRIIA, is expressed on macrophages and platelets and may play an important role in the pathophysiology of immune-mediated thrombocytopenia. Mice lack the genetic equivalent of human FcgammaRIIA. To better understand the role of FcgammaRIIA in vivo, FcgammaRIIA transgenic mice were generated and characterized. One transgenic mouse line expressed FcgammaRIIA on platelets and macrophages at levels equivalent to human cells, and cross-linking FcgammaRIIA on these platelets induced platelet aggregation. Immune-mediated thrombocytopenia in this transgenic line was studied using i.v. and i.p. administration of anti-mouse platelet Ab. In comparison with matched wild-type littermates that are negative for the FcgammaRIIA transgene, Ab-mediated thrombocytopenia was significantly more severe in the FcgammaRIIA transgenic mice. In contrast, FcR gamma-chain knockout mice that lack functional expression of the Fc receptors FcgammaRI and FcgammaRIII on splenic macrophages did not demonstrate Ab-mediated thrombocytopenia. We generated FcgammaRIIA transgenic x FcR gamma-chain knockout mice to examine the role of FcgammaRIIA in immune clearance in the absence of functional FcgammaRI and FcgammaRIII. In FcgammaRIIA transgenic x FcR gamma-chain knockout mice, severe immune thrombocytopenia mediated by FcgammaRIIA was observed. These results demonstrate that FcgammaRIIA does not require the FcR gamma-chain for expression or function in vivo. Furthermore, taken together, the data suggest that the human Fc receptor FcgammaRIIA plays a significant role in the immune clearance of platelets in vivo.
Rotation–vibration spectra of icosahedral molecules. II. Icosahedral symmetry, vibrational eigenfrequencies, and normal modes of buckminsterfullerene (1989)

The icosahedral symmetry of molecules such as buckyball, B12H12−2, and C20H20, is analyzed using subgroup chain defined projection operators. The icosahedral analysis is used to determine the eigenvalues and eigenvectors of a classical spring mass model of buckyball. A spectrum of Raman and dipole active modes is given using the spring constants of benzene. Corresponding dipole active and Raman active normal modes are displayed stereographically. Several choices for springs constants are discussed and a comparison with spring mass systems of reduced symmetry is made.
RECOMBINATION AND MIGRATION RATES IN NATURAL POPULATIONS OFBACILLUS SUBTILISANDBACILLUS MOJAVENSIS (1995)

We have investigated the rates of recombination and migration in native populations of two closely related, naturally competent Bacillus species. Native soil isolates of Bacillus subtilis and Bacillus mojavensis were obtained from three continents and, within North America, from populations at a range of geographical distances from one another. The rate of recombination within populations of each species was estimated from restriction-site data for three genes. Recombination was shown to occur within each species at about the same rate as neutral mutation, whatever the geographical scale or phylogenetic scale over which strains were sampled. The rate of migration between populations was estimated by a cladistic analysis and was shown to be high (i.e., Nm > 1), even among populations on different continents. The level of migration within each species is sufficient to prevent neutral geographical divergence within species.
Risk Factors for Postoperative Nausea and Vomiting (2006)

Knowledge of postoperative nausea and vomiting (PONV) risk factors allows anesthesiologists to optimize the use of prophylactic regimens. Modern PONV risk research began in the 1990s with publication of studies using logistic regression analysis to simultaneously identify multiple independent PONV predictors and publication of meta-analyses and systematic reviews. This literature shows that female gender post-puberty, nonsmoking status, history of PONV or motion sickness, childhood after infancy and younger adulthood, increasing duration of surgery, and use of volatile anesthetics, nitrous oxide, large-dose neostigmine, or intraoperative or postoperative opioids are well established PONV risk factors. Possible risk factors include history of migraine, history of PONV or motion sickness in a child's parent or sibling, better ASA physical status, intense preoperative anxiety, certain ethnicities or surgery types, decreased perioperative fluids, crystalloid versus colloid administration, increasing duration of anesthesia, general versus regional anesthesia or sedation, balanced versus total IV anesthesia, and use of longer-acting versus shorter-acting opioids. Early-phase menstruation, obesity and lack of supplemental oxygen are disproved risk factors. Current risk scoring systems have approximately 55%-80% accuracy in predicting which patient groups will suffer PONV. Further research examining genetic and under-investigated clinical patient characteristics as potential risk factors, and involving outpatients and children, should improve predictive systems.
NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells (2005)

Cu is an essential cofactor of cellular proteins but is toxic in its free state. The hepatic Cu-ATPase ATP7B has two functions in Cu homeostasis: it loads Cu+ onto newly synthesized apoceruloplasmin in the secretory pathway, thereby activating the plasma protein; and it participates in the excretion of excess Cu+ into the bile. To carry out these two functions, the membrane protein responds to changes in intracellular Cu levels by cycling between the Golgi and apical region. We used polarized hepatic WIF-B cells and high-resolution confocal microscopy to map the itinerary of endogenous and exogenous ATP7B under different Cu conditions. In Cu-depleted cells, ATP7B resided in a post-trans-Golgi network compartment that also contained syntaxin 6, whereas in Cu-loaded cells, the protein relocated to unique vesicles very near to the apical plasma membrane as well as the membrane itself. To determine the role of ATP7B's cytoplasmic NH2 terminus in regulating its intracellular movements, we generated seven mutations/deletions in this large [approximately 650 amino acid (AA)] domain and analyzed the Cu-dependent behavior of the mutant ATP7B proteins in WIF-B cells. Truncation of the ATP7B NH2 terminus up to the fifth copper-binding domain (CBD5) yielded an active ATPase that was insensitive to cellular Cu levels and constitutively trafficked to the opposite (basolateral) plasma membrane domain. Fusion of the NH2-terminal 63 AA of ATP7B to the truncated protein restored both its Cu responsiveness and correct intracellular targeting. These results indicate that important targeting information is contained in this relatively short sequence, which is absent from the related CuATPase, ATP7A.