gebhart/patrepeval huggingface dataset:
Two trans-acting regulatory genes (vir and mod) control antigenic modulation in Bordetella pertussis (1988)

Expression of virulence factors by Bordetella pertussis is altered by environmental signals (antigenic modulation) and is dependent on an activator encoded by a gene called vir. We have used TnphoA (Tn5 IS50L::phoA) gene fusions to define two sets of genes whose expression is either activated (vag loci) or repressed (vrg loci) by modulation signals. Both groups of genes appear to be regulated by the vir gene product in that, in the absence of modulators, null mutations in vir lead to the repression of vag gene fusions and derepression of vrg gene fusions. Mutants of B. pertussis were isolated that constitutively express virulence factors in the presence of the modulator MgSO4, nicotinic acid, or low incubation temperature. We designate the gene that carries such mutations mod (modulation) and have characterized one (mod-1) of these mod constitutive mutations. A method was developed for the insertional inactivation of the vir gene by using the integration of a suicide replicon. Inactivation of the vir gene in the mod-1 mutant, followed by transcomplementation with the cloned wild-type vir gene, gives the Mod-1 constitutive phenotype, showing that the mod-1 mutation defines a gene distinct from vir. The gene carrying the mod-1 mutation is linked to vir and was cloned on a recombinant cosmid (pLAF-C1) which transcomplements the vir-1::Tn5 mutation in B. pertussis 347. Introduction of pLAF-C1 into vir mutant and vir+ B. pertussis strains also gives the Mod-1 constitutive phenotype, indicating that mod-1 is a dominant allele. These data suggest that the mod gene product could have sensory functions for the environmental signals that affect the expression of vir-regulated genes of B. pertussis. The mod constitutive strains and plasmids described here also have applications in pertussis vaccine development.
The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis (2016)

Anti-PD-1/PD-L1 antibodies have high response rates and low adverse effect rates for advanced or refractory cancers.
The DRAGON system--An overview (1975)

This paper briefly describes the major features of the DRAGON speech understanding system. DRAGON makes systematic use of a general abstract model to represent each of the knowledge sources necessary for automatic recognition of continuous speech. The model--that of a probabilistic function of a Markov process--is very flexible and leads to features which allow DRAGON to function despite high error rates from individual knowledge sources. Repeated use of a simple abstract model produces a system which is simple in structure, but powerful in capabilities.
Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia (2017)

Thyroid hormones have important effects on cellular development, growth, and metabolism and are necessary for the healthy function of almost all tissues. Hyperthyroid patients with excess thyroid hormone levels experience tachycardia, fatigue, muscle wasting, and osteoporosis. However, although high thyroid hormone levels have adverse effects, efforts have been made to harness the beneficial effects, such as reduced serum low-density lipoprotein (LDL) cholesterol levels, elevated basal metabolic rate, and weight loss. Thyroid hormones interact with nuclear thyroid hormone receptors (TRs), and cholesterol levels are reduced through TRβ, whereas extrahepatic adverse actions are primarily connected to TRα. Thus, to develop a useful compound for clinical use, efforts have been focusing on developing compounds with isomer-specific functions based on the structure of thyroid hormones, i.e., thyromimetics that are liver and/or TRβ specific. In this short review, we discuss the development of the early thyromimetics that enabled, through modern molecular techniques, the progress towards improved design of TRβ-selective thyromimetics. We also address the early promise shown in human clinical trials and the current status of these drugs and other emerging compounds.
RNA Editing as a Therapeutic Approach for Retinal Gene Therapy Requiring Long Coding Sequences (2020)

RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as <i>USH2A</i> and <i>ABCA4</i>, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.
The vertebrate genome: isochores and evolution. (1993)

Vertebrate genomes are mosaics of isochores--namely, of long (> 300 kb), compositionally homogeneous DNA segments that can be subdivided into a small number of families characterized by different GC levels. In the human genome (which is representative of a number of mammalian genomes, and, more broadly, of the genomes of warm-blooded vertebrates), the compositional range of isochores is 30%-60% GC, and five families of isochores have been identified: two GC-poor families, L1 and L2, together representing 62% of the genome, and three GC-rich families, H1, H2, and H3, representing 22%, 9%, and 3%, respectively (the remaining 4% of the genome is formed by satellite and ribosomal DNA). Gene concentration is strikingly nonuniform, being highest in the H3 isochore family, lowest in the L1 + L2 families, and intermediate in the H1 + H2 families. The H3 family corresponds to T(elomeric) bands of metaphase chromosomes, and the L1 + L2 families correspond to G(iemsa) bands, whereas R(everse) bands comprise both GC-poor and GC-rich isochores. The compositional distributions of large genome fragments, of exons (and their codon positions), and of introns are correlated with each other. They represent compositional patterns and are very different between the genomes of cold- and warm-blooded vertebrates, mainly in that the former are much less heterogeneous in base composition and never reach the highest GC levels attained by the latter. Only relatively small compositional differences are found among the genomes of either cold- or warm-blooded vertebrates. Compositional patterns allow one to define two modes in genome evolution: a conservative mode, with no compositional change, and a transitional (or shifting) mode, with compositional changes. The conservative mode can be observed among either cold- or warm-blooded vertebrates. The transitional mode comprises both major and minor compositional changes. In vertebrate genomes, the major changes are associated with the appearance of GC-rich and very GC-rich isochores in mammalian and avian genomes. Mutational biases play a role in both modes of compositional evolution. According to one viewpoint, the fixation of compositionally biased mutations is responsible for the transitional mode of evolution of bacterial genomes; in the conservative mode of evolution of vertebrates, they accomplish their role in conjunction with differences either in chromatin structures that modulate replication errors or in chromatin transcriptional activities that may lead to various extents of repair-DNA synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
ABC Transporters and the Blood-Brain Barrier (2004)

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier to the free diffusion of many polar solutes into the brain. Many metabolites that are polar have their brain entry facilitated by specific inwardly-directed transport mechanisms. In general the more lipid soluble a molecule or drug is, the more readily it will tend to partition into brain tissue. However, a very significant number of lipid soluble molecules, among them many useful therapeutic drugs have lower brain permeability than would be predicted from a determination of their lipid solubility. These molecules are substrates for the ABC efflux transporters which are present in the BBB and BCSB and the activity of these transporters very efficiently removes the drug from the CNS, thus limiting brain uptake. P-glycoprotein (Pgp) was the first of these ABC transporters to be described, followed by the multidrug resistance-associated proteins (MRP) and more recently breast cancer resistance protein (BCRP). All are expressed in the BBB and BCSFB and combine to reduce the brain penetration of many drugs. This phenomenon of "multidrug resistance" is a major hurdle when it comes to the delivery of therapeutics to the brain, not to mention the problem of cancer chemotherapy in general. Therefore, the development of strategies for bypassing the influence of these ABC transporters and for the design of effective drugs that are not substrates and the development of inhibitors for the ABC transporters becomes a high imperative for the pharmaceutical industry.
Characterization of a novel transporter family that includes multiple Escherichia coli gluconate transporters and their homologues (2006)

The nucleotide sequences of seven Escherichia coli genes that encode members of the gluconate permease (GntP) family have recently become available. These genes include gntP, gntU, gntW, ORf449, dsdX, and ORFo454. The deduced amino acid sequences of all seven E. coli genes are homologous to the gntP gene products from Bacillus subtilis and B. licheniformis as well as two additional gene products from Haemophilus influenzae. These 11 proteins are not demonstrably homologous to members of the major facilitator superfamily or other recognized permease families. Four of the E. coli gluconate transporter genes have been cloned and shown to encode gluconate transporters with apparent affinities ranging from 6 to 212 microM. These studies serve to characterize a novel family of bacterial permeases.
Sphingolipids and the Balancing of Immune Cell Function: Lessons from the Mast Cell (2005)

Recent studies reveal that metabolites of sphingomyelin are critically important for initiation and maintenance of diverse aspects of immune cell activation and function. The conversion of sphingomyelin to ceramide, sphingosine, or sphingosine-1-phosphate (S1P) provides interconvertible metabolites with distinct biological activities. Whereas ceramide and sphingosine function to induce apoptosis and to dampen mast cell responsiveness, S1P functions as a chemoattractant and can up-regulate some effector responses. Many of the S1P effects are mediated through S1P receptor family members (S1P(1-5)). S1P(1), which is required for thymocyte emigration and lymphocyte recirculation, is also essential for Ag-induced mast cell chemotaxis, whereas S1P(2) is important for mast cell degranulation. S1P is released to the extracellular milieu by Ag-stimulated mast cells, enhancing inflammatory cell functions. Modulation of S1P receptor expression profiles, and of enzymes involved in sphingolipid metabolism, particularly sphingosine kinases, are key in balancing mast cell and immune cell responses. Current efforts are unraveling the complex underlying mechanisms regulating the sphingolipid pathway. Pharmacological intervention of these key processes may hold promise for controlling unwanted immune responses.
Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis (2011)

Currently, surgery remains the treatment of choice for patients with TGCT/PVNS. Localized TGCT/PVNS is managed by marginal excision. Recurrences occur in 8-20% of patients and are easily managed by re-excision. Diffuse TGCT/PVNS tends to recur more often (33-50%) and has a much more aggressive clinical course. Patients are often symptomatic and require multiple surgical procedures during their lifetime. For patients with unresectable disease or multiple recurrences, systemic therapy using CSF1R inhibitors may help delay or avoid surgical procedures and improve functional outcomes.
Loss-aware Weight Quantization of Deep Networks (2018)

The huge size of deep networks hinders their use in small computing devices. In this paper, we consider compressing the network by weight quantization. We extend a recently proposed loss-aware weight binarization scheme to ternarization, with possibly different scaling parameters for the positive and negative weights, and m-bit (where m &gt; 2) quantization. Experiments on feedforward and recurrent neural networks show that the proposed scheme outperforms state-of-the-art weight quantization algorithms, and is as accurate (or even more accurate) than the full-precision network.
Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats (2015)

VNS paired with rehabilitative training confers significantly greater recovery of forelimb function after chronic ischemic stroke in rats.
Phase-shift mask pattern accuracy requirements and inspection technology (1991)

Computer simulations and i-line phase shift lithography experiments with programmed 5X phase shift reticle defects were used to investigate the effect of opaque and phase-shift layer defects on sub-half-micron lines. Both the simulations and the experiments show that defects in the phase shift layer print larger than corresponding opaque defects, with 0.3-0.4 micrometers defects affecting sub-half-micron critical dimensions by more than the allowable 10%. Inspection of programmed phase shift defects with a prototype mask inspection system confirmed that the system finds the 0.3-0.4 micrometers phase shift defects critical to sub-half-micron lithography.
Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis (2003)

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.
Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis (2006)

Boundaries between cellular compartments often serve as signaling interfaces during embryogenesis. The coronal suture is a major growth center of the skull vault and develops at a boundary between cells derived from neural crest and mesodermal origin, forming the frontal and parietal bones, respectively. Premature fusion of these bones, termed coronal synostosis, is a common human developmental anomaly. Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2. In Twist1(+/-) mice with coronal synostosis, we found that the frontal-parietal boundary is defective. Specifically, neural crest cells invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal suture. This boundary defect is accompanied by an expansion in Msx2 expression and reduction in ephrin-A4 distribution. Reduced dosage of Msx2 in the Twist1 mutant background restores the expression of ephrin-A4, rescues the suture boundary and inhibits craniosynostosis. Underlining the importance of ephrin-A4, we identified heterozygous mutations in the human orthologue, EFNA4, in three of 81 patients with non-syndromic coronal synostosis. This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis.
Neuronutrient effects on weight loss in carbohydrate bingers: an open clinical trial. (1990)

In as much as neurotransmitters and neuromodulators are known to stimulate or inhibit eating behavior, we elected to examine the effects of precursor amino acid loading and enkephalinase inhibition. We investigated the effect of the experimental neuronutrient PCAL-103 on weight loss, uncontrollable carbohydrate binging, and relapse rates in outpatients attending a supervised diet-controlled treatment program
A Structural Basis for the Acute Effects of HIV Protease Inhibitors on GLUT4 Intrinsic Activity (2004)

Human immunodeficiency virus (HIV) protease inhibitors (PIs) act as reversible noncompetitive inhibitors of GLUT4 with binding affinities in the low micromolar range and are known to contribute to alterations in glucose homeostasis during treatment of HIV infection. As aspartyl protease inhibitors, these compounds all possess a core peptidomimetic structure together with flanking hydrophobic moieties. To determine the molecular basis for GLUT4 inhibition, a family of related oligopeptides containing structural elements found in PIs was screened for their ability to inhibit 2-deoxyglucose transport in primary rat adipocytes. The peptide oxybenzylcarbonyl-His-Phe-Phe-O-ethyl ester (zHFFe) was identified as a potent inhibitor of zero-trans glucose flux with a K(i) of 26 mum. Similar to PIs, transport inhibition by this peptide was acute, noncompetitive, and reversible. Within a Xenopus oocyte expression system, zHFFe acutely and reversibly inhibited GLUT4-mediated glucose uptake, whereas GLUT1 activity was unaffected at concentrations as high as 1 mm. The related photoactivatable peptide zHFF-p-benzoylphenylalanine-[(125)I]Tyr-O-ethyl ester selectively labeled GLUT4 in rat adipocytes and indinavir effectively protected against photolabeling. Furthermore, GLUT4 bound to a peptide affinity column containing the zHFF sequence and was eluted by indinavir. These data establish a structural basis for PI effects on GLUT4 activity and support the direct binding of PIs to the transport protein as the mechanism for acute inhibition of insulin-stimulated glucose uptake.
Microspore Culture in Brassica (2003)

Pioneering research in Brassica microspore culture (1,2,3)rapidly led to the realization that microspores provide a powerful alternative to protoplast culture as a single-celled culture method in plants. These two single-celled systems are fundamentally different, both in tissue origin and in genetic variability. The microspore system improves significantly on the protoplast system by virtually eliminating the large somaclonal variation associated with protoplast selection, by utilizing a true haploid cell system, and by resulting in a more synchronized embryo development that facilitates accurate mutation and selection methods. Most critical, however, are the observations that plant regeneration frequencies in excess of 80% can be readily obtained and that the entire sequence from microspore isolation to plantlet development may take place in as little as 4 wk (4).
Electroacoustic characteristics of marine seismic streamers (1970)

Abstract To specify intelligently an unambiguous tow-noise level in marine seismic exploration, the electroacoustic characteristics of the streamer must be understood. In this paper, these characteristics are examined as a basis for an industry-wide standard for specifying streamer tow-noise level.Sources of tow noise--including electrical, ambient, flow, radiated, and mechanically induced--are examined and the important parameters that control their amplitude spectrum are presented. The theoretical bases for various means of reducing the components of tow noise are analyzed and compared with experimental results.With this background of tow-noise sources and noise-reduction schemes, the noise signal is traced from the hydrophone/seawater interface to the recording system. The hydrophone array's amplitude response and phase response are determined from the transfer characteristics of the coupling circuit and the recording system.Finally, a method for specifying tow-noise level is proposed. The specified tow-noise level is referenced to the hydrophone input terminals and is monitored at the output of the recording system. Therefore, the standard requires that the important electroacoustic characteristics outlined in this paper be specified.
Genome-Wide Reprogramming of Primary and Secondary Metabolism, Protein Synthesis, Cellular Growth Processes, and the Regulatory Infrastructure of Arabidopsis in Response to Nitrogen (2004)

Transcriptome analysis, using Affymetrix ATH1 arrays and a real-time reverse transcription-PCR platform for >1,400 transcription factors, was performed to identify processes affected by long-term nitrogen-deprivation or short-term nitrate nutrition in Arabidopsis. Two days of nitrogen deprivation led to coordinate repression of the majority of the genes assigned to photosynthesis, chlorophyll synthesis, plastid protein synthesis, induction of many genes for secondary metabolism, and reprogramming of mitochondrial electron transport. Nitrate readdition led to rapid, widespread, and coordinated changes. Multiple genes for the uptake and reduction of nitrate, the generation of reducing equivalents, and organic acid skeletons were induced within 30 min, before primary metabolites changed significantly. By 3 h, most genes assigned to amino acid and nucleotide biosynthesis and scavenging were induced, while most genes assigned to amino acid and nucleotide breakdown were repressed. There was coordinate induction of many genes assigned to RNA synthesis and processing and most of the genes assigned to amino acid activation and protein synthesis. Although amino acids involved in central metabolism increased, minor amino acids decreased, providing independent evidence for the activation of protein synthesis. Specific genes encoding expansin and tonoplast intrinsic proteins were induced, indicating activation of cell expansion and growth in response to nitrate nutrition. There were rapid responses in the expression of many genes potentially involved in regulation, including genes for trehalose metabolism and hormone metabolism, protein kinases and phosphatases, receptor kinases, and transcription factors.