gebhart/patrepeval huggingface dataset:
Conventional identification characteristics, mycolate and fatty acid composition, and clinical significance of MAIX AccuProbe-positive isolates of Mycobacterium avium complex (1993)

A total of 145 isolates belonging to the Mycobacterium avium complex (MAC) were tested with commercial acridinium ester-labeled DNA probes (AccuProbe, Gen-Probe). M. avium and M. intracellulare probes reacted with 102 and 36 isolates, respectively. The remaining seven isolates were clearly positive with the new probe, designated MAIX. Thus, the combined sensitivity of M. avium and M. intracellulare probes was 95.2%. The MAIX probe improved the sensitivity up to 100%. The MAIX probe also reacted with all M. avium (n = 20) and M. intracellulare (n = 20) isolates tested. Three of the seven MAIX-positive isolates were considered clinically significant. We conclude that the new MAIX probe should be used, in addition to M. avium and M. intracellulare probes, for the identification of MAC isolates. Our results also suggest that the probe may be used alone to cover the whole MAC when species differentiation is not required.
Naltrexone utility in depressed alcoholics. (1998)

The aim of this open-label pilot study was to evaluate the utility of naltrexone (50 mg per day) in decreasing alcohol use and to examine its impact on depressive symptoms among depressed alcoholics who have failed to abstain from alcohol use despite treatment with a selective serotonin reuptake inhibitor (SSRI). Fourteen ambulatory care patients, aged 18 to 65 years, with DSM-III-R comorbid diagnoses of alcohol dependence and major depressive disorder, who failed to abstain despite treatment with an antidepressant medication were enrolled in the study. Patients were followed for 12 weeks with weekly assessment of drinking behavior, depressive symptoms, functioning, alcohol craving, and side effects. The results of this study indicated a significant decrease in alcohol use and in urges to drink alcohol in the presence of the usual triggers. There was also a trend suggesting improvement in depressive symptoms and overall functioning. Naltrexone was well tolerated, with mild side effects reported at the onset of treatment.
Riboswitches: Ancient and Promising Genetic Regulators (2008)

BAIT AND SWITCH: Metabolite-sensing riboswitches make use of RNA structural modulation to regulate gene expression, as illustrated in the scheme, in response to subtle changes in metabolite concentrations. This review describes the current knowledge about naturally occurring riboswitches and their growing potential as antibacterial cellular targets and as molecular biosensors. Newly discovered metabolite-sensing riboswitches have revealed that cellular processes extensively make use of RNA structural modulation to regulate gene expression in response to subtle changes in metabolite concentrations. Riboswitches are involved at various regulation levels of gene expression, such as transcription attenuation, translation initiation, mRNA splicing and mRNA processing. Riboswitches are found in the three kingdoms of life, and in various cases, are involved in the regulation of essential genes, which makes their regulation an essential part of cell survival. Because riboswitches operate without the assistance of accessory proteins, they are believed to be remnants of an ancient time, when gene regulation was strictly based on RNA, from which are left numerous "living molecular fossils", as exemplified by ribozymes, and more spectacularly, by the ribosome. Due to their nature, riboswitches hold high expectations for the manipulation of gene expression and the detection of small metabolites, and also offer an unprecedented potential for the discovery of novel classes of antimicrobial agents.
Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers (2001)

The 5' untranslated CGG repeat in the fragile X mental retardation-1 (FMR1) gene is expanded in families with fragile X syndrome, with more than 200 CGGs resulting in mental retardation due to the absence of the encoded fragile X mental retardation protein (FMRP). Intermediate and premutation alleles, containing between approximately 40 and 200 repeats, express grossly normal FMRP levels and such carriers are widely believed to be non-penetrant, despite continued reports of subtle cognitive/psychosocial impairment and other phenotypes. Using a highly sensitive quantification assay, we demonstrate significantly diminished FMRP levels in carriers, negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpress FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate and premutation FMR1 alleles, found in approximately 4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.
Brain Natriuretic Peptide and C‐Type Natriuretic Peptide Maintain Porcine Oocyte Meiotic Arrest (2014)

Recent studies have shown that C-type natriuretic peptide (CNP) serves as a key control system during mouse oocyte maturation. We used pig models (in vitro and in vivo) to explore the role played by the natriuretic peptide family in porcine oocyte maturation. We reported the expression and location of natriuretic peptide system in different stages of porcine antral follicles. Atrial natriuretic peptide (ANP) and CNP were expressed primarily in granulosa cells, whereas brain natriuretic peptide (BNP) and natriuretic peptide receptor-B (NPRB) receptor were expressed in granulosa cells (both cumulus and mural granulosa cells) and thecal internal cells, and the natriuretic peptide receptor-A (NPRA) receptor predominantly in thecal cells. Upon in vitro culture, BNP and CNP maintained meiotic arrest of oocytes associated with cumulus cells. The expression levels of BNP, CNP, and the NPRB receptor increased upon treatment of prepubertal gilts with pregnant mare's serum gonadotropin and decreased upon subsequent human chorionic gonadotropin injection. Such dynamic changes in the expression of natriuretic peptides and their receptor paralleled the proportions of oocytes exhibiting nuclear maturation in vivo. These data indicated that BNP and CNP co-contributed to maintaining porcine meiotic arrest under physiological condition and lutenizing hormone (LH) relieved this inhibitory effect by decreasing the expression levels of BNP and CNP in vivo. Our present work, combined with previous data, improved the understanding of the oocyte meiotic arrest mechanisms and further revealed that natriuretic peptides serve as oocyte maturation inhibitor (OMI) to inhibit oocyte maturation in mammals.
Trivalent Chromium: Assessing the Genotoxic Risk of an Essential Trace Element and Widely Used Human and Animal Nutritional Supplement (2008)

Trivalent chromium [Cr(III)] is recognized as an essential nutrient, and is widely used as a nutritional supplement for humans and animals. Recent reports of the induction of genetic damage in cultured cells exposed to Cr(III) compounds in vitro have heightened the concern that Cr(III) compounds may exert genotoxic effects under certain conditions, raising the question of the relative benefit versus risk of dietary and feed supplementation practices. We have reviewed the literature since 1990 on genotoxic effects of Cr(III) compounds to determine whether recent findings provide a sufficient weight of evidence to modify the conclusions about the safety of this dietary supplement reached in the several comprehensive reviews conducted during the period 1990-2004. The extensive literature on genotoxic effects of Cr(III) compounds includes many instances of conflicting information, with both negative and positive findings often reported in similar test systems. Outcomes of in vitro tests conducted with Cr(III) in cultured cells are quite variable regardless of the chemical form of the chromium compound tested. The in vitro data show that Cr(III) has the potential to react with DNA and to cause DNA damage in cell culture systems, but under normal circumstances, restricted access of Cr(III) to cells in vivo limits or prevents genotoxicity in biological systems. The available in vivo evidence suggests that genotoxic effects are very unlikely to occur in humans or animals exposed to nutritional or to moderate recommended supplemental levels of Cr(III). However, excessive intake of Cr(III) supplements does not appear to be warranted at this time. Thus, like other nutrients that have exhibited genotoxic effects in vitro under high exposure conditions, nutritional benefits appear to outweigh the theoretical risk of genotoxic effects in vivo at normal or modestly elevated physiological intake levels.
Dictionary-driven protein annotation (2002)

Computational methods seeking to automatically determine the properties (functional, structural, physicochemical, etc.) of a protein directly from the sequence have long been the focus of numerous research groups. With the advent of advanced sequencing methods and systems, the number of amino acid sequences that are being deposited in the public databases has been increasing steadily. This has in turn generated a renewed demand for automated approaches that can annotate individual sequences and complete genomes quickly, exhaustively and objectively. In this paper, we present one such approach that is centered around and exploits the Bio-Dictionary, a collection of amino acid patterns that completely covers the natural sequence space and can capture functional and structural signals that have been reused during evolution, within and across protein families. Our annotation approach also makes use of a weighted, position-specific scoring scheme that is unaffected by the over-representation of well-conserved proteins and protein fragments in the databases used. For a given query sequence, the method permits one to determine, in a single pass, the following: local and global similarities between the query and any protein already present in a public database; the likeness of the query to all available archaeal/ bacterial/eukaryotic/viral sequences in the database as a function of amino acid position within the query; the character of secondary structure of the query as a function of amino acid position within the query; the cytoplasmic, transmembrane or extracellular behavior of the query; the nature and position of binding domains, active sites, post-translationally modified sites, signal peptides, etc. In terms of performance, the proposed method is exhaustive, objective and allows for the rapid annotation of individual sequences and full genomes. Annotation examples are presented and discussed in Results, including individual queries and complete genomes that were released publicly after we built the Bio-Dictionary that is used in our experiments. Finally, we have computed the annotations of more than 70 complete genomes and made them available on the World Wide Web at http://cbcsrv.watson.ibm.com/Annotations/.
Efficient and accurate methods for updating generalized linear models with multiple feature additions (2014)

In this paper, we propose an approach for learning regression models efficiently in an environment where multiple features and data-points are added incrementally in a multi-step process. At each step, any finite number of features maybe added and hence, the setting is not amenable to low rank updates. We show that our approach is not only efficient and optimal for ordinary least squares, weighted least squares, generalized least squares and ridge regression, but also more generally for generalized linear models and lasso regression that use iterated re-weighted least squares for maximum likelihood estimation. Our approach instantiated to linear settings has close relations to the partitioned matrix inversion mechanism based on Schur’s complement. For arbitrary regression methods, even a relaxation of the approach is no worse than using the model from the previous step or using a model that learns on the additional features and optimizes the residual of the model at the previous step. Such problems are commonplace in complex manufacturing operations consisting of hundreds of steps, where multiple measurements are taken at each step to monitor the quality of the final product. Accurately predicting if the finished product will meet specifications at each or, at least, important intermediate steps can be extremely useful in enhancing productivity. We further validate our claims through experiments on synthetic and real industrial data sets.
Therapeutic potential of benfotiamine and its molecular targets. (2018)

The water-soluble vitamin, thiamine forms an important part of the diet because of its role in the energy metabolism. The protective effects of thiamine against diabetic vascular complications have been well documented. However, slower absorption and reduced bioavailability is a major limiting factor for its clinical use. To overcome this issue, lipid-soluble derivatives of thiamine (allithiamines) was developed. Among the many synthetic lipophilic derivatives of thiamine, benfotiamine (BFT) is regarded as the first choice based on its safety and clinical efficacy data. BFT facilitates the action of thiamine diphosphate, a cofactor for the enzyme transketolase. The activation of transketolase enzyme accelerates the precursors of advanced glycation end products (AGEs) towards the pentose phosphate pathway thereby reducing the production of AGEs. The reduction in AGEs subsequently decreases metabolic stress which benefits vascular complications seen in diabetes. The effects of BFT on the AGE-dependent pathway is well established. However, several studies have shown that BFT also modulates pathways other than AGE such as arachidonic acid (AA), nuclear transcription Factor κB (NF-κβ), protein kinase B, mitogen-activated protein kinases (MAPK) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways. In the present review, we have comprehensively reviewed all the molecular targets modulated by BFT to provide mechanistic perspective to highlight its pleiotropic effects.
Different 8-Hydroxyquinolines Protect Models of TDP-43 Protein, α-Synuclein, and Polyglutamine Proteotoxicity through Distinct Mechanisms (2011)

No current therapies target the underlying cellular pathologies of age-related neurodegenerative diseases. Model organisms provide a platform for discovering compounds that protect against the toxic, misfolded proteins that initiate these diseases. One such protein, TDP-43, is implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In yeast, TDP-43 expression is toxic, and genetic modifiers first discovered in yeast have proven to modulate TDP-43 toxicity in both neurons and humans. Here, we describe a phenotypic screen for small molecules that reverse TDP-43 toxicity in yeast. One group of hit compounds was 8-hydroxyquinolines (8-OHQ), a class of clinically relevant bioactive metal chelators related to clioquinol. Surprisingly, in otherwise wild-type yeast cells, different 8-OHQs had selectivity for rescuing the distinct toxicities caused by the expression of TDP-43, α-synuclein, or polyglutamine proteins. In fact, each 8-OHQ synergized with the other, clearly establishing that they function in different ways. Comparative growth and molecular analyses also revealed that 8-OHQs have distinct metal chelation and ionophore activities. The diverse bioactivity of 8-OHQs indicates that altering different aspects of metal homeostasis and/or metalloprotein activity elicits distinct protective mechanisms against several neurotoxic proteins. Indeed, phase II clinical trials of an 8-OHQ has produced encouraging results in modifying Alzheimer disease. Our unbiased identification of 8-OHQs in a yeast TDP-43 toxicity model suggests that tailoring 8-OHQ activity to a particular neurodegenerative disease may be a viable therapeutic strategy.
Cell Entry of Dengue Virus (2008)

Dengue virus is an expanding public health problem in tropical and subtropical regions of the world, mainly owing to failure in the maintenance of control programs for the mosquito vector Aedes aegypti and increasing and unplanned urbanization. It has been estimated that over 50 million dengue virus infections of varying severity occur globally each year, making this virus the most significant mosquito-borne human pathogen. However, there is no specific antiviral therapy or vaccine for treatment or prevention. This review focuses on recent data describing the putative molecules and mechanisms involved in the complex process of dengue virus binding and entry into mosquito and mammalian cells in primary infections. Furthermore, the perspectives of these early events in the virus life cycle as a target for antidengue therapeutic strategies are also considered.
Evaluating Potential Genetic Gains in Wheat Associated with Stress‐Adaptive Trait Expression in Elite Genetic Resources under Drought and Heat Stress (2007)

ABSTRACT While genetic resources provide an invaluable gene pool for crop breeding, the majority of accessions in germplasm collections remain uncharacterized and their potential to improve stress adaptation is not quantified. A selection of 25 elite genetic resources for wheat ( Triticum aestivum L.) were characterized for agronomic and physiological trait expression in drought‐ and heat‐stressed environments. Under drought, the physiological traits best associated with yield were canopy temperature, associated with water uptake, and carbon isotope discrimination, associated with transpiration efficiency. Under heat stress stomatal conductance, leaf chlorophyll content, and canopy temperature (associated with radiation use efficiency in this environment) were well correlated with yield. Theoretical yield gains based on extrapolating the best trait expression to the highest yielding backgrounds were also estimated. Under drought, the best expression of canopy temperature and carbon isotope discrimination suggested potential yield gains of approximately 10 and 9% above the best yielding cultivars, respectively; under heat stress, canopy temperature and remobilization of stem carbohydrates suggested potential yield gains of approximately 7 and 9%, respectively. Other physiological trait expression was associated with potential yield gains to varying degrees. When considering agronomic traits, the best expression of harvest index suggested yield gains of approximately 14 and 24% in drought and hot environments, respectively, while the combined best expression of both harvest index and final aboveground biomass suggested yield gains of 30 and 34%, respectively. Principal component analysis indicated that many of the physiological traits that were associated with yield and biomass were not strongly associated with each other, suggesting potential cumulative gene action for yield if traits were combined. When comparing trait expression across drought and hot environments, several physiological traits (e.g., canopy temperature) showed closer association with each other than did performance traits, supporting the idea that such stress‐adaptive traits have generic value across stresses.
SMYD Proteins: Key Regulators in Skeletal and Cardiac Muscle Development and Function (2014)

Muscle fibers are composed of myofibrils, one of the most highly ordered macromolecular assemblies in cells. Recent studies demonstrate that members of the Smyd family play critical roles in myofibril assembly of skeletal and cardiac muscle during development. The Smyd family consists of five members including Smyd1, Smyd2, Smyd3, Smyd4, and Smyd5. They share two highly conserved structural and functional domains, namely the SET and MYND domains involved in lysine methylation and protein-protein interaction, respectively. Smyd1 is specifically expressed in muscle cells under the regulation of myogenic transcriptional factors of the MyoD and Mef2 families and the serum responsive factor. Loss of function studies reveal that Smyd1 is required for cardiomyogenesis and sarcomere assembly in skeletal and cardiac muscles. Smyd2, on another hand, is dispensable for heart development in mice. However, Smyd2 appears to play a role in myofilament organization in both skeletal and cardiac muscles via Hsp90 methylation. A Drosophila Smyd4 homologue is a muscle-specific transcriptional modulator involved in the development or function of adult muscle. The molecular mechanisms by which Smyd family proteins function in muscle cells are not well understood. It has been suggested that members of the Smyd family may use multiple mechanisms to control muscle development and cell differentiation, including transcriptional regulation, epigenetic regulation via histone methylation, and methylation of proteins other than histones, such as molecular chaperone Hsp90.
Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease (2014)

Epigenetics is a field that encompasses chemical modifications of DNA and histone proteins, both of which alter gene expression without changing the underlying nucleotide sequence. DNA methylation and modifications of histone tails have been studied in detail and are now known to be global gene regulatory mechanisms. An analogous post-transcriptional modification is chemical modification of specific nucleotides in RNA. Study of RNA modifications is a nascent field as yet, and the significance of these marks in controlling cell growth and differentiation is just beginning to be appreciated. The addition of a methyl group to adenosine (N-methyl-6-adenosine) or m6A is the most abundant modification in mammalian mRNAs. Though identified four decades ago, interest in this particular modification was set off by the discovery that the obesity gene FTO was an RNA demethylase. Since then, many studies have investigated m6A modification in different species. In this review, we summarize the current literature and hypotheses about the presence and function of this ubiquitous RNA modification in mammals, viruses, yeast and plants in terms of the consensus sequence and the methyltransferase/demethylation machinery identified thus far. We discuss its potential role in regulating molecular and physiological processes in each of these organisms, especially its role in RNA splicing, RNA degradation and development. We also enlist the methodologies developed so far, both locus-specific and transcriptome-wide, to study this modification. Lastly, we discuss whether m6A alterations have consequences on modulating disease aetiology, and speculate about its potential role in cancer.
<i>ALK</i> Fusion Detection in Circulating Free DNA: Finding an Important Needle in the Haystack (2017)

ALK rearrangements have emerged as important therapeutic targets in oncology. This commentary, in light of recently reported cases, discusses the emerging role of liquid biopsies in molecular testing and new therapeutic options for oncology patients.