gebhart/patrepeval huggingface dataset:
Selectivity Changes in Site-Directed Mutants of the VDAC Ion Channel: Structural Implications (1990)

The gene encoding the yeast mitochondrial outer membrane channel VDAC was subjected to site-directed mutagenesis to change amino acids at 29 positions to residues differing in charge from the wild-type sequence. The mutant genes were then expressed in yeast, and the physiological consequences of single and multiple amino acid changes were assessed after isolation and insertion of mutant channels into phospholipid bilayers. Selectivity changes were observed at 14 sites distributed throughout the length of the molecule. These sites are likely to define the position of the protein walls lining the aqueous pore and hence, the transmembrane segments. These results have been used to develop a model of the open state of the channel in which each polypeptide contributes 12 beta strands and one alpha helix to form the aqueous transmembrane pathway.
Lattice-based optimization of sequence classification criteria for neural-network acoustic modeling (2009)

Acoustic models used in hidden Markov model/neural-network (HMM/NN) speech recognition systems are usually trained with a frame-based cross-entropy error criterion. In contrast, Gaussian mixture HMM systems are discriminatively trained using sequence-based criteria, such as minimum phone error or maximum mutual information, that are more directly related to speech recognition accuracy. This paper demonstrates that neural-network acoustic models can be trained with sequence classification criteria using exactly the same lattice-based methods that have been developed for Gaussian mixture HMMs, and that using a sequence classification criterion in training leads to considerably better performance. A neural network acoustic model with 153K weights trained on 50 hours of broadcast news has a word error rate of 34.0% on the rt04 English broadcast news test set. When this model is trained with the state-level minimum Bayes risk criterion, the rt04 word error rate is 27.7%.
Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. (1995)

The significance of melanotropic hormones as physiologic regulators of cutaneous pigmentation in humans is still controversial. Until recently, no direct effect for melanotropins could be demonstrated on human melanocytes. Here we present conclusive evidence that alpha-melanotropin (alpha-melanocyte-stimulating hormone, alpha-MSH) and the related hormone corticotropin (adrenocorticotropic hormone, ACTH) stimulate the proliferation and melanogenesis of human melanocytes maintained in culture in a growth medium lacking any AMP inducer. The minimal effective dose of either hormone is 0.1 nM. In time-course experiments, the increase in cell number and tyrosinase activity became evident after one treatment of the melanocytes with 100 nM alpha-MSH for 48 hr. The mitogenic effect gradually increased to 50-270% above control, depending on the individual melanocyte strain, with continuous treatment with 100 nM alpha-MSH for 8 days, whereas the melanogenic effect became maximal (70-450% increase above control) after 4 days of treatment. Western blot analysis of tyrosinase and the tyrosinase-related proteins TRP-1 and TRP-2 revealed that alpha-MSH increased the expression of those three melanogenic proteins. This was not accompanied by any change in their mRNA levels after brief (1.5-24 hr) or prolonged (6 days) treatment with 100 nM alpha-MSH, suggesting that the increased expression of these melanogenic proteins was due to posttranscriptional events. These results demonstrate both mitogenic and melanogenic effects of alpha-MSH and ACTH on human melanocytes. That both hormones are effective at subnanomolar concentrations, combined with the presence of melanotropin receptors on human melanocytes, strongly suggests that these melanotropins play a physiologic role in regulating human cutaneous pigmentation.
Multiphoton intrapulse interference. II. Control of two- and three-photon laser induced fluorescence with shaped pulses (2003)

Nonlinear optical processes are controlled by modulating the phase of ultrafast laser pulses taking advantage of multiphoton intrapulse interference. Experimental results show orders of magnitude control over two- and three-photon excitation of large organic molecules in solution using specific phase functions. We show simulations on the effect of phase modulation on the second- and third-order amplitude of the electric field spectrum, and demonstrate that the observed control is not caused by simple changes in peak intensity.
The clinical implementation of non‐invasive prenatal diagnosis for single‐gene disorders: challenges and progress made (2013)

Recently, we have witnessed the rapid translation into clinical practice of non-invasive prenatal testing for the common aneuploidies, most notably within the United States and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium-risk pregnancies identified by serum screening and/or ultrasound scanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single-gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour-intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single-gene disorders, and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here, we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders.
Mutations affecting the enzymes involved in the utilization of 4‐aminobutyric acid as nitrogen source by the yeast Saccharomyces cerevisiae (1985)

We present genetic evidence for the enzymes 4‐aminobutyrate: 2‐oxoglutarate aminotransferase (EC 2.6.1.19) and succinate‐semialdehyde dehydrogenase [NAD(P) + ] (EC 1.2.1.16) constituting the functional pathway for the utilization of 4‐aminobutyric acid as a nitrogen source by Saccharomyces cerevisiae . We show that the pathway is induced by 4‐aminobutyric acid and that the presence of the pathway enzymes probably requires the integrity of a positive control element.
Highly Divergent Methyltransferases Catalyze a Conserved Reaction in Tocopherol and Plastoquinone Synthesis in Cyanobacteria and Photosynthetic Eukaryotes (2003)

Tocopherols are lipid-soluble compounds synthesized only by photosynthetic eukaryotes and oxygenic cyanobacteria. The pathway and enzymes for tocopherol synthesis are homologous in cyanobacteria and plants except for 2-methyl-6-phytyl-1,4-benzoquinone/2-methyl-6-solanyl-1,4-benzoquinone methyltransferase (MPBQ/MSBQ MT), which catalyzes a key methylation step in both tocopherol and plastoquinone (PQ) synthesis. Using a combined genomic, genetic, and biochemical approach, we isolated and characterized the VTE3 (vitamin E defective) locus, which encodes MPBQ/MSBQ MT in Arabidopsis. The phenotypes of vte3 mutants are consistent with the disruption of MPBQ/MSBQ MT activity to varying extents. The ethyl methanesulfonate-derived vte3-1 allele alters tocopherol composition but has little impact on PQ levels, whereas the null vte3-2 allele is deficient in PQ and alpha- and gamma-tocopherols. In vitro enzyme assays confirmed that VTE3 is the plant functional equivalent of the previously characterized MPBQ/MSBQ MT (Sll0418) from Synechocystis sp PCC6803, although the two proteins are highly divergent in primary sequence. Sll0418 orthologs are present in all fully sequenced cyanobacterial genomes, Chlamydomonas reinhardtii, and the diatom Thalassiosira pseudonana but absent from vascular and nonvascular plant databases. VTE3 orthologs are present in all vascular and nonvascular plant databases and in C. reinhardtii but absent from cyanobacterial genomes. Intriguingly, the only prokaryotic genomes that contain VTE3-like sequences are those of two species of archea, suggesting that, in contrast to all other enzymes of the plant tocopherol pathway, the evolutionary origin of VTE3 may have been archeal rather than cyanobacterial. In vivo analyses of vte3 mutants and the corresponding homozygous Synechocystis sp PCC6803 sll0418::aphII mutant revealed important differences in enzyme redundancy, the regulation of tocopherol synthesis, and the integration of tocopherol and PQ biosynthesis in cyanobacteria and plants.
Vitamin Profile of 563 Gravidas during Trimesters of Pregnancy (2002)

Despite vitamin supplementation, a vitamin profile of pregnancy indicates that vitamin deficits exist during the trimesters. Also, combination hypovitaminemias of deficient vitamins were noted; this indicates that a vitamin deficit during pregnancy does not occur in isolation.
Development of a single-phase high frequency UPS with backup PEM fuel cell and battery (2007)

This paper presents a 300 W single-phase high frequency uninterrupted power supply (UPS) with backup proton exchange membrane fuel cell (PEMFC) and battery, DC/AC inverter, DC/DC converter, AC/DC rectifier, and AC/DC recharger. The principle and structure of the PEMFC/battery hybrid UPS system are introduced and discussed. Key practical techniques of the design are presented, including the design of the PEMFC generating system, the control technique of the AC/DC rectifier, AC/DC recharger, DC/AC inverter and DC/DC converter based on a microcomputer MC68HC11K4 and other integrated circuit chips. Experimental results show that during the switching process from battery to PEMFC, and vice versa, the UPS can provide an uninterrupted alternate voltage for the load, with low cost, low weight, small volume and size, great reliability and m aintainability.
In vitro production of IL-6, IL-1 beta, and tumor necrosis factor-alpha by human embryonic microglial and neural cells (1993)

The abilities of the different cells from human central nervous system (CNS) to produce IL-6, IL-1 beta, and TNF-alpha were tested in vitro using either cultures enriched in human embryonic microglial cells or primary cultures of human embryonic CNS cells. High amounts of IL-6, low amounts of IL-1 beta but no TNF-alpha were detected in supernatants of microglial cells, kept either in FCS-free conditions or in FCS-containing medium. Moreover, IL-6 mRNA was also present in 45 to 55% of microglial cells cultured in the presence of FCS as visualized by in situ hybridization, whereas IL-1 beta mRNA remained undetectable. After prestimulation of microglial cells with LPS or IL-1 alpha, the percentage of cells labeled with an antisense IL-6 mRNA probe increased to 70% and hybridization with an antisense IL-1 beta mRNA probe became detectable. In contrast to this dyscoordinate production of cytokines by microglial cells, human monocytes, freshly isolated from blood and kept in the same culture conditions, produced high levels of the three cytokines tested. In primary cultures of human embryonic CNS cells, IL-6, IL-1 beta, and TNF-alpha were produced mostly or only by microglial cells because no IL-1 beta mRNA or IL-6 mRNA were detected in astrocytes, even after prestimulation with LPS or IL-1 alpha. Finally, IL-1 was the main inducer of IL-6 production because IL-1 alpha, but not LPS, induced a significant increase in IL-6 synthesis in cultures kept in FCS-free medium. However, in presence of FCS, LPS appeared to initiate a cascade reaction involving the production of IL-1 by microglial cells, acting as an autocrine loop to trigger IL-6 synthesis.
A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks (2007)

It has been shown that stromal-vascular fraction isolated from adipose tissues contains an abundance of CD34+ cells. Histological analysis of adipose tissue revealed that CD34+ cells are widely distributed among adipocytes and are predominantly associated with vascular structures. The majority of CD34+ cells from freshly isolated stromal-vascular fraction were CD31-/CD144- and could be separated from a distinct population of CD34+/CD31+/CD144+ (endothelial) cells by differential attachment on uncoated plastic. The localization of CD34+ cells within adipose tissue suggested that the nonendothelial population of these cells occupied a pericytic position. Analysis of surface and intracellular markers of the freshly isolated CD34+/CD31-/CD144- adipose-derived stromal cells (ASCs) showed that >90% coexpress mesenchymal (CD10, CD13, and CD90), pericytic (chondroitin sulfate proteoglycan, CD140a, and CD140b), and smooth muscle (alpha-actin, caldesmon, and calponin) markers. ASCs demonstrated polygonal self-assembly on Matrigel, as did human microvascular endothelial cells. Coculture of ASCs with human microvascular endothelial cells on Matrigel led to cooperative network assembly, with enhanced stability of endothelial networks and preferential localization of ASCs on the abluminal side of cords. Bidirectional paracrine interaction between these cells was supported by identification of angiogenic factors (vascular endothelial growth factor, hepatocyte growth factor, basic fibroblast growth factor), inflammatory factors (interleukin-6 and -8 and monocyte chemoattractant protein-1 and -2), and mobilization factors (macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor) in media conditioned by CD34+ ASCs, as well a robust mitogenic response of ASCs to basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor-BB, factors produced by endothelial cells. These results demonstrate for the first time that the majority of adipose-derived adherent CD34+ cells are resident pericytes that play a role in vascular stabilization by mutual structural and functional interaction with endothelial cells.
Mechanism of Antibacterial Activity of Choline-Based Ionic Liquids (CAGE) (2018)

The continued emergence of antibiotic-resistant organisms has severely depleted our arsenal of effective antimicrobials. Ionic liquids (ILs) show great promise as antibacterial agents but understanding the mechanism of attack on bacterial cells is key to ensuring that design of IL-based biocides impart maximum efficacy with minimal toxicity, while also avoiding the potential for the target organisms to become resistant. Here we report the antibacterial attributes of a set of choline and geranate (CAGE)-based ILs and identify the mechanism by which they interact with the Gram-negative cell wall of <i>Escherichia coli</i>. CAGE is envisaged as an antimicrobial agent to treat topical infections in skin. Our earlier work has shown that CAGE is highly effective across a breadth of bacterial, fungal, and viral species and is benign to human cells. This combination makes CAGE an ideal antimicrobial for human use. Four CAGE variants with varying ratios of choline and geranic acid were synthesized and tested for their antibacterial activity (1:4, 1:2, 1:1, and 2:1 choline:geranic acid). The minimum bactericidal concentration required to kill <i>E. coli</i> correlated with the geranic acid content. Using molecular dynamics (MD) simulations, we identified the mechanism of CAGE action on the <i>E. coli</i> membrane, namely that choline is attracted to the negatively charged cell membrane and consequently inserts geranic acid into the lipid bilayer. The disruption of the cell membrane was confirmed with propidium iodide staining via flow cytometry and scanning electron microscopy. Fourier Transform infrared spectroscopic analysis of treated cells showed an altered lipid profile similar to phase transition, indicating the disruption of the lipid bilayer conformation. <i>E. coli</i> cells repeatedly exposed to CAGE did not exhibit resistance. This study provides the fundamental mechanism of the action of choline-based ILs on Gram-negative bacteria and demonstrates the promise of CAGE as a powerful antimicrobial agent to treat infections.
Interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-6 plasma levels and cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic parameters. (2000)

Our data demonstrate that in B-CLL, plasma levels of IL-1 beta, IL-1Ra and IL-6 differ from normal, and mechanisms other than allelic imbalance of their genes account for the distinct cytokine profiles observed in this disease.
Activation of a nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus (1995)

We have characterized a cationic membrane conductance activated by metabotropic glutamatergic and muscarinic cholinergic agonists in CA3 neurons in hippocampal slice cultures using the patch-clamp technique. When the potassium concentration in the superfusing fluid was raised above 5 mM, a biphasic current was observed in cells held at -60 mV in response to stimulation of postsynaptic metabotropic glutamate receptors (mGluRs) with 1S,3R-ACPD (50 microM) or muscarinic receptors with methacholine (MCh, 5 microM). The initial inward component was due to an increase in a cationic membrane conductance as determined by its reversal potential and its sensitivity to changes in extracellular K+ or Na+. The conductance underlying this current displayed no apparent voltage sensitivity over the range -120 to -50 mV. The response was reduced by extracellular application of Ba2+, Cd2+, Mg2+, or TEA, whereas extracellular Cs+ or loading cells with BAPTA or Cs+ did not affect the current. The effects of 1S,3R-ACPD were reversibly inhibited by bath-applied MCPG, an antagonist at mGluRs. Experiments with atropine and pirenzepine indicated that non-M1 muscarinic receptors mediated the MCh-induced current. A decrease in a resting leak potassium conductance (IK,leak) was responsible for the late component of the 1S,3R-ACPD- and MCh-induced response, seen as an outward current in the bathing solution with high K+ concentration. Loading cells with GDP beta S, GTP gamma S, or GTP did not alter the cationic current, while, in the same cells, the reduction in IKleak was abolished or irreversibly activated. Single-channel recordings of cationic channel activity in the cell-attached configuration provided evidence for the requirement of second messengers in coupling these receptors to the cationic channels. The data indicate that in addition to the previously described reduction of IK,leak, IM, and IAHP, both 1S,3R-ACPD and MCh activate a nonselective cationic conductance that is clearly revealed upon elevating external K+ concentration. This current is mediated by activation of metabotropic receptors, although no evidence could be obtained to show an involvement of G-proteins.
Managing the symptoms of Beh�et?s disease (2004)

Behçet’s disease (BD) is a chronic, relapsing, systemic inflammatory vasculitis of unknown aetiology with a myriad of immunological and pathological consequences. Patients with BD are clustered along the ancient silk road, extending from Far-East Asia to Turkey. The disease affects both genders of all ages from infants to the elderly. It is a long-term, cyclical disease and such patients may have symptom-free periods of weeks, months or years that are interrupted by exacerbations of varying intensities lasting a few days, weeks or months. Clinical features include oral aphthae, genital ulcers, ocular inflammation, skin lesions, as well as articular, vascular, neurological, pulmonary, gastrointestinal, renal and genitourinary manifestations. The main histopathological finding is a widespread vasculitis of the arteries and veins of any size or thrombophilia according to the site of involvement. BD may start with just one or two small symptoms but other symptoms may gradually appear over the years. Recurrent ocular inflammation, which occurs in ∼ 50% of cases, is the major morbidity that may eventually lead to blindness. The treatment of BD is usually symptomatic and palliative. Therefore, the main objectives are to relieve symptoms associated with mucocutaneous lesions and arthritis, to modify the course of the disease, to control inflammatory eye disease, clinically suppress the inflammation and vasculitis, to prevent recurrences and thus, prevent irreversible damage. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected. The preferred treatment modalities are combined drug therapy and include topical therapies as well as systemic corticosteroids, NSAIDs, colchicine, dapsone and immunosuppressive and cytotoxic agents. Such therapies are tailored to the individual patient depending on clinical manifestations. Thalidomide, tacrolimus, IFN-α and anti-TNF monoclonal antibody have recently attracted attention as novel therapeutic approaches.
Optical Coherence Tomography Findings After an Intravitreal Injection of Bevacizumab (Avastin®) for Macular Edema From Central Retinal Vein Occlusion (2005)

Abstract. To determine whether bevacizumab could improve visual acuity and optical coherence tomography outcomes in a patient with macular edema from central retinal vein occlusion, an intravitreal injection of bevacizumab (1.0 mg) was given. Prior intravitreal injections of triamcinolone acetonide resulted in vision improvement but worsening cataract and borderline glaucoma. Wthin 1 week of the bevacizumab injection, visual acuity improved from 20/200 to 20/50 and optical coherence tomography revealed resolution of the cystic maculopathy. The improvements were maintained for at least 4 weeks. Intravitreal injections of bevacizumab may provide another treatment option for patients with macular edema from vein occlusions. [Ophthalmic Surg Lasers Imaging 2005;36:336-339.]
Cerebrospinal fluid and serum concentrations of beta‐trace protein during pregnancy (2005)

We conducted a prospective observational study among a cohort of 40 term parturients undergoing spinal anaesthesia for elective Caesarean section, to determine the concentration of beta-trace protein in cerebrospinal fluid (CSF) and serum. Serum and CSF samples, taken at the time of dural puncture, were assayed by nephelometry. The mean serum beta-trace protein concentration was 0.39 mg.l(-1) and the mean CSF concentration was 27.9 mg.l(-1), giving a mean ratio of CSF to serum concentration of 76. This ratio is higher than that published for non-pregnant females and for males because of both a higher mean CSF and a lower mean serum beta-trace protein concentration. The concentration correlated positively with both serum creatinine and gestational age. If these concentrations are used to estimate the normal range, we propose that the nephelometric measurement of beta-trace protein might prove a useful diagnostic test for cerebrospinal fluid-cutaneous fistula in parturients.