gebhart/patrepeval huggingface dataset:
Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus (1993)

The importance of the vpr gene for simian immunodeficiency virus (SIV) replication, persistence, and disease progression was examined by using the infectious pathogenic molecular clone called SIVmac239. The ATG start codon of the vpr gene was converted to TTG by site-specific mutagenesis. The constructed Vpr- mutant virus is identical with the parental SIVmac239/nef-stop virus with the exception of this one nucleotide. These viruses replicated with similar kinetics and to similar extents in rhesus monkey lymphocyte cultures and in the human CEMX174 cell line. Five rhesus monkeys were inoculated with the Vpr- variant of SIVmac239/nef-stop, and two monkeys received SIVmac239/nef-stop as controls. Both controls showed reversion of the TAA stop signal in nef by 2 weeks postinfection, as has been observed previously. Reversion of the TAA stop codon in nef also occurred in the five monkeys that received the Vpr- variant, but reversion was delayed on average to about 4 weeks. Thus, the mutation in vpr appeared to delay the rapidity with which reversion occurred in the nef gene. Reversion of the TTG sequence in vpr to ATG was observed in three of the five test animals. Reversion in vpr was first observed in these three animals 4 to 8 weeks postinfection. No vpr revertants were found over the entire 66 weeks of observation in the other two test animals that received the vpr mutant. Antibodies to vpr developed in those three animals in which reversion of vpr was documented, but antibodies to vpr were not observed in the two animals in which reversion of vpr was not detected. Antibody responses to gag and to whole virus antigens were of similar strength in all seven animals. Both control animals and two of the test animals in which vpr reverted maintained high virus loads and developed progressive disease. Low virus burden and no disease have been observed in the two animals in which vpr did not revert and in the one animal in which vpr reversion was first detected only at 8 weeks. The reversion of vpr in three of the five test animals indicates that there is significant selective pressure for functional forms of vpr in vivo. Furthermore, the results suggest that both vpr and nef are important for maximal SIV replication and persistence in vivo and for disease progression.
Pulmonary Surfactant Protein A Modulates the Cellular Response to Smooth and Rough Lipopolysaccharides by Interaction with CD14 (1999)

Pulmonary surfactant protein A (SP-A) plays an important part in Ab-independent host defense mechanisms of the lung. In this study we investigated how SP-A interacts with distinct serotypes of bacterial LPS and modulates LPS-elicited cellular responses. SP-A bound to rough forms but not to smooth forms of LPS. In the macrophage-like cell line U937, SP-A inhibited mRNA expression and secretion of TNF-alpha induced by smooth LPS, but rough LPS-induced TNF-alpha expression was unaffected by SP-A. When U937 cells and rat alveolar macrophages were preincubated with SP-A, smooth LPS failed to induce TNF-alpha secretion, whereas rough LPS-induced TNF-alpha secretion was modestly increased. To clarify the mechanism by which SP-A modulates LPS-elicited cellular responses, we further examined the interaction of SP-A with CD14, which is known as a major LPS receptor. Western blot analysis revealed that CD14 was one of the SP-A binding proteins isolated from solubilized U937 cells. In addition, SP-A directly bound to recombinant soluble CD14 (rsCD14). When rsCD14 was preincubated with SP-A, the binding of rsCD14 to smooth LPS was significantly reduced but the association of rsCD14 with rough LPS was augmented. These results demonstrate the different actions of SP-A upon distinct serotypes of LPS and indicate that the direct interaction of SP-A with CD14 constitutes a likely mechanism by which SP-A modulates LPS-elicited cellular responses.
Can immunoglobulin C(H)1 constant region domain modulate antigen binding affinity of antibodies? (1996)

Although the switch process is frequently associated with affinity maturation, the constant region is not assumed to play a role in Ag-Ab binding. In the present work, we demonstrate that two clonally related human monoclonal Igs sharing identical V(H) and V(L) sequences, but expressing different isotypes (IgA1kappa(PER) and IgG1kappa(PER)), bind tubulin with significantly different affinities. This difference was mainly accounted for by a disparity in the association rate constants. These results suggest that affinity maturation of this clone could be achieved through class switching in the absence of further somatic mutations. Since the differences observed were found at the Fab level, they also suggest a role for the C(H)1 domain in structuring the Ag-binding site into a more kinetically competent form.
Fast and efficient alkaline peroxide treatment to enhance the enzymatic digestibility of steam‐exploded softwood substrates (2002)

The enzymatic digestibility of steam-exploded Douglas-fir wood chips (steam exploded at 195 degrees C, 4.5 min, and 4.5% (w/w) SO(2)) was significantly improved using an optimized alkaline peroxide treatment. Best hydrolysis yields were attained when the steam-exploded material was post-treated with 1% hydrogen peroxide at pH 11.5 and 80 degrees C for 45 min. This alkaline peroxide treatment was applied directly to the water-washed, steam-exploded material eliminating the need for independent alkali treatment with 0.4% NaOH, which has been traditionally used to post-treat wood samples to try to remove residual lignin. Approximately 90% of the lignin in the original wood was solubilized by this novel procedure, leaving a cellulose-rich residue that was completely hydrolyzed within 48 h, using an enzyme loading of 10 FPU/g cellulose. About 82% of the originally available polysaccharide components of the wood could be recovered. The 18% of the carbohydrate that was not recovered was lost primarily to sugar degradation during steam explosion.
Anti-Tumor Necrosis Factor-α Induced Systemic Lupus Erythematosus§ (2012)

Anti-tumor necrosis factor-alpha induced lupus (ATIL) represents a major diagnostic and therapeutic challenge. Most cases of ATIL are caused by infliximab, followed by etanercept and adalimumab. Symptoms can range from common, mild cutaneous lesions to rare, serious pleural or pericardial effusions, deep venous thrombosis, life-threatening pneumonitis, and neuritis. Constitutional symptoms often present in association with positive autoantibody serology. Diagnosis can be considered if there is a temporal relationship between symptoms and anti-tumor necrosis factor-α (TNF- α) therapy and at least one serologic and one non-serologic American College of Rheumatology criteria. Since it is contraindicated to use anti-TNF-α drugs in patients with systemic lupus erythematosus, it is recommended to perform a thorough immunological screening in any patient with polyarthritis to assure accurate diagnosis. In addition, prior to anti- TNF therapy, baseline immunological investigations (including antinuclear antibodies) should be performed, and there should be close follow up to assess the development of lupus manifestations. The main approach in the treatment of ATIL is withdrawal of the offending drug. Traditional therapy with corticosteroids and immunosuppressive agents may be required to achieve full resolution of lupus symptoms. In this review, we discuss the pathogenesis, clinical manifestations, and management of ATIL.
Physiological role and potential clinical interest of mycobacterial pigments (2011)

The production of pigments by bacterial colonies has sparked interest among bacteriologists since the 19th century, whether for taxonomy or, in the case of carotenoids for their association with antibiotics resistance. Mycobacteria have gained a very special place in the bacterial world due to their clinical importance. Alone, Mycobacterium tuberculosis is responsible for about two million deaths annually worldwide making tuberculosis one of the most influential diseases in the history of mankind. Almost half of the Nontuberculous Mycobacteria species identified are associated with opportunistic infections in animals and humans. Mycobacterial pigmentary characteristics started to be documented about 80 years ago; but to date, their main use has been only for limited taxonomic and identification purposes. While mycobacterial pigments, especially carotenoids have been clearly associated with cellular photoprotection and survival, the regulation of their production and their physiological role have been largely unstudied. Recent advances in deciphering mycobacterial genomes and characterization of carotenoid synthesis genes, combined with an urgent need for innovative approaches to understand Mycobacterium tuberculosis pathogenic properties open new avenues for exciting research opportunities that might lead to new therapeutic strategies against a devastating secular disease.
Real-world safety data and differentiation of second-line (2L) 5-fluorouracil (5-FU) based regimens among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). (2021)

390 Background: Chemotherapy related adverse events (AEs) can impact the treatment of patients, reducing quality of life and leading to dose delays and treatment discontinuation. This study examined the proportion of patients (pts) with mPDAC treated with 5-FU-based regimens in the 2L setting who experienced AEs during treatment. Methods: Data were extracted for pts diagnosed with mPDAC who initiated 2L treatment between January 2016 and July 2020 from the Flatiron Health electronic health database. Pts included in the study were treated with FOLFIRINOX (FFX), FOLFOX, FOLFIRI, or a regimen containing liposomal irinotecan. The occurrence of grade 3 (G3) and grade 4 (G4) neutropenia, G3/G4 elevated alanine transaminase (ALT) and anemia where transfusion was indicated were determined using lab results and the grading criteria from the Common Terminology Criteria for Adverse Events v4.03. The occurrence of diarrhea, fatigue, nausea and vomiting (N/V), and neuropathy were identified from structured diagnosis records through ICD-10-CM codes. Duration of therapy (DOT) was assessed for each regimen. Descriptive statistics for AEs and DOT were reported. Results: Of the 804 pts included in the study, 28.4% (n=228) received FFX, 39.8% (n=320) received regimens containing liposomal irinotecan, 24.8% (n=199) received FOLFOX, and 7.1% (n=57) received FOLFIRI. The median DOT (IQR) was 86 days (d) (43 – 206), 79d (41 – 169), 72d (43 – 166), and 84d (46 – 148) for pts who received FFX, liposomal irinotecan, FOLFOX, and FOLFIRI, respectively. G3/G4 neutropenia (&lt;1000/mm3) presented in 28.1% (n=64) of pts treated with FFX, 11.9% (n=38) of pts treated with liposomal irinotecan, 17.1% (n=34) of pts treated with FOLFOX, and 36.8% (n=21) of pts treated with FOLFIRI. NV occurred in 14.9% (n=34), 13.1% (n=42), 12.6% (n=25), and 10.5% (n=6), respectively. The full AE results are summarized in the table. Conclusions: In this assessment of often dose-limiting AEs among pts with mPDAC treated in 2L, pts who received liposomal irinotecan had the lowest proportion of neutropenia. No clear pattern was noted for N/V, neuropathy, fatigue, anemia, and elevated ALT. Further research is necessary to determine the real-world cost implications of AEs in this patient population. [Table: see text]
Pharmacological Suppression of Hepcidin Increases Macrophage Cholesterol Efflux and Reduces Foam Cell Formation and Atherosclerosis (2011)

These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.
The Streptococcal Hyaluronan Synthases Are Inhibited by Sulfhydryl-modifying Reagents, but Conserved Cysteine Residues Are Not Essential for Enzyme Function (2002)

Hyaluronan (HA) synthase (HAS) is a membrane-bound enzyme that utilizes UDP-glucuronic acid (GlcUA) and UDP-GlcNAc to synthesize HA. The HAS from Streptococcus pyogenes (spHAS, 419 amino acids) contains six Cys residues, whereas the enzyme from Streptococcus equisimilis (seHAS, 417 amino acids) contains four Cys residues. These Cys residues of seHAS are highly conserved in all Class I HAS family members. Here we investigated the structural and functional roles of these conserved cysteines in seHAS by using site-directed mutagenesis and sensitivity to sulfhydryl modifying reagents. Both seHAS and spHAS were inhibited by sulfhydryl reagents such as N-ethylmaleimide (NEM) and iodoacetamide in a dose-dependent and time-dependent manner. These inhibition curves were biphasic, indicating the presence of sensitive and insensitive components. After treatment of seHAS with NEM, the V(max) value was decreased approximately 50%, and the K(m) values changed only slightly. All the Cys-to-Ala mutants of seHAS were partially active. The least active single (C226A), double (C226A,C262A), or triple (C226A,C262A,C367A) Cys mutants retained 24, 3.2, and 1.4% activity, respectively, compared with wild-type enzyme. Surprisingly, the V(max) value of the seHAS(cys-null) mutant was approximately 17% of wild-type, although the K(m) values for both substrates were increased 3-6-fold. Cys residues, therefore, are not involved in a critical interaction necessary for either substrate binding or catalysis. However, the distribution of HA products was shifted to a smaller size in approximately 25% of the seHAS Cys mutants, particularly the triple mutants. Mass spectroscopic analysis of wild-type and Cys-null seHAS as well as the labeling of all double Cys-to-Ala mutants with [(14)C]NEM demonstrated that seHAS contains no disulfide bonds. We conclude that the four Cys residues in seHAS are not directly involved in catalysis, but that one or more of these Cys residues are located in or near substrate binding or glycosyltransferase active sites, so that their modification hinders the functions of HAS.
Diffusion-tensor imaging—guided tracking of fibers of the pyramidal tract combined with intraoperative cortical stimulation mapping in patients with gliomas (2004)

The use of precise intraoperative cortical mapping information and DT images of fiber tracks can reveal the course of motor pathways beneath the cortex. The subcortical fiber tracks generated are consistent with the known anatomical course and somatotopic organization of the motor tract in relation to its cortical origins. Tracking fibers by using DT imaging in combination with functional localization has the potential to reduce surgical morbidity by revealing subcortical connections of the functional cortex.
Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain (2007)

Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then approximately 2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100 mm VAS) or two-point discrimination (TPD) during a no-treatment waiting period, nor during the stimulation phase (p > 0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS = 27 mm (14-40 mm) and for TPD = 5.7 mm (2.9-8. ), p < 0.015 for both]. These gains were maintained at three-month follow-up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli.
Effect of Increased Bile Acid Synthesis or Fecal Excretion in Irritable Bowel Syndrome-Diarrhea (2014)

IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.
Immunological and biological potencies of the different molecular species of gonadotrophins (1988)

Pituitary gonadotrophins (follicle-stimulating hormone, FSH; luteinizing hormone, LH) exist in different molecular forms within the anterior pituitary gland and serum of several non-mammalian and mammalian species, including man. The number and relative abundance of each gonadotrophin species will depend on the specific technique utilized for their isolation, the tissue source and the physiological status of the donor. Intracellular FSH and LH from glands of rodents (hamsters and rats) and primates exhibit charge heterogeneity and therefore may be separated into several forms or iso-hormones by isoelectric focusing (IEF). These FSH and LH species differ from each other not only in their isoelectric point (pI) but also in their relative abundance, receptor binding activity, biological activity and plasma half-life. Almost all gonadotrophin species isolated from pituitary extracts have also been detected in vitro and in vivo as secreted forms. Less basic rodent LH and FSH forms exhibit low receptor binding and in-vitro biological activities; a similar trend is found in LH and FSH species isolated from glands of monkeys and humans. However, these relatively acidic isohormones have longer circulatory half-lives and higher in-vivo biological activities than less negatively charged forms. The overall pattern of charge heterogeneity of gonadotrophins varies according to the specific endocrine status of the donor. Sex steroid hormones (mainly oestrogens) and gonadotrophin-releasing hormone seem to act in concert at the pituitary level to influence the physicochemical and functional characteristics of gonadotrophins and therefore their biological expression at the target cell. The effects of these factors appear to be mediated through the incorporation of specific carbohydrate residues and/or degree of terminal sugar sulphation at co-post-translational levels. The first result of these complex interactions between the gonad and the hypothalamic-pituitary unit is the production and secretion of various types of gonadotrophin molecules in proportions according with the physiological requirements of the subject at a given time, to perform specific actions upon gonadal maturation and/or function.
Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis (2008)

Increased FGF-23 levels appear to be independently associated with mortality among patients who are beginning hemodialysis treatment. Future studies might investigate whether FGF-23 is a potential biomarker that can be used to guide strategies for the management of phosphorus balance in patients with chronic kidney disease.
Application-Specific Pipelines for Exploiting Instruction-Level Parallelism (1998)

Application-specific processor design is a promising approach for meeting the performance and cost goals of a system. Application-specific processors are especially promising for embedded systems (e.g., automobile control systems, avionics, cellular phones, etc.) where a small increase in performance and decrease in cost can have a large impact on a product&#39;s viability. Sutherland, Sproull, and Molnar have proposed a new pipeline organization called the Counterflow Pipeline (CFP). This paper shows that the CFP is an ideal architecture for fast, low-cost design of high-performance processors customized for computation-intensive embedded applications. First, we describe why CFP&#39;s are particularly well suited to realizing application-specific processors. Second, we describe how a CFP tailored to an application can be constructed automatically. Third, we present measurements that show CFP&#39;s elegantly and simply provide speculative execution, out-of-order execution, and register renaming that is matched to the application. These measurements show that CFP&#39;s speculative and out-of-order execution allow it to tolerate frequent control dependences and high-latency operation such as memory accesses. Finally, we show that asynchronous counterflow pipelines may achieve very high-performance by reducing the average execution latency of instructions over synchronous implementations. Application speedups of up to 7.8 are achieved using custom counterflow pipelines for several well-known kernel loops.
Epithelial sodium channel regulated by aldosterone-induced protein sgk (1999)

Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate electrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na+ absorption and thus in the control of extracellular fluid volume, blood pressure, and sodium homeostasis.
Stability and folding of ultrastable proteins: eye lens crystalline and enzymes from thermophiles 1 (1996)

Soluble globular proteins exhibit marginal stabilities, equivalent to only a few weak intermolecular interactions. Extreme conditions in the biosphere, as well as acute physiological stress, require either mutative adaptation or stabilization by accessory proteins or extrinsic factors such as metabolites, cofactors, or compatible solvent components. No general strategies of stabilization have yet been established. However, certain contributions to stability have been elucidated by analyzing extremely stable proteins, such as crystallins from the eye lens, or proteins from hyperthermophilic microorganisms. Relating the structure and stability of homologous proteins from mesophiles and extremophiles, it becomes clear that stability increments may accumulate from 1) local interactions, 2) secondary or supersecondary structure, 3) packing and docking of domains, 4) association of subunits, and 5) conjugation with prosthetic groups, carbohydrate moieties, or nucleic acids, etc. Single and multiple point mutations, nicking and swapping of folding units in domain proteins, grafting of linker peptides between domains, and dissociation-reassociation of oligomeric proteins give insight into the cumulative nature of protein stability and its relation to the hierarchy of protein structure and folding. In this review, beta gamma-crystallins and enzymes from hyperthermophilic microorganisms are used as models to discuss mechanisms of protein stabilization.