gebhart/patrepeval huggingface dataset:
Toxicity of Excipients--A Food and Drug Administration Perspective (2003)

Excipients are essential components of drug products. They are also potential toxicants. Examples of known excipient-induced toxicities include renal failure and death from diethylene glycol, osmotic diarrhea caused byingested mannitol, hypersensitivity reactions from lanolin, and cardiotoxicity induced by propylene glycol. Proposals to test or market new drug products in the United States should adequately address the safety of the proposed exposure to the excipients in those products. The specific safety data that may be needed will vary depending upon the clinical situation, including such factors as the duration, level, and route of exposure, but may include acute, repeat-dose, reproductive, and genetic toxicity data, carcinogenicity data, and specialized toxicology information, such as sensitization or local irritation data. Many guidances exist to aid in the development of pharmaceuticals, including the International Conference on Harmonization (ICH) documents and various Food and Drug Administration/Center for Drug Evaluation and Research (FDA/CDER) pharmacology and toxicology guidances. The FDA/CDER has recently adopted a new guidance for industry, “Nonclinical Studies for Development of Pharmaceutical Excipients,” which focuses on issues associated with development of safety databases that will support clinical use of excipients in drug products. The new guidance document is introduced and discussed in this article.
Levodopa methyl ester treatment of Parkinson's disease (1987)

Intravenously administered levodopa is effective although relatively impractical for the chronic treatment of patients with Parkinson's disease who are disabled by motor fluctuation. In view of its greater solubility, levodopa methyl ester (LDME) was evaluated in seven advanced parkinsonian patients as a potentially more convenient alternative. Compared with oral levodopa, LDME infusions resulted in marked reductions of both plasma levodopa variations and motor response fluctuations in patients with either wearing-off or on-off phenomena. During infusions lasting approximately 1 week, there were no complications except for peripheral vein phlebitis. The results suggest that LDME might be a practical parenteral treatment for those with severe Parkinson's disease. It appears that central venous access or its equivalent will be necessary for its chronic administration.
Detection of the extracellular domain of c‐erbB‐2 oncoprotein in sera from patients with various carcinomas: Correlation with tumor markers (1993)

Using a serum enzyme immunoassay (EIA) kit from Triton diagnostics we detected c-erbB-2 oncoprotein activity in random sera containing highly elevated tumor markers and also in serial specimens from cancer patients expressing elevated oncoprotein activities. Elevated oncoprotein activity was found not only in sera of breast and ovarian carcinomas but also in sera from colorectal, pancreatic, and prostate carcinomas and even from primary hepatoma. Whenever oncoprotein was overexpressed in an individual patient, there was usually an excellent correlation between the oncoprotein activity and the level of dominant tumor marker in serial serum specimens. Based on the size exclusion S-200 column chromatography, we found only a single molecule containing c-erbB-2 oncoprotein activity in pooled sera from cancer patients whereas two oncoproteins slightly different in size were detected in breast tumor tissue cytosol. Using HPLC on a Superose 12 HR column, the serum portion of the oncoprotein was eluted at a position near IgG, suggesting that the extracellular domain of the oncoprotein exists as a dimer in the serum.
The synthesis of the first spiropentasilane, octamethylsiropentasilane (1984)

The action of lithium metal on tetrakis(dimethylbromisilyl)silane or tetrakis(dimethylchlorosilyl)silane in tetrahydrofuran produces the first spiropentasilane, a higly strained polysilane that undergoes efficient cleavage reactions with lithium aluminium hydride, methylmagnesium bromide and phosphorus pentachloride.
Enhancement of Nitrate Reduction in Fe0-Packed Columns by Selected Cations (2005)

Tests were conducted in Fe0-packed columns to investigate the effects of adding selected cations on nitrate removal by Fe0. Due to a rapid passivation of Fe0, only negligible nitrate was reduced in the columns without adding the selected cation. However, adding certain selected cations (Fe2+, Fe3+, or Al3+) in feed solution can significantly enhance nitrate reduction. Extending hydraulic retention time (HRT) increased nitrate removal by the columns, but the increase was not linearly proportional to HRT. Decreases in columns’ hydraulic conductivity (K) were monitored in an 8month operating period. A modest decrease in K was recorded in the upper and the middle section of the media bed, whereas a significant decrease in K occurred in the inlet section. X-ray diffraction analyses indicate that magnetite (Fe3O4) was the dominant species of the iron corrosion products in the entire height of the column media under anoxic and other test conditions. In the inlet section, however, lepidocrocite and goethite were also identified. Cementation was found to occur only in the inlet section, suggesting that lepidocrocite and goethite, rather than magnetite, might be responsible for the cementation and thereby cause the hydraulic clogging. The magnetite coating would not necessarily cause clogging of the media.
Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone (2007)

Mutations within the CFTR gene are central to the pathophysiology of cystic fibrosis. CFTR encodes a chloride channel that is located primarily on epithelial cell membranes and is responsible for the regulation of transmembrane chloride and other ion transport. Recent studies indicate a potential association between mutation of the CFTR gene and osteoporosis in patients with CF. Dif et al 1 reported an abnormal skeletal phenotype in CFTR-null mice with striking osteopenia, reduced cortical width and thinning of the trabeculae, while in a study of adults with CF, the ΔF508 mutation was shown to be an independent risk factor for low bone mineral density.2 An association between CFTR mutations and bone disease might be mediated either indirectly by effects of the mutations on other systems (for example, the endocrine system), or it could be due to abnormally …
The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity (2003)

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.
Incidence and Subtypes of MCI and Dementia 1 Year after First-Ever Stroke in Patients without Pre-Existing Cognitive Impairment (2011)

Fifty-seven percent suffered from cognitive impairment one year after stroke and only one third from isolated vascular cognitive disease. Post-stroke cognitive impairment is complex with a high coexistence of vascular and degenerative changes.
Thin silicon oxides grown by low-temperature rf plasma anodization and deposition (1987)

We have studied the low-temperature (&amp;lt;500 °C) growth and deposition of thin silicon oxides in an rf plasma system. Oxides were grown by plasma anodization, sputter deposition, and combinations of these two processes. The oxides were electrically characterized with high-frequency and low-frequency capacitance-voltage techniques and the quality was found to depend strongly on plasma process parameters. In particular, we found strong dependences on bias current, plasma potential, and oxygen partial pressure. Under presently optimal conditions we have fabricated oxides with oxide charge densities Qox&amp;lt;1×1011 charges/cm2, interface state densities Dss&amp;lt;2×1011 states/cm2/eV, and breakdown fields Eb&amp;gt;13 MV/cm. Finally, we have studied the reduction of fast surface states in the plasma oxides by rapid thermal annealing.
Paramedian thalamic and midbrain infarcts: Clinical and neuropathological study (1981)

The clinical and neuropathological findings in 28 cases of paramedian thalamic and midbrain infarcts are reported. The 4 instances of unilateral paramedian thalamic infarct were characterized by mood and behavioral changes, limitation of the infarct to the center of the anatomical paramedian territory, and symmetrical configuration of the paramedian thalamic arteries. Basilar artery occlusion was found in 1 patient. The 5 cases of bilateral paramedian thalamic infarcts were characterized by disturbances of consciousness and behavior, extension of the infarct (to the mammillothalamic tracts in 4 cases, the red nuclei in 3, and the hypothalamus in 2), and a variable paramedian thalamic arterial pattern. The arterial pattern was symmetrical in 2 cases, asymmetrical in 1, and unilateral in 1. The basilar artery was occluded in 1 case, the basilar communicating and posterior cerebral arteries in 1, and a third patient had occlusion involving an aneurysm of the basilar artery. The 19 patients with paramedian thalamopeduncular infarcts had marked disturbances of consciousness (hypersomnia, deep coma, akinetic mutism) associated with ocular motility changes. Later, abnormal movements--always delayed--and memory disturbances were observed in some. Thalamic changes were restricted to beh paramedian territory in only 3 cases. The arterial pattern was symmetrical in 5. The basilar and posterior cerebral arteries were occluded in 4 patients each. Paramedian infarcts were rarely found as isolated lesions and were always bilateral when there was only one arterial pedicle. The paramedian thalamic pedicle can supply the polar thalamic territory.
Exploring A nopheles gut bacteria for P lasmodium blocking activity (2014)

Malaria parasite transmission requires the successful development of Plasmodium gametocytes into flagellated microgametes upon mosquito blood ingestion, and the subsequent fertilization of microgametes and macrogametes for the development of motile zygotes, called ookinetes, which invade and transverse the Anopheles vector mosquito midgut at around 18-36 h after blood ingestion. Within the mosquito midgut, the malaria parasite has to withstand the mosquito's innate immune response and the detrimental effect of its commensal bacterial flora. We have assessed the midgut colonization capacity of five gut bacterial isolates from field-derived, and two from laboratory colony, mosquitoes and their effect on Plasmodium development in vivo and in vitro, along with their impact on mosquito survival. Some bacterial isolates activated the mosquito's immune system, affected the mosquito's lifespan, and were capable of blocking Plasmodium development. We have also shown that the ability of these bacteria to inhibit the parasites is likely to involve different mechanisms and factors. A Serratia marcescens isolate was particularly efficient in colonizing the mosquitoes' gut, compromising mosquito survival and inhibiting both Plasmodium sexual- and asexual-stage through secreted factors, thereby rendering it a potential candidate for the development of a malaria transmission intervention strategy.
Whole-proteome interaction mining (2002)

The interaction mining approach was demonstrated by building a learning system based on 1,039 experimentally validated protein-protein interactions in the human gastric bacterium Helicobacter pylori. An estimate of the generalization performance of the classifier was derived from 10-fold cross-validation, which indicated expected upper bounds on precision of 80% and sensitivity of 69% when applied to related organisms. One such organism is the enteric pathogen Campylobacter jejuni, in which comprehensive machine learning prediction of all possible pairwise protein-protein interactions was performed. The resulting network of interactions shares an average protein connectivity characteristic in common with previous investigations reported in the literature, offering strong evidence supporting the biological feasibility of the hypothesized map. For inferences about complete proteomes in which the number of pairwise non-interactions is expected to be much larger than the number of actual interactions, we anticipate that the sensitivity will remain the same but precision may decrease. We present specific biological examples of two subnetworks of protein-protein interactions in C. jejuni resulting from the application of this approach, including elements of a two-component signal transduction systems for thermoregulation, and a ferritin uptake network.
[Clinical evaluation of several tumor markers in the diagnosis of primary hepatic cancer]. (1998)

AFP and AFu are superior to GGT, SA and CEA in the diagnosis of PHC; simultaneous detection of AFP, AFu, GGT and SA might increase the diagnositic sensitivity and specificity of PHC. CEA was less helpful in the diagnosis of PHC, but might be used to differentiate PHC from hepatic metastasis of gastrointestinal cancer.
Is Continuous PENG Block the New 3-in-1? (2019)

Fascia iliaca or femoral nerve blocks are used frequently for hip fracture patients due to the opioid-sparing effects. However, these techniques prove to be insufficient in many cases. A recent anatomical study on hip innervation, led to the identification of relevant landmarks to target the hip articular branches, namely the Pericapsular Nerve Group (PENG), which allowed a novel ultrasound-guided approach. The aim of this case report is to show an anesthetic technique not described previously, that included an ultra-sound guided PENG block with perineural catheter.
Charged macromolecules in external fields. I. The sphere (1980)

The response of rigid macroions in aqueous solution to an external electric field is considered. The external field, which may be steady or oscillating, induces perturbations in the distribution of coions and counterions, and also in the electrical and solvent velocity fields. The basic equations that describe the various fields are reviewed, and then specialized to the special problem of thin double layers. Boundary conditions are derived which differ from those used in previous work. Previous treatments of the counterion flux into the double layer have either omitted the flux, or taken it to be in phase with the applied field. We find that this flux is large, and has a significant component out of phase. The new boundary conditions make substantial changes in the complex dielectric response. The dominant slow process that controls relaxation is the slow diffusion of neutral salt in the environment of the macromolecule. Large perturbations are induced in the neutral salt concentration by charge distortions in the double layer, and in turn modify the response of the charge. The slow diffusion of the salt gives rise to broad dielectric dispersion. An application is made to the charged sphere, and the results are compared with dielectric response measurements on polystyrene latex spheres, and with the theory of Schwarz.
The Antimicrobial Activity of the Cathelicidin LL37 Is Inhibited by F-actin Bundles and Restored by Gelsolin (2003)

Antimicrobial peptides are part of the innate host defense system, and inactivation of these peptides is implicated in airway infections in cystic fibrosis (CF). The sputum of patients with CF contains anionic polyelectrolytes, including F-actin and DNA not found in normal airway fluid. These anionic filaments aggregate to contribute to the altered viscoelastic properties of CF sputum. We hypothesized that the airway components stabilizing bundles of F-actin and DNA are in part cationic antimicrobial agents, and that appropriate modification of diseased airway fluid of patients with CF might dissociate these bundles and restore antimicrobial activity. We demonstrate that the human cathelicidin peptide LL37 forms bundles with F-actin and DNA, which are dissolved by gelsolin and DNase, respectively. Coincident with bundle formation, antimicrobial activity of LL37 is inhibited by F-actin and DNA. Pseudomonas bacteria were killed by low concentrations of LL37, but killing was significantly reduced in the presence of F-actin. The actin filament-fragmenting protein gelsolin restored bactericidal activity nearly completely. In a growth inhibition assay, the effects of F-actin were confirmed, and DNA was also shown to inhibit the activity of LL37. When added to CF sputum, gelsolin significantly reduced the growth of bacteria, suggesting activation of endogenous antimicrobial factors. These findings may have therapeutic implications for treatments previously thought to alter only the viscoelastic properties of airway secretions and amplify the possible advantage of gelsolin in CF treatment.
Unexpectedly broad target recognition of the CRISPR-mediated virus defence system in the archaeon Sulfolobus solfataricus (2013)

The hyperthermophilic archaeon Sulfolobus solfataricus carries an extensive array of clustered regularly interspaced short palindromic repeats (CRISPR) systems able to mediate DNA degradation of invading genetic elements when complementarity to the small CRISPR-derived (cr)RNAs is given. Studying virus defence in vivo with recombinant viral variants, we demonstrate here that an unexpectedly high number of mutations are tolerated between the CRISPR-derived guide RNAs (crRNAs) and their target sequences (protospacer). Up to 15 mismatches in the crRNA still led to ∼50% of DNA degradation, when these mutations were outside the 'seed' region. More than 15 mutations were necessary to fully abolished interference. Different from other CRISPR systems investigated in vivo, mutations outside the protospacer region indicated no need for a protospacer adjacent motif sequence to confer DNA interference. However, complementarity of only 3 nucleotides between the repeat-derived 5' handle of the crRNA and nucleotides adjacent to the protospacer enabled self-recognition, i.e. protection of the host locus. Our findings show commonalities and differences among the various CRISPR-mediated defence systems and suggest that they should not merely be perceived as a 'first-barrier-defence system' but may be considered to have a broader mechanism that allows host cells to cope with viruses keeping them at reduced levels.
The Integration of Biological Pathway Knowledge in Cancer Genomics: A review of existing computational approaches (2011)

We review existing computational approaches for the integration of cancer genomic data with regulatory mechanisms represented in biological pathway databases and suggest opportunities for the signal processing community to contribute to this exciting field.
Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics (1990)

Abstract An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described. The graphically controlled, atom‐based system allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state‐of‐the‐art molecular mechanics on any subset of up to 1,000 atoms. The system semiautomates the graphical construction and analysis of complex structures ranging from polycyclic organic molecules to biopolymers to mixed molecular complexes. We have placed emphasis on providing effective searches of conformational space by a number of different methods and on highly optimized molecular mechanics energy calculations using widely used force fields which are supplied as external files. Little experience is required to operate the system effectively and even novices can use it to carry out sophisticated modeling operations. The software has been designed to run on Digital Equipment Corporation VAX computers interfaced to a variety of graphics devices ranging from inexpensive monochrome terminals to the sophisticated graphics displays of the Evans &amp; Sutherland PS300 series.
Sequence variation in two ipaH genes of Shigella flexneri 5 and homology to the LRG‐like family of proteins (1991)

Oligonucleotide primers derived from the ipaH7.8 sequence have been used to determine the boundaries of DNA sequence homology among five ipaH genes on the invasion plasmid (pWR100) of Shigella flexneri 5, strain M9OT-W. The primary structure of IpaH4.5 has been established from DNA sequence analysis. The first 197 amino acids in IpaH7.8 were replaced in IpaH4.5 by a unique set of 251 amino acids, generating two related proteins with variable and conserved sequences. The amino-terminal region of IpaH4.5 displayed an internal repeat structure, also seen in IpaH7.8, characteristic of members of the leucine-rich glycoprotein (LRG) family. The DNA sequences of ipaH2.5 and ipaH1.4 indicate that these genes are truncated versions of ipaH7.8. Western blot analysis of a lambda gt11 ipaH recombinant (W7) subclone demonstrated that the antigenicity of IpaH7.8 resides outside the leucine-rich repetitive region.
EIN2, a Bifunctional Transducer of Ethylene and Stress Responses in Arabidopsis (1999)

Ethylene regulates plant growth, development, and responsiveness to a variety of stresses. Cloning of the Arabidopsis EIN2 gene identifies a central component of the ethylene signaling pathway. The amino-terminal integral membrane domain of EIN2 shows similarity to the disease-related Nramp family of metal-ion transporters. Expression of the EIN2 CEND is sufficient to constitutively activate ethylene responses and restores responsiveness to jasmonic acid and paraquat-induced oxygen radicals to mutant plants. EIN2 is thus recognized as a molecular link between previously distinct hormone response pathways. Plants may use a combinatorial mechanism for assessing various stresses by enlisting a common set of signaling molecules.