gebhart/patrepeval huggingface dataset:
Toxicity of interferon. (1981)

The effects of partially purified human leucocyte interferon (PIF) and of a preparation purified by passage twice through a monoclonal antibody affinity chromatography column (NK21F) were compared with those of a control solution in healhty volunteers. After intramuscular injections both interferon preparations caused rises in pulse rate and body temperature, changes in circulating white cell counts, and various unpleasant symptoms, the most common of which were headache, malaise, and fever. Slightly lower doses of NK21F were given, and this was reflected in lower peak serum concentrations. Mean symptom scores, however, were not lower after NK21F than after PIF. Local inflammatory reactions eight hours after intradermal inoculations of these interferons were similar. Purification of interferon using a monoclonal antibody does not reduce the facets of its activity considered in this study. They are therefore inherent in the leucocyte interferon type selected by the antibody.
Characterization of micromachined spiked biopotential electrodes (2002)

We present the characterization of dry spiked biopotential electrodes and test their suitability to be used in anesthesia monitoring systems based on the measurement of electroencephalographic signals. The spiked electrode consists of an array of microneedles penetrating the outer skin layers. We found a significant dependency of the electrode-skin-electrode impedance (ESEI) on the electrode size (i.e., the number of spikes) and the coating material of the spikes. Electrodes larger than 3 x 3 mm2 coated with Ag-AgCl have sufficiently low ESEI to be well suited for electroencephalograph (EEG) recordings. The maximum measured ESEI was 4.24 k(omega) and 87 k(omega), at 1 kHz and 0.6 Hz, respectively. The minimum ESEI was 0.65 k(omega) an 16 k(omega), at the same frequencies. The ESEI of spiked electrodes is stable over an extended period of time. The arithmetic mean of the generated dc offset voltage is 11.8 mV immediately after application on the skin and 9.8 mV after 20-30 min. A spectral study of the generated potential difference revealed that the ac part was unstable at frequencies below approximately 0.8 Hz. Thus, the signal does not interfere with a number of clinical applications using real-time EEG. Comparing raw EEG recordings of the spiked electrode with commercial Zipprep electrodes showed that both signals were similar. Due to the mechanical strength of the silicon microneedles and the fact that neither skin preparation nor electrolytic gel is required, use of the spiked electrode is convenient. The spiked electrode is very comfortable for the patient.
Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics (2017)

Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.
The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice (2010)

The vascular pathobiology of sickle cell anemia involves inflammation, coagulation, vascular stasis, reperfusion injury, iron-based oxidative biochemistry, deficient nitric oxide (NO) bioavailability, and red cell sickling. These disparate pathobiologies intersect and overlap, so it is probable that multimodality therapy will be necessary for this disease. We have, therefore, tested a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), for efficacy in reducing endothelial activation. We found that pulmonary vascular endothelial VCAM-1 and tissue factor (TF) expression (both are indicators of endothelial activation) are powerfully and significantly inhibited by TSA. This is seen both with pretreatment before the inducing stress of hypoxia/reoxygenation (NY1DD sickle transgenic mouse), and upon longer-term therapy after endothelial activation has already occurred (hBERK1 sickle mouse at ambient air). In addition, TSA prevented vascular stasis in sickle mice, it exhibited activity as an iron chelator, and it induced expression of the antisickling hemoglobin, hemoglobin F. Notably, the TSA analog SAHA (suberoylanilide hydroxaminc acid) that is already approved for human clinical use exhibits the same spectrum of biologic effects as TSA. We suggest that SAHA possibly could provide true, multimodality, salubrious effects for prevention and treatment of the chronic vasculopathy of sickle cell anemia.
Influence of the HDL receptor SR-BI on atherosclerosis (1999)

The scavenger receptor class B, type I (SR-BI) is an HDL receptor that mediates selective cholesterol uptake from HDL to cells. In rodents, SR-BI has a critical influence on plasma HDL-cholesterol concentration and structure, the delivery of cholesterol to steroidogenic tissues, female fertility, and biliary cholesterol concentration. SR-BI can also serve as a receptor for non-HDL lipoproteins and appears to play an important role in reverse cholesterol transport. Recent studies involving the manipulation of SR-BI expression in mice, either using adenovirus-mediated or transgenic hepatic overexpression or using homologous recombination for complete functional ablation, indicate that the expression of SR-BI protects against atherosclerosis. If SR-BI has a similar activity in humans, it may become an attractive target for therapeutic intervention.
Invited review: Genomic selection in dairy cattle: Progress and challenges (2009)

A new technology called genomic selection is revolutionizing dairy cattle breeding. Genomic selection refers to selection decisions based on genomic breeding values (GEBV). The GEBV are calculated as the sum of the effects of dense genetic markers, or haplotypes of these markers, across the entire genome, thereby potentially capturing all the quantitative trait loci (QTL) that contribute to variation in a trait. The QTL effects, inferred from either haplotypes or individual single nucleotide polymorphism markers, are first estimated in a large reference population with phenotypic information. In subsequent generations, only marker information is required to calculate GEBV. The reliability of GEBV predicted in this way has already been evaluated in experiments in the United States, New Zealand, Australia, and the Netherlands. These experiments used reference populations of between 650 and 4,500 progeny-tested Holstein-Friesian bulls, genotyped for approximately 50,000 genome-wide markers. Reliabilities of GEBV for young bulls without progeny test results in the reference population were between 20 and 67%. The reliability achieved depended on the heritability of the trait evaluated, the number of bulls in the reference population, the statistical method used to estimate the single nucleotide polymorphism effects in the reference population, and the method used to calculate the reliability. A common finding in 3 countries (United States, New Zealand, and Australia) was that a straightforward BLUP method for estimating the marker effects gave reliabilities of GEBV almost as high as more complex methods. The BLUP method is attractive because the only prior information required is the additive genetic variance of the trait. All countries included a polygenic effect (parent average breeding value) in their GEBV calculation. This inclusion is recommended to capture any genetic variance not associated with the markers, and to put some selection pressure on low-frequency QTL that may not be captured by the markers. The reliabilities of GEBV achieved were significantly greater than the reliability of parental average breeding values, the current criteria for selection of bull calves to enter progeny test teams. The increase in reliability is sufficiently high that at least 2 dairy breeding companies are already marketing bull teams for commercial use based on their GEBV only, at 2 yr of age. This strategy should at least double the rate of genetic gain in the dairy industry. Many challenges with genomic selection and its implementation remain, including increasing the accuracy of GEBV, integrating genomic information into national and international genetic evaluations, and managing long-term genetic gain.
Cytometric analysis of TH1/TH2 cytokines in the urine of patients undergoing kidney transplantation. (2009)

The results of our study suggest that higher concentrations of IFN-gamma, TNF-alpha and IL-10 in the urine of patients shortly after the kidney transplantation can be considered as risk factors increasing the probability of AR episodes.
Dietary Fatty Acid Composition and the Hibernation Patterns in Free‐Ranging Arctic Ground Squirrels (2008)

Laboratory experiments have demonstrated that the amount of polyunsaturated fatty acids (PUFAs) in the diet before hibernation influences patterns of mammalian torpor. The hibernation ability of ground squirrels is greatest (longest torpor bouts, greatest number of animals entering torpor) when the PUFA content of their fall diets is 33-74 mg/g, under laboratory conditions. The extent to which natural fall diets both (a) vary in PUFA content and (b) influence the torpor patterns of free-ranging populations of hibernating mammals is unknown, however. We conducted a 3-yr study on the diet PUFA contents and subsequent hibernation patterns of free-ranging arctic ground squirrels (Spermophilus parryii) in the Brooks Range of Alaska. We found that the PUFA contents of fall diets varied more than threefold among individuals. Our study also revealed that arctic ground squirrels that consumed a moderate-PUFA (33-74 mg/g) diet had (a) longer torpor bouts, (b) fewer arousals from torpor, (c) shorter arousal periods, (d) more days in torpor, and (e) greater probability of persisting in the population than those that consumed a high-PUFA (>74 mg/g) diet during the fall. No animals were demonstrated to have consumed a diet representing low-PUFA (<33 mg/g) values. Our study is therefore the first to demonstrate that estimated dietary PUFA levels of a free-ranging hibernator influence subsequent torpor patterns.
Electrostatic surface plasmon resonance: Direct electric field-induced hybridization and denaturation in monolayer nucleic acid films and label-free discrimination of base mismatches (2001)

We demonstrate that in situ optical surface plasmon resonance spectroscopy can be used to monitor hybridization kinetics for unlabeled DNA in tethered monolayer nucleic acid films on gold in the presence of an applied electrostatic field. The dc field can enhance or retard hybridization and can also denature surface-immobilized DNA duplexes. Discrimination between matched and mismatched hybrids is achieved by simple adjustment of the electrode potential. Although the electric field at the interface is extremely large, the tethered single-stranded DNA thiol probes remain bound and can be reused for subsequent hybridization reactions without loss of efficiency. Only capacitive charging currents are drawn; redox reactions are avoided by maintaining the gold electrode potential within the ideally polarizable region. Because of potential-induced changes in the shape of the surface plasmon resonance curve, we account for the full curve rather than simply the shift in the resonance minimum.
Synthesis and characterization of poly(ethylene glycol) derivatives (1984)

Abstract Five general routes for the preparation of polyoxyethylene [generally referred to as poly(ethylene glycol) or PEG] derivatives are described. These routes are (1) nucleophilic displacements with the alkoxide of PEG, (2) nucleophilic displacement on PEG–tosylate, –mesylate, or –bromide, (3) reductive amination of PEG–aldehyde, (4) reductive amination of PEG–amine, and (5) nucleophilic displacements on the s ‐triazine derivatives prepared from s ‐triazine trichloride (cyanuric chloride) and PEG. Eighteen derivatives are prepared and potential applications to catalysis, cell purifications, and other areas are discussed briefly.
SYNTHESIS OF AMIDES FROM ESTERS AND AMINES UNDER MICROWAVE IRRADIATION (2002)

ABSTRACT Formamide, primary and secondary amines react with esters in the presence of potassium tert-butoxide under microwave irradiation. Substituted amides are formed in yields (generally more than 70%) much higher than under conventional heating.
HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells (2006)

Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.
Control of Transcription Factor Activity and Osteoblast Differentiation in Mammalian Cells Using an Evolved Small-Molecule-Dependent Intein (2006)

Inteins are naturally occurring protein elements that catalyze their own excision from within a larger protein together with the ligation of the flanking "extein" sequences. Previously we reported the directed evolution of an intein-based molecular switch in which intein splicing in yeast cells was made dependent on the cell-permeable small molecule 4-hydroxytamoxifen (4-HT). Here we show that these evolved inteins are effective means of rendering protein function and biological signaling pathway activation dependent on 4-HT in mammalian cells. We have characterized the generality, speed, and dose dependence of ligand-induced protein splicing in murine NIH3T3 cells and in human HEK293 cells. Evolved inteins were used to control in mammalian cells the function of Gli1 and a truncated form of Gli3, two transcriptional mediators of the Hedgehog signaling pathway. Finally, we show that a complex biological process such as osteoblast differentiation can be made dependent on 4-HT using the evolved intein system. Our findings suggest that evolved small-molecule-dependent inteins may serve as a general means of achieving gene-specific, dose-dependent, post-translational, and small-molecule-induced control over protein activity in mammalian systems.
Regulation of Wnt/LRP Signaling by Distinct Domains of Dickkopf Proteins (2002)

Dickkopfs (Dkks) are secreted developmental regulators composed of two cysteine-rich domains. We report that the effects of Dkks depend on molecular context. Although Wnt8 signaling is inhibited by both Dkk1 and Dkk2 in Xenopus embryos, the same pathway is activated upon interaction of Dkk2 with the Wnt coreceptor LRP6. Analysis of individual Dkk domains and chimeric Dkks shows that the carboxy-terminal domains of both Dkks associate with LRP6 and are necessary and sufficient for Wnt8 inhibition, whereas the amino-terminal domain of Dkk1 plays an inhibitory role in Dkk-LRP interactions. Our study illustrates how an inhibitor of a pathway may be converted into an activator and is the first study to suggest a molecular mechanism for how a ligand other than Wnt can positively regulate beta-catenin signaling.
Interaction of 1‐Methyl‐4‐Phenylpyridinium Ion (MPP+) and Its Analogs with the Rotenone/Piericidin Binding Site of NADH Dehydrogenase (1991)

Nigrostriatal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease results from the inhibition of mitochondrial respiration by 1-methyl-4-phenylpyridinium (MPP+). MPP+ blocks electron flow from NADH dehydrogenase to coenzyme Q at or near the same site as do rotenone and piericidin and protects against binding of and loss of activity due to these inhibitors. The 4'-analogs of MPP+ showed increasing affinity for the site with increasing length of alkyl chain, with the lowest Ki, for 4'-heptyl-MPP+, being 6 microM. The 4'-analogs compete with rotenone for the binding site in a concentration-dependent manner. They protect the activity of the enzyme from inhibition by piericidin in parallel to preventing its binding, indicating that the analogs and piericidin bind at the same inhibitory site(s). The optimum protection, however, was afforded by 4'-propyl-MPP+. The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q.
Restricted homology between human alpha 1 type IV and other procollagen chains. (1985)

Screening of a human fibroblast cDNA library with a mouse type IV procollagen clone resulted in one 1.05-kilobase isolate that was used to identify a 1.7-kilobase clone overlapping the former by less than 150 nucleotides. EcoRII digestion revealed that the larger clone exhibited the pattern characteristic of DNA coding for a collagenous sequence. Blot hybridization to RNA from mouse F9 stem cells and from these cells treated with retinoic acid and N6, O2'-dibutyryl-cAMP showed induction of type IV mRNA. DNA sequencing and comparison of the derived amino acids with the reported protein data demonstrated that the clones encode part of the alpha 1 chain of human type IV procollagen. Alignment of alpha 1 (IV) with other human procollagens showed minimal but detectable homology. A small cluster of charged residues in the alpha chain is partially shared by type IV. In close proximity is an interruption in the alpha 1 (IV) Gly-Xaa-Yaa region corresponding to the 3' end of a unique proline-free, and therefore also less rigid, area in other collagen triple helices. Analysis of the carboxyl-terminal alpha 1 (IV) peptide showed a repeat symmetry possibly dictated by the six cysteines in each half of the structure. The position of five cysteines in addition to four tyrosine/tryptophan groups allowed a correlation to be drawn between the 3' noncollagenous type IV region and the larger, highly conserved carboxyl propeptides of other human procollagens. Such similarities in the different chains may define functional domains conserved throughout evolution.
Requirement of the C-terminal proline residue for stability of the Ca2+-activated photoprotein aequorin (1993)

cDNA coding for the Ca(2+)-activated photoprotein aequorin from the jellyfish Aequorea victoria has been engineered to investigate the role of the C-terminal proline residue in bioluminescence. Recombinant aequorin proteins were synthesized by PCR followed by in vitro transcription/translation, and characterized by specific activity, stability, and affinity for coelenterazine. The C-terminal proline residue of aequorin was shown to be essential for the long-term stability of the bound coelenterazine. Aequorin minus proline had only 1% of the specific activity of the wild-type after 2 h, and was virtually inactive after 18 h. The instability of this variant was further demonstrated by re-activating with a coelenterazine analogue (epsilon-coelenterazine), where maximum reactivation was reached in 15 min, and the luminescent activity was almost completely abolished within 3 h. Replacement of the C-terminal proline residue with histidine or glutamic acid decreased the specific activity to 10 and 19% of that of the wild-type respectively. However these variants were also unstable, having t1/2 values of 2.4 h and 2.3 h respectively. Enhancement of the Ca(2+)-independent light emission when proline was replaced by histidine confirmed the stabilizing role of the C-terminal proline. No significant effect of removal of the C-terminal proline was detected on the affinity for coelenterazine.
Doppler optical micro-angiography for volumetric imaging of vascular perfusion in vivo (2009)

We propose a Doppler optical micro-angiography (DOMAG) method to image flow velocities of the blood flowing in functional vessels within microcirculatory tissue beds in vivo. The method takes the advantages of recently developed optical micro-angiography (OMAG) technology, in which the endogenous optical signals backscattered from the moving blood cells are isolated from those originated from the tissue background, i.e., the tissue microstructures. The phase difference between adjacent A scans of OMAG flow signals is used to evaluate the flow velocity, similar to phase-resolved Doppler optical coherence tomography (PRDOCT). To meet the requirement of correlation between adjacent A scans in using the phase resolved technique to evaluate flow velocity, an ideal tissue-sample background (i.e., optically homogeneous tissue sample) is digitally reconstructed to replace the signals that represent the heterogeneous features of the static sample that are rejected in the OMAG flow images. Because of the ideal optical-homogeneous sample, DOMAG is free from the characteristic texture pattern noise due to the heterogeneous property of sample, leading to dramatic improvement of the imaging performance. A series of phantom flow experiments are performed to evaluate quantitatively the improved imaging performance. We then conduct in vivo experiments on a mouse brain to demonstrate that DOMAG is capable of quantifying the flow velocities within cerebrovascular network, down to capillary level resolution. Finally, we compare the in vivo imaging performance of DOMAG with that of PRDOCT, and show that DOMAG delivers at least 15-fold increase over the PRDOCT method in terms of the lower limit of flow velocity that can be detected.
The plant ER: a dynamic organelle composed of a large number of discrete functional domains (1997)

The endoplasmic reticulum (ER) of plants is comprised of a three-dimensional network of continuous tubules and sheets that underlies the plasma membrane, courses through the cytoplasm, and links up with the nuclear envelope. Aside from discussing the dynamic properties of this versatile and adaptable organelle, the review highlights the structure and the functional properties of 16 types of morphologically defined ER membrane domains. Owing to their labile or transient nature, several of these domains can only be visualized reliably through the use of ultrarapid freezing techniques. The ER domains discussed are: the lamin receptor domain; the nuclear pores; the nuclear envelope-ER gates, the microtubule nucleation domains; the protein and oil body-forming domains; the vacuole-forming ER; the actin-binding, the plasma membrane-anchoring and the vacuole and mitochondrion-attachment domains; the lipid recycling ER cisternae and the plasmodesmata. Preliminary evidence suggests that this list will have to be expanded in the near future. Understanding the assembly, the functional roles, and the developmental regulation of these domains has implications both for understanding cell structure and function, and for exploiting plants for agricultural and biotechnological purposes.