gebhart/patrepeval huggingface dataset:
Baroreflex control of muscle sympathetic nerve activity: a nonpharmacological measure of baroreflex sensitivity (2009)

The sensitivity of baroreflex control of sympathetic nerve activity (SNA) represents the responsiveness of SNA to changes in blood pressure. In a slightly different analysis, the baroreflex threshold measures the probability of whether a sympathetic burst will occur at a given diastolic blood pressure. We hypothesized that baroreflex threshold analysis could be used to estimate the sensitivity of the sympathetic baroreflex measured by the pharmacological modified Oxford test. We compared four measures of sympathetic baroreflex sensitivity in 25 young healthy participants: the "gold standard" modified Oxford analysis (nitroprusside and phenylephrine), nonbinned spontaneous baroreflex analysis, binned spontaneous baroreflex analysis, and threshold analysis. The latter three were performed during a quiet baseline period before pharmacological intervention. The modified Oxford baroreflex sensitivity was significantly related to the threshold slope (r = 0.71, P < 0.05) but not to the binned (1 mmHg bins) and the nonbinned spontaneous baroreflex sensitivity (r = 0.22 and 0.36, respectively, P > 0.05), which included burst area. The threshold analysis was also performed during the modified Oxford manipulation. Interestingly, we found that the threshold analysis results were not altered by the vasoactive drugs infused for the modified Oxford. We conclude that the noninvasive threshold analysis technique can be used as an indicator of muscle SNA baroreflex sensitivity as assessed by the modified Oxford technique. Furthermore, the modified Oxford method does not appear to alter the properties of the baroreflex.
Participation of the CD94 Receptor Complex in Costimulation of Human Natural Killer Cells (1998)

Optimal proliferation and expansion of human NK cells require mitogenic cytokines together with cell contact-dependent co-stimulation. Production of mAb that can modulate human NK cell proliferation yielded NKH3, which recognizes the CD94 Ag. NKH3 immunoprecipitates contain approximately 70-kDa heterodimeric complexes consisting of a approximately 25-kDa glycoprotein and approximately 40- to 45-kDa molecules. Analysis by two-dimensional isoelectric focusing/SDS-PAGE suggests that several different 40- to 45-kDa species are present in the CD94 receptor complex in human NK cells. NKH3 reacted with essentially all resting NK cells, although CD94 is expressed at higher levels on the CD56(bright) (i.e., high level of CD56) CD16(dim/neg) (i.e., low level of or absent CD16) subpopulation than on the more abundant CD56(dim)CD16(bright) NK cell subset. Moreover, the Z199 mAb, which appears to recognize NKG2-A species that can form heterodimers with CD94, stained virtually all CD56(bright) NK cells, but only a subset of CD56(dim) NK cells. Ligation of CD94 augmented the proliferation of CD56(bright) NK cells in response to IL-2 or IL-15 by as much as 10-fold. Secretion of IFN-gamma by CD56(bright) NK cells stimulated with IL-2 or IL-15 was also enhanced up to 10-fold after CD94 ligation. CD94 mAb did not consistently costimulate proliferation of or IFN-gamma production by CD56(dim) NK cells cultured with IL-2 or IL-15. In contrast, irradiated K562 cells costimulated proliferation of both CD56(bright) and CD56(dim) NK cells. These results indicate that CD56(bright) and CD56(dim) NK cells can be costimulated through different receptors, which may allow these distinct NK cell subsets to be independently regulated in vivo.
Interleaved thinned linear arrays (2005)

This paper presents three approaches to improving the efficiency of an array aperture by interleaving two arrays in the same aperture area. The interleaved arrays have aperiodic spacings that are integer multiples of a set minimum spacing and are optimized to reduce the maximum sidelobe level. Fully and partially interleaved sum arrays operating at the same frequencies are demonstrated as well as interleaved sum and difference arrays for a monopulse system. A genetic algorithm is used to optimize arrays of isotropic point sources as well as arrays of dipoles modeled using the method of moments. Narrow beamwidths are possible while avoiding high sidelobes. The available aperture area is efficiently used.
Ex vivo expansion and selection of human CD34+ peripheral blood progenitor cells after introduction of a mutated dihydrofolate reductase cDNA via retroviral gene transfer (1995)

Retroviral gene transfer into human myeloid precursor cells allows introduction of marker genes as well as genes conferring resistance to chemotherapeutic drugs. We transduced a human mutant dihydrofolate reductase (DHFR) cDNA into CD34 antigen-positive peripheral blood cells from patients with breast or ovarian cancer obtained after treatment with chemotherapy and granulocyte colony-stimulating factor (G-CSF). This mutant DHFR has been shown to confer resistance to methotrexate (MTX) in murine bone marrow. We established a transduction protocol that permitted ex vivo expansion and selection of transduced early progenitor cells. The number of progenitor cells from transduced CD34- positive cells increased 50-fold after cytokine prestimulation with interleukin-1 (IL-1), c-kit ligand (KL; stem cell factor), and IL-3 and 2 weeks in liquid culture. Transduced colony-forming unit-granulocyte- macrophage (CFU-GM), assayed directly after the transduction procedure, were protected completely against 2 x 10(-8) mol/L MTX, a concentration that significantly reduced the CFU-GM detected in the control population. Gene transfer of the mutant DHFR led to a twofold selective advantage for a pre-CFU population after exposure to MTX in liquid culture (P &lt; .001). Polybrene, in contrast with protamine, significantly inhibited the expansion of progenitors. The presence of proviral DNA was monitored by polymerase chain reaction (PCR) and was detected in greater than 80% of CFU-GM and ex vivo expanded pre-CFU. We have demonstrated that human hematopoietic precursor cells can be expanded extensively after retroviral gene transfer. The same population of early progenitors can be selected ex vivo with low-dose MTX. As long-term expression of transduced genes in human hematopoietic cells remains a problem in vivo, these results may have implications for future clinical trials, especially for the introduction of nonselectable genes.
Future Directions of Next-Generation Novel Therapies, Combination Approaches, and the Development of Personalized Medicine in Myeloma (2011)

Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the "driver" molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.
Mutations at the S1 Sites of Methionine Aminopeptidases from Escherichia coli and Homo sapiens Reveal the Residues Critical for Substrate Specificity (2004)

Methionine aminopeptidase (MetAP) catalyzes the removal of methionine from newly synthesized polypeptides. MetAP carries out this cleavage with high precision, and Met is the only natural amino acid residue at the N terminus that is accepted, although type I and type II MetAPs use two different sets of residues to form the hydrophobic S1 site. Characteristics of the S1 binding pocket in type I MetAP were investigated by systematic mutation of each of the seven S1 residues in Escherichia coli MetAP type I (EcMetAP1) and human MetAP type I (HsMetAP1). We found that Tyr-65 and Trp-221 in EcMetAP1, as well as the corresponding residues Phe-197 and Trp-352 in HsMetAP1, were essential for the hydrolysis of a thiopeptolide substrate, Met-S-Gly-Phe. Mutation of Phe-191 to Ala in HsMetAP1 caused inactivity in contrast to the full activity of EcMetAP1(Y62A), which may suggest a subtle difference between the two type I enzymes. The more striking finding is that mutation of Cys-70 in EcMetAP1 or Cys-202 in HsMetAP1 opens up the S1 pocket. The thiopeptolides Leu-S-Gly-Phe and Phe-S-Gly-Phe, with previously unacceptable Leu or Phe as the N-terminal residue, became efficient substrates of EcMetAP1(C70A) and HsMetAP1(C202A). The relaxed specificity shown in these S1 site mutants for the N-terminal residues was confirmed by hydrolysis of peptide substrates and inhibition by reaction products. The structural features at the enzyme active site will be useful information for designing specific MetAP inhibitors for therapeutic applications.
Antibody Complementarity-Determining Regions (CDRs) Can Display Differential Antimicrobial, Antiviral and Antitumor Activities (2008)

The high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. The easy production and low cost of small sized synthetic peptides representing Ig CDRs and the possibility of peptide engineering and chemical optimization associated to new delivery mechanisms are expected to give rise to a new generation of therapeutic agents.
Vision-based eye-gaze tracking for human computer interface (2003)

Eye-gaze is an input mode which has the potential for an efficient computer interface. Eye movement has been the focus of research in this area. Non-intrusive eye-gaze tracking that allows slight head movement is addressed in this paper. A small 2D mark is employed as a reference to compensate for this movement. The iris center has been chosen for the purposes of measuring eye movement. The gaze point is estimated after acquiring the eye movement data. Preliminary experimental results are given through a screen pointing application.
Estimation of the number of routing layers and total wirelength in a PCB through wiring distribution analysis (1996)

This paper describes a model to estimate the number of routing layers and total wirelength for a printed circuit board given the netlist, partslist, placement and board form factor. The estimation model is based on analysis of the wiring distribution on the board. The wiring distribution consists of the net distribution and net segmentation. An algorithm is presented which determines the contribution of net distribution. A statistical model has been developed to estimate net segmentation as wrong way routes due to obstacles and congestion on a board. Routability estimations are substituted for the routing task while searching the design space, significantly reducing the design time since routing is the most time consuming design task. These estimation techniques have been successfully applied to the board estimations of several designs, including a multiprocessor printed circuit board and the results are presented.
Evidence for Long‐Term Cervical Persistence ofChlamydia trachomatisbyomp1Genotyping (2000)

Recurrent Chlamydia trachomatis infections are common among sexually active women. Although recurrences with a new chlamydial serovar indicate reinfection, same-serovar recurrences may be due to persistence. Because persistence has important implications for pathogenesis and patient management, we identified 552 women with >3 recurrences over 2 years. Among these, 130 women (24%) had same-serovar recurrences; 58 (45%) were C class serovars (odds ratio, 2.4; 95% confidence interval, 1.7-3.5; P<.0001). Forty-five isolates from 7 women with 3-10 repeated, same-serovar infections over 2-5 years were studied. As determined by omp1 genotyping, 4 women had identical genotypes at each recurrence; 2 women had 1 or 2 amino acid changes following treatment, and one was persistently infected with a unique genotype, Ja. Many intervening culture-negative samples were positive when tested by ligase chain reaction, which suggests persistence. These data demonstrate that cervical infections with C class serovars can persist for years and may have specific biologic properties that allow for modulation of the major outer membrane protein in response to immune selection.
Systems level engineering of Corynebacterium glutamicum – Reprogramming translational efficiency for superior production (2010)

Abstract In this study, we replaced the natural start codons of different enzymes in the central carbon metabolism of Corynebacterium glutamicum to influence their activity toward improved production of the feed amino acid lysine. It was found that the translational start codon directly affects the intracellular activity of the encoded enzyme, whereby the common ATG generally led to higher values as compared with the rare variant GTG. This could be exploited to specifically amplify or attenuate enzyme activities in order to redirect carbon flux from undesired, competing pathways toward reactions supporting lysine formation. Replacement of the natural ATG codon by GTG reduced the specific enzyme activity of pyruvate dehydrogenase (PDH) and phosphoglucoisomerase by 60 and 40%, respectively. Vice versa , the activity of glucose 6‐phosphate dehydrogenase was increased by 40% by the substitution GTG‐&gt;ATG. Implementation of the attenuated pyruvate dehydrogenase in the background of lysine producing C. glutamicum increased product yield by 17%. This was related to a redirection of the metabolic flux toward the supply of the lysine precursor oxaloacetate. The amplified expression of glucose 6‐phosphate dehydrogenase by the start codon exchange increased lysine yield by 10%, linked to an increased flux toward NADPH supply in the pentose phosphate pathway.
The murine Ah locus. Comparison of the complete cytochrome P1-450 and P3-450 cDNA nucleotide and amino acid sequences. (1984)

Mouse cytochrome P1-450 and P3-450 are most closely associated with induced aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.1) and acetanilide 4-hydroxylase activity, respectively. Full-length cDNA clones of P1-450 and P3-450 were generated from mRNA isolated from 3-methylcholanthrene-treated C57BL/6N mouse liver. P1-450 cDNA is 2620 nucleotides in length and has a coding region (base 110 to 1,675) that produces a protein with 521 residues (Mr = 58,914). P3-450 cDNA is 1,894 nucleotides in length and yields a protein with 513 residues (Mr = 58,183). P1-450 mRNA is the first reported example in mouse in which UAG is used as the termination codon. P1-450 and P3-450, both induced by polycyclic hydrocarbons and regulated by the Ah receptor, exhibit overall nucleotide and protein homology of 68, and 73%, respectively. Segments of high homology, interspersed with regions of low homology, support the hypothesis of gene conversion or unequal crossing over as possible mechanisms for divergence of these two genes. Mouse P1-450 and P3-450 cDNAs were compared with previously published data on rat P-450e cDNA and rabbit form 2 protein, corresponding to two P-450 genes from the "phenobarbital inducible" P-450 gene subfamily. Nucleotide homology between a member of either gene subfamily is about 30%, and protein homology is about 15%, suggesting that the Ah locus-associated P-450 gene subfamily diverged from the phenobarbital inducible P-450 subfamily more than 200 million years ago. An N-terminal and a C-terminal cysteinyl fragment corresponding to the regions around P1-450 Cys-158 and Cys-458, respectively, are the only two cysteinyl peptides conserved among all four proteins compared. Because of greater homology in the C-terminal conserved cysteinyl fragment between the two gene subfamilies and a greater hydrophobic pocket in the C-terminal conserved cysteinyl fragment, the data favor this cysteine as the more likely candidate for the thiolate ligand to the heme iron in the P-450 enzyme active-site.
Biological rationale for the design of polymeric anti-cancer nanomedicines (2012)

Understanding the biological features of cancer is the basis for designing efficient anti-cancer nanomedicines. On one hand, important therapeutic targets for anti-cancer nanomedicines need to be identified based on cancer biology, to address the unmet medical needs. On the other hand, the unique pathophysiological properties of cancer affect the delivery and interactions of anti-cancer nanomedicines with their therapeutic targets. This review discusses several critical cancer biological properties that challenge the currently available anti-cancer treatments, including cancer heterogeneity and cancer stem cells, the complexcity of tumor microenvironment, and the inevitable cancer metastases. In addition, the biological bases of the enhanced permeability and retention (EPR) effect and tumor-specific active targeting, as well as the physiological barriers for passive and active targeting of anti-cancer nanomedicines are covered in this review. Correspondingly, possible nanomedicine strategies to target cancer heterogeneity, cancer stem cells and metastases, to overcome the challenges related to tumor passive targeting and tumor penetration, and to improve the interactions of therapeutic payloads with the therapeutic targets are discussed. The focus is mainly on the designs of polymeric anti-cancer nanomedicines.
Detection of point mutations in type I collagen by RNase digestion of RNA/RNA hybrids (1990)

We have developed a strategy for the detection, localization and sequence determination of point mutations in the mRNA coding for the alpha 1(I) and alpha 2(I) chains of type I collagen. Point mutations are detected by RNase A cleavage of mismatches in RNA/RNA hybrids. The mRNAs coding for the fibrillar collagens present special problems for hybrid analysis because of their large size and their GC-rich and repetitive sequences. We have generated a series of overlapping antisense riboprobes covering the entire pro alpha 1(I) and pro alpha 2(I) mRNAs. Uniformly labelled normal antisense riboprobes are hybridized with the total fibroblast RNA of patients with possible mutations in type I collagen. Mismatches in the resulting RNA/RNA hybrids are cleaved with RNase A and the labelled riboprobe cleavage products are examined electrophoretically. The sensitivity and specificity of the system were demonstrated by the detection and localization of a known point mutation in the codon for alpha 1(I) glycine 988 (1). DNA for sequencing the mutations localized by hybrid analysis may be obtained by either (1) generation of a fibroblast cDNA library and isolation of both alleles by plaque screening, or (2) a more rapid method using first strand cDNA synthesis from poly (A+)-mRNA, followed by PCR amplification of the mutation-containing region of the DNA/RNA hybrid. This strategy for detection and isolation has wide application not only for mutations causing connective tissue disorders, but also for mutations in other large and repetitive genes. We have used this strategy for the detection and sequencing of a point mutation in alpha 2(I) mRNA associated with a case of lethal osteogenesis imperfecta. The G----A point mutation in the codon for alpha 2(I) glycine residue 805 results in the substitution of an aspartic acid at this position and is consistent with the proband's collagen protein data.
An efficient method for generation and subcloning of tandemly repeated DNA sequences with defined length, orientation and spacing (1996)

Tandemly repeated DNA sequences generated from single synthetic oligonucleotide monomers are useful for many purposes. With conventional ligation procedures low yields and random orientation of oligomers makes cloning of defined repeated sequences difficult. We solved these problems using 2 bp overhangs to direct orientation and random incorporation of linkers containing restriction sites during ligation. Ligation products are amplified by PCR using the linker oligonucleotides as primers. Restriction digestion of the PCR products generate multimer distributions whose length is controlled by the monomer/linker ratio. The concatenated DNA fragments of defined length, orientation and spacing can be directly used for subcloning or other applications without further treatment.
p53 Lesions in Leukemic Transformation (2011)

To the Editor: Myeloproliferative neoplasms have an inherent tendency toward leukemic transformation. The genetic mechanisms of transformation remain largely unknown. We analyzed biopsy specimens of myeloproliferative neoplastic tissue from 330 patients for chromosomal aberrations associated with leukemic transformation (the analysis was performed with the use of Genome-Wide Human SNP [single-nucleotide polymorphism] Array, Affymetrix). Of those patients, 308 had chronic-phase myeloproliferative neoplasms and 22 had postmyeloproliferative-phase neoplasm secondary acute myeloid leukemia (AML). Among these 22 patients, 1 carried the myeloproliferative leukemia virus oncogene (MPL) W515L and all others carried the Janus kinase 2 gene (JAK2) V617F mutation. . . .
Application of the Tisler Triazolopyrimidine Cyclization to the Synthesis of a Crop Protection Agent and an Intermediate (2006)

A new synthetic route to the Dow AgroSciences early stage sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)-N-(5,7-dimethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)pyridinesulfonamide (pyroxsulam) has been developed. The synthesis is based on formation of the triazole ring as the final step, utilizing the Tisler triazolopyrimidine cyclization. A Tisler cyclization route to 2-amino-5,7-dimethoxy-1,2,4-trazolo[1,5-a]pyrimidine starting with 2-chloro-4,6-dimethoxypyrimidine has also been demonstrated.