gebhart/patrepeval huggingface dataset:
Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies (2014)

The recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naïve-antibody library (containing ∼10(11) antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 μg/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses. Importance: A novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV.
Exonuclease VII of Escherichia coli (1974)

Abstract A new deoxyribonuclease, exonuclease VII, has been identified and purified 1,700-fold from Escherichia coli K12. The enzyme is an exonuclease specific for single-stranded DNA or duplex DNA containing single-stranded termini. The purified enzyme is active in the presence of EDTA, but is stimulated 25% by MgCl2. Optimal activity occurs at pH 7.9 in potassium phosphate buffer. The molecular weight, as determined by gel filtration and sedimentation analysis, is 88,000; the Stokes radius is 89 A. The friction coefficient of the enzyme is 3.07, suggesting an asymmetric structure. In the accompanying paper (Chase, J. W., and Richardson, C. C. (1974) J. Biol. Chem. 249, 4553–4561) we show that the enzyme is an exonuclease which can initiate hydrolysis at both 3' and 5' termini to yield products which are exclusively oligonucleotides.
Structure-Activity Relationship Studies: M2 and CCR5 Receptor Antagonists (2003)

A wide range of neurotransmitters, polypeptides and inflammatory mediators transduce their signals into the interior of cell by specific interactions with cell-surface receptors that are coupled to G-protein. The most familiar G-protein-coupled receptors are muscarinic receptors, adrenergic receptors, dopaminergic receptors and opioid receptors. A single polypeptide chain of 400-500 residues forms most of these receptors. There are seven hydrophobic regions in the receptor and they correspond to transmembrane alpha-helices, which are membrane spanning domains. This topology is highly conserved among various members of the family of G-protein coupled receptors. The amino-terminal extracellular domain contains potential N-linked glycosylation sites in most receptors. The carboxyl-terminal is involved in the coupling to G-proteins and contains a cysteine site and phosphorylation site (Thr, Ser) and both are involved in receptor desensitization. In this section of the review we will discuss the development of potent, selective, low molecular weight antagonists of two G-protein coupled receptors (M(2) muscarinic receptor and CCR5 chemokine receptor) and their potential therapeutic utilities. The initial leads in both antagonist programs came from in house screening of our sample collections. As expected, most of the initial leads for both programs shared a similar pharmacophore and because of this showed strong affinity to many if not few a other G-protein coupled receptors. The initial significant challenge in both programs in terms of structure-activity studies was not only to optimize the structures for potency but also selectivity versus other subtype receptors. In the M(2) antagonist program the selectivity versus M(1) and other subtypes was a major challenge. Similarly in the CCR5 antagonist program the selectivity versus M(2) was a significant issue to overcome. In this review we will discuss in detail the structure activity relationships that resulted in potent and selective antagonists.
Exposure of human megakaryocytes to high shear rates accelerates platelet production (2009)

Platelets originate from megakaryocytes (MKs) by cytoplasmic elongation into proplatelets. Direct platelet release is not seen in bone marrow hematopoietic islands. It was suggested that proplatelet fragmentation into platelets can occur intravascularly, yet evidence of its dependence on hydrodynamic forces is missing. Therefore, we investigated whether platelet production from MKs could be up-regulated by circulatory forces. Human mature MKs were perfused at a high shear rate on von Willebrand factor. Cells were observed in real time by videomicroscopy, and by confocal and electron microscopy after fixation. Dramatic cellular modifications followed exposure to high shear rates: 30% to 45% adherent MKs were converted into proplatelets and released platelets within 20 minutes, contrary to static conditions that required several hours, often without platelet release. Tubulin was present in elongated proplatelets and platelets, thus ruling out membrane tethers. By using inhibitors, we demonstrated the fundamental roles of microtubule assembly and MK receptor GPIb. Secretory granules were present along the proplatelet shafts and in shed platelets, as shown by P-selectin labeling. Platelets generated in vitro were functional since they responded to thrombin by P-selectin expression and cytoskeletal reorganization. In conclusion, MK exposure to high shear rates promotes platelet production via GPIb, depending on microtubule assembly and elongation.
Developing organ-on-a-chip concepts using bio-mechatronic design methodology (2017)

Mechatronic design is an engineering methodology for conceiving, configuring and optimising the design of a technical device or product to the needs and requirements of the final user. In this article, we show how the basic principles of this methodology can be exploited for in vitro cell cultures-often referred to as organ-on-a-chip devices. Due to the key role of the biological cells, we have introduced the term bio-mechatronic design, to highlight the complexity of designing a system that should integrate biology, mechanics and electronics in the same device structure. The strength of the mechatronic design is to match the needs of the potential users to a systematic evaluation of overall functional design alternative. It may be especially attractive for organs-on-chips where biological constituents such as cells and tissues in 3D settings and in a fluidic environment should be compared, screened and selected. Through this approach, design solutions ranked to customer needs are generated according to specified criteria, thereby defining the key constraints of the fabrication. As an example, the bio-mechatronic methodology is applied to a liver-on-a-chip based on information extrapolated from previous theoretical and experimental knowledge. It is concluded that the methodology can generate new fabrication solutions for devices, as well as efficient guidelines for refining the design and fabrication of many of today's organ-on-a-chip devices.
Antisense ferritin oligonucleotides inhibit growth and induce apoptosis in human breast carcinoma cells. (2002)

This study demonstrates that antisense ODNs to ferritin genes are about two-fold more cytotoxic than sense ODNs, and that antisense ODNs are specific inhibitors of ferritin gene expression at both the transcriptional and the translational levels. Further, the antisense ferritin ODNs promote programmed cell death with low ratios of Bcl-2 to Bax mRNA and protein expression providing evidence that antisense ferritin ODNs specifically inhibit MCF-7 breast carcinoma cell growth through increased apoptosis. Finally, since the IC50 concentrations of FerH-A1 and FerH-A2, and FerL-A1 and FerL-A2 are very similar for inhibition of DNA synthesis and gene expression in human breast carcinoma MCF-7 cells, it does not seem necessary for the antisense ODNs to overlap the starting codons of ferritin gene to maximize inhibition.
Spatial frequency domain image processing for biometric recognition (2003)

Biometric recognition refers to the process of matching an input biometric to stored biometric information. In particular, biometric verification refers to matching the live biometric input from an individual to the stored biometric template about that individual. Examples of biometrics include face images, fingerprint images, iris images, retinal scans, etc. Thus, image processing techniques prove useful in the biometric recognition. We discuss spatial frequency domain image processing methods useful for biometric recognition.
Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS (2015)

Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-γ signaling. Here, we found that in the mutant SOD1(G93A) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-γ levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.
Activation of the immune system by bacterial CpG‐DNA (2002)

The past decade has seen a remarkable process of refocusing in immunology. Cells of the innate immune system, especially macrophages and dendritic cells, have been at the centre of this process. These cells had been regarded by some scientists as non-specific, sometimes perhaps even confined to the menial job of serving T cells by scavenging antigen and presenting it to the sophisticated adaptive immune system. Only over the last few years has it become unequivocally clear that cells of the innate immunity hold, by variation of context and mode of antigen presentation, the power of shaping an adaptive immune response. The innate immune response, in turn, is to a significant degree the result of stimulation by so-called pathogen-associated molecular patterns (PAMPs). One compound with high stimulatory potential for the innate immune system is bacterial DNA. Here we will review recent evidence that bacterial DNA should be ranked with other PAMPs such as lipopolysaccharide (LPS) and lipoteichoic acid. We will further review our present knowledge of DNA recognition and DNA-dependent signal transduction in cells of the immune system.
Towards a reading coach that listens: automated detection of oral reading errors (1993)

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Expression of ECRG4, a novel esophageal cancer-related gene, downregulated by CpG island hypermethylation in human esophageal squamous cell carcinoma (2003)

These results indicate that the inactivation of ECRG 4 gene by hypermethylation is a frequent molecular event in ESCC and may be involved in the carcinogenesis of this cancer.
Ultra-high throughput detection of single cell β-galactosidase activity in droplets using micro-optical lens array (2013)

We demonstrate the use of a hybrid microfluidic-micro-optical system for the screening of enzymatic activity at the single cell level. <i>Escherichia coli</i> β-galactosidase activity is revealed by a fluorogenic assay in 100 pl droplets. Individual droplets containing cells are screened by measuring their fluorescence signal using a high-speed camera. The measurement is parallelized over 100 channels equipped with microlenses and analyzed by image processing. A reinjection rate of 1 ml of emulsion per minute was reached corresponding to more than 10<sup>5</sup> droplets per second, an analytical throughput larger than those obtained using flow cytometry.
Primary Chemoprevention of Familial Adenomatous Polyposis with Sulindac (2002)

Standard doses of sulindac did not prevent the development of adenomas in subjects with familial adenomatous polyposis.
Comparison of Zygote Intrafallopian Transfer and Intrauterine Embryo Transfer for Male-factor Infertility After Intracytoplasmic Sperm Injection (2004)

In vitro fertilization and embryo transfer (IVF-ET) have been increasingly used for treating male-factor infertility. However, zygote intrafallopian transfer (ZIFT) allows early embryo development to occur within the natural environment of the tubal lumen. The purpose of this study was to analyze whether the mode of embryo transfer, ZIFT versus intrauterine ET, affected the pregnancy outcome in the IVF cycle after intracytoplasmic sperm injection (ICSI) for the treatment of male-factor infertility. A total of 140 ICSI procedures (69 ET, 71 ZIFT) were analyzed. A maximum of four cleaving embryos were transferred into the fallopian tube or uterine cavity 48 and 72 hours after oocyte retrieval, respectively. Several variables, including mean age, IVF cycle day 2 hormone levels, peak E2 level, number of oocytes retrieved, number of embryos transferred, endometrial thickness, pulsatility index and resistance index of the uterine artery, and clinical pregnancy rate, were analyzed. The clinical pregnancy rate for ET was 25.4%, versus 24.7% for ZIFT. There was no significant difference between the two groups in the other variables, except for mean age. The data presented in this report demonstrate that there was no therapeutic improvement associated with the increased complexity of ZIFT as compared with intrauterine ET after ICSI for the treatment of male-factor infertility. With the advent of improvements in culture techniques in the IVF laboratory, intrauterine ET remains the technique of choice.
Lossless transmission of 2 ps pulses over 45 kmof standard fibre at 1.3 µm using distributed Raman amplification (1998)

A 10 GHz, 2 ps pulse stream at 1.3 µm is transmitted over a 45 km span of standard telecommunications fibre using distributed Raman amplification pumped with a compact and highly efficient fibre laser. When the pulse source is tuned to the minimum dispersion wavelength of the fibre, lossless, distortionless pulse transmission is demonstrated. By increasing the Raman pump power, a net gain of 8 dB over the span has been achieved, allowing the demonstration of nonlinear pulse compression.
ApoE-4 and Age at Onset of Alzheimer's Disease (1997)

This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years.
Escherichia coli RNA polymerase terminates transcription efficiently at rho-independent terminators on single-stranded DNA templates (1997)

Several models have been proposed for the mechanism of transcript termination by Escherichia coli RNA polymerase at rho-independent terminators. Yager and von Hippel (Yager, T. D. & von Hippel, P. H. (1991) Biochemistry 30, 1097-118) postulated that the transcription complex is stabilized by enzyme-nucleic acid interactions and the favorable free energy of a 12-bp RNA-DNA hybrid but is destabilized by the free energy required to maintain an extended transcription bubble. Termination, by their model, is viewed simply as displacement of the RNA transcript from the hybrid helix by reformation of the DNA helix. We have proposed an alternative model where the RNA transcript is stably bound to RNA polymerase primarily through interactions with two single-strand specific RNA-binding sites; termination is triggered by formation of an RNA hairpin that reduces binding of the RNA to one RNA-binding site and, ultimately, leads to its ejection from the complex. To distinguish between these models, we have tested whether E. coli RNA polymerase can terminate transcription at rho-independent terminators on single-stranded DNA. RNA polymerase cannot form a transcription bubble on these templates; thus, the Yager-von Hippel model predicts that intrinsic termination will not occur. We find that transcript elongation on single-stranded DNA templates is hindered somewhat by DNA secondary structure. However, E. coli RNA polymerase efficiently terminates and releases transcripts at several rho-independent terminators on such templates at the same positions as termination occurs on duplex DNAs. Therefore, neither the nontranscribed DNA strand nor the transcription bubble is essential for rho-independent termination by E. coli RNA polymerase.
Analysis of interleukin-6, interleukin-10 and leukemia inhibitory factor (LIF) production by peripheral blood cells from patients with systemic lupus erythematosus identifies LIF as a potential marker of disease activity. (1999)

The objective of this study was to determine the extent of interleukin (IL)-6, -10 and/or LIF involvement in systemic lupus erythematosus (SLE). Specific ELISA were used to measure cytokines in the supernatants of 48 hours cultures of whole blood stimulated or not by lipopolysaccharide and phytohemagglutinin, from controls (n = 10) or SLE patients divided according to the median of the SLE activity measurements (SLAM): < 9, group 1 (n = 11), and 9, group 2 (n = 10). Comparing median basal and stimulated cytokine concentrations from patients and controls, IL-6 was significantly higher in all SLE patients, IL-10 was significantly higher in both non- and stimulated situations only for SLE group 1 patients. With regard to LIF, it was significantly enhanced only in stimulated cultures of whole blood from group 2 patients as compared to control subjects. In conclusion, the production of cytokines involved in B-cell regulation and inflammation was altered in SLE, and LIF appears to be a potential marker of disease activity.
Psychoanalysts without a Specific Professional Identity: A Utopian Dream? (2004)

The subject matter of identity belongs to the orthodox psychoanalytic movement. For about the last 15 years, the International Psychoanalytic Association (IPA) has successfully tried to facilitate research and to promote projects. If the resistance of influential analysts against empirical investigation decreases further, “psychoanalytic movement” and its unfavourable concomitants will be a thing of the past. The development to a scientific community will no longer be hampered by controversies over professional identity. The psychosocial dimension and its normative implications put the concept of identity into question. Instead the author suggests that we speak of a psychoanalytic attitude. This professional self is closely connected to the personal self. It is however, necessary to separate the method from the person. For a long time the genealogy of the training analyst determined the membership in the ever‐growing family of psychoanalysts. There have been black sheep right from the beginning. Dissidents, therefore, belong to the history of Psychoanalysis. The official acceptance of pluralism within the IPA invites comparisons between the various schools according to scientific criteria. The methodology of modern psychoanalytic process and outcome research provides principles for writing treatment reports. Group identities in their dogmatic aspects are detrimental for the future of psychoanalysis. The message of the paper is to express the hope that a critical eclecticism might replace psychoanalytic schools.
Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome (2001)

To measure effect of bone marrow stromal cells (MSCs) administered i.v. on rats subjected to traumatic brain injury (TBI), we injected MSCs labeled by BrdU into the tail vein 24 h after TBI and sacrificed rats 15 days later. The neurological severity score (NSS) and the Rotarod test were used to evaluate neurological function. The distribution of the donor cells in brain, heart, lung, kidney, liver and spleen were analyzed in recipient rats using immunohistochemical staining. MSCs injected i.v. significantly reduced motor and neurological deficits compared with control groups by day 15 after TBI. The cells preferentially entered and migrated into the parenchyma of the injured brain and expressed the neuronal marker NeuN and the astrocytic marker GFAP. MSCs were also found in other organs and primarily localized to the vascular structures, without any obvious adverse effects. Our data suggest that i.v. administration of MSCs may be useful in the treatment of TBI.