gebhart/patrepeval huggingface dataset:
Controlled Generation of Progenitor T-cells from Hematopoietic Stem Cells and Pluripotent Stem Cells (2017)

The thymus integrates multiple niche molecules including cytokines, ligands and extracellular matrix to drive T-cell development in vivo. We hypothesized that engineering technologies to integrate essential thymic niche molecules required for progenitor T-cell development would enable defined in vitro generation and quantification of T-cells. We optimized a defined 2D serum-free culture system using Notch ligand Delta-like-4 (DL4) for producing progenitor T-cells from mouse Sca-1+cKit+ hematopoietic stem and progenitor cells (HSPCs). Serum-free culture enabled us to define assay design criteria such as input cell density, DL4 presentation and cytokine concentrations. The fully defined engineered in vitro niche revealed synergistic interactions between DL4 and vascular cell adhesion molecule-1 (VCAM-1), and its role in enhancing downstream Notch pathway activation, progenitor T-cell migration and differentiation. The engineered niche also enabled scalable differentiation of human umbilical cord blood-derived CD34+ HSPCs to CD7+ progenitor T-cells, yielding 25-fold total cell expansion with 59.3±10.8% CD7+ T-cells. CD7+ progenitor T-cells generated in the engineered niche were capable of thymic engraftment in lymphodeficient SIRPa-/- Rag2-/- gc-/- mice and generated mature functional CD3+ T-cells in vivo. Building on this system, we next immobilized DL4 in a 3D methylcellulose hydrogel (DL4-MC) using thiol-maleimide chemistry. DL4-MC hydrogels exhibited a dose-dependent increase in Notch pathway activation. We demonstrated that production of progenitor T-cells from HSPCs encapsulated in DL4-MC hydrogels could be enhanced when VCAM-MC was incorporated, creating a 3D engineered hydrogel thymus-like niche. Thus, controlled and reproducible differentiation of progenitor T-cells from stem cells can be achieved by engineering a thymus-like niche in vitro using minimum essential cues required for T-cell development. This provides an important step towards systematically engineering the niche for progenitor T-cell development with the ultimate goal of generating histocompatible “off-the-shelf” T-cells from normal or gene-edited stem cells for T-cell immunotherapeutic applications.
Modified Vaccinia Virus Ankara-Based Vaccine Vectors Induce Apoptosis in Dendritic Cells Draining from the Skin via both the Extrinsic and Intrinsic Caspase Pathways, Preventing Efficient Antigen Presentation (2012)

Dendritic cells (DC) are potent antigen-presenting cells and central to the induction of immune responses following infection or vaccination. The collection of DC migrating from peripheral tissues by cannulation of the afferent lymphatic vessels provides DC which can be used directly ex vivo without extensive in vitro manipulations. We have previously used bovine migrating DC to show that recombinant human adenovirus 5 vectors efficiently transduce afferent lymph migrating DEC-205(+) CD11c(+) CD8(-) DC (ALDC). We have also shown that recombinant modified vaccinia virus Ankara (MVA) infects ALDC in vitro, causing downregulation of costimulatory molecules, apoptosis, and cell death. We now show that in the bovine system, modified vaccinia virus Ankara-induced apoptosis in DC draining from the skin occurs soon after virus binding via the caspase 8 pathway and is not associated with viral gene expression. We also show that after virus entry, the caspase 9 pathway cascade is initiated. The magnitude of T cell responses to mycobacterial antigen 85A (Ag85A) expressed by recombinant MVA-infected ALDC is increased by blocking caspase-induced apoptosis. Apoptotic bodies generated by recombinant MVA (rMVA)-Ag85A-infected ALDC and containing Ag85A were phagocytosed by noninfected migrating ALDC expressing SIRPα via actin-dependent phagocytosis, and these ALDC in turn presented antigen. However, the addition of fresh ALDC to MVA-infected cultures did not improve on the magnitude of the T cell responses; in contrast, these noninfected DC showed downregulation of major histocompatibility complex class II (MHC-II), CD40, CD80, and CD86. We also observed that MVA-infected ALDC promoted migration of DEC-205(+) SIRPα(+) CD21(+) DC as well as CD4(+) and CD8(+) T cells independently of caspase activation. These in vitro studies show that induction of apoptosis in DC by MVA vectors is detrimental to the subsequent induction of T cell responses.
Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms (2013)

Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).
Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. I. Rejection by syngeneic mice. (1980)

We have reported that it is possible to obtain variants that are incapable of forming progressive tumour in syngeneic mice (tum-) by mutagenesis and cloning of a teratocarcinoma and a Lewis lung carcinoma cell line. These observations were extended to the ascitic P815 mastocytoma of mouse strain DB/2. After a treatment with the mutagen N-methyl-N"-nitro-N-nitrosoguanidine, we obtained a high frequency (14%) of tum- clones. A colony assay indicated that after a period of rapid multiplication extending to approximately 10 d after injection, the P815 tum- cells were rejected by a process that was usually completed by day 15. No rejection was observed in sublethally irradiated animals. The immunological nature of the rejection of the P815 variants was further inferred because, upon rejection, the mice acquired a radioresistant specific protection that could be transferred adoptively with spleen cells. Cross-immunization patterns demonstrated the presence of singular antigenic specificities on three of the five variants that were examined. In addition, a common antigen was found on all the tum- variants and the original cells that were capable of forming progressive tumors in syngeneic mice (tum+). Mice injected with tum- cells were significantly protected against a tum+ challenge, even though no significant protection was generated by irradiated tum+ cells. A study of the T lymphocyte-mediated cytolysis against the P815 variants described here is presented in the accompanying report (9).
Polymorphonuclear leukocytes as a significant source of tumor necrosis factor-alpha in endotoxin-challenged lung tissue. (1993)

The kinetic expression and potential cellular source of tumor necrosis factor-alpha (TNF-alpha) in lipopolysaccharide-(LPS) induced acute lung inflammation was investigated using a rat model by Northern blot analysis, in situ hybridization and immunohistochemistry. LPS induced a polymorphonuclear leukocyte infiltrate in the lung that peaked between 6 and 24 hours. TNF-alpha messenger (m)RNA was strongly induced by LPS in whole lung tissues shown by Northern analysis. Both alveolar macrophages and polymorphonuclear leukocytes (PMNs), purified from bronchoalveolar lavage fluids of LPS-treated rats, were shown to express TNF-alpha mRNA by Northern analysis. However, PMNs displayed several times more TNF-alpha mRNA, relative to actin mRNA, than alveolar macrophages at 6 and 12 hours. By in situ hybridization, most of the cells positive for TNF-alpha mRNA at 6 and 12 hours seemed to be PMNs located within the tissue near bronchioles or vessels. By immunohistochemistry, TNF-alpha protein was localized mainly to alveolar macrophages at early times (1 to 3 hours) after LPS challenge, and thereafter, PMNs seemed to be the predominant source of TNF-alpha protein as more than 90% of total intraalveolar positive cells at 6 and 12 hours were PMN. Thus, our data provide the first in vivo evidence that PMNs can serve as a significant source of TNF-alpha at sites of acute inflammation.
An overview of full-waveform inversion in exploration geophysics (2009)

Abstract Full-waveform inversion (FWI) is a challenging data-fitting procedure based on full-wavefield modeling to extract quantitative information from seismograms. High-resolution imaging at half the propagated wavelength is expected. Recent advances in high-performance computing and multifold/multicomponent wide-aperture and wide-azimuth acquisitions make 3D acoustic FWI feasible today. Key ingredients of FWI are an efficient forward-modeling engine and a local differential approach, in which the gradient and the Hessian operators are efficiently estimated. Local optimization does not, however, prevent convergence of the misfit function toward local minima because of the limited accuracy of the starting model, the lack of low frequencies, the presence of noise, and the approximate modeling of thewave-physics complexity. Different hierarchical multiscale strategies are designed to mitigate the nonlinearity and ill-posedness of FWI by incorporating progressively shorter wavelengths in the parameter space. Synthetic and real-data case studies address reconstructing various parameters, from VP and VS velocities to density, anisotropy, and attenuation. This review attempts to illuminate the state of the art of FWI. Crucial jumps, however, remain necessary to make it as popular as migration techniques. The challenges can be categorized as (1) building accurate starting models with automatic procedures and/or recording low frequencies, (2) defining new minimization criteria to mitigate the sensitivity of FWI to amplitude errors and increasing the robustness of FWI when multiple parameter classes are estimated, and (3) improving computational efficiency by data-compression techniques to make 3D elastic FWI feasible.
Certolizumab Pegol (2010)

Certolizumab pegol (Cimzia(®)) is currently the only PEGylated anti-TNFα biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pegol was approved as a treatment for rheumatoid arthritis in the EU, US and Canada in 2009, and as a treatment for Crohn disease in Switzerland in 2007 and the US in 2008. Certolizumab pegol is entering into an increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical data demonstrate benefits across a range of clinical, radiographic and patient reported outcomes.
End-to-End Header Compression over Software-Defined Networks: A Low Latency Network Architecture (2012)

The overhead portion especially for a small packet is one of the most significant parameters that can lower the efficiency of the link utilization. Therefore, many traditional hop-by-hop header compression techniques were introduced to reduce the amount of packet header before transmission. However, those techniques still cannot overcome the time performance issue as compression mechanism requires longer processing time. In the time-sensitive applications such as VoIP, high network latency can lead to voice quality problems. To improve the time performance, instead of using hop-by-hop basis, the authors propose a new header compression mechanism which can be deployed in end-to-end nodes using the Software-Defined Network concept. This mechanism can reduce both packet size and time delay. This research will show the results of round-trip time between our end-to-end header compression mechanism, multiple hop-by-hop header compression mechanism, and normal IP routing algorithm.
Looking forward: An update on some of the pediatricians, medical schools, hospitals in the path of the storm (2007)

Editor's note: This special AAP News report examines how children and medical personnel are faring on the second anniversary of Hurricane Katrina. ![][1] 

After Katrina, a Disaster Medical Assistance Team (DMAT) worked out of tents in front of Ochsner Medical Center to treat
Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents (2016)

A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.
Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects (2015)

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.
Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis (2013)

Genome engineering in human pluripotent stem cells (hPSCs) holds great promise for biomedical research and regenerative medicine. Recently, an RNA-guided, DNA-cleaving interference pathway from bacteria [the type II clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) pathway] has been adapted for use in eukaryotic cells, greatly facilitating genome editing. Only two CRISPR-Cas systems (from Streptococcus pyogenes and Streptococcus thermophilus), each with their own distinct targeting requirements and limitations, have been developed for genome editing thus far. Furthermore, limited information exists about homology-directed repair (HDR)-mediated gene targeting using long donor DNA templates in hPSCs with these systems. Here, using a distinct CRISPR-Cas system from Neisseria meningitidis, we demonstrate efficient targeting of an endogenous gene in three hPSC lines using HDR. The Cas9 RNA-guided endonuclease from N. meningitidis (NmCas9) recognizes a 5'-NNNNGATT-3' protospacer adjacent motif (PAM) different from those recognized by Cas9 proteins from S. pyogenes and S. thermophilus (SpCas9 and StCas9, respectively). Similar to SpCas9, NmCas9 is able to use a single-guide RNA (sgRNA) to direct its activity. Because of its distinct protospacer adjacent motif, the N. meningitidis CRISPR-Cas machinery increases the sequence contexts amenable to RNA-directed genome editing.
Pharmacology of β- l -Thymidine and β- l -2′-Deoxycytidine in HepG2 Cells and Primary Human Hepatocytes: Relevance to Chemotherapeutic Efficacy against Hepatitis B Virus (2002)

beta-L-Thymidine (L-dT) and beta-L-2'-deoxycytidine (L-dC) are potent and highly specific inhibitors of hepatitis B virus (HBV) replication both in vivo and in vitro (50% effective concentrations, 0.19 to 0.24 microM in 2.2.15 cells). The intracellular metabolisms of L-dT and L-dC were investigated in HepG2 cells and primary cultured human hepatocytes. L-dT and L-dC were extensively phosphorylated in both cell types, with the 5'-triphosphate derivative being the predominant metabolite. In HepG2 cells, the 5'-triphosphate levels were 27.7 +/- 12.1 and 72.4 +/- 1.8 pmol/10(6) cells for L-dT and L-dC, respectively. In primary human hepatocytes, the 5'-triphosphate levels were 16.5 +/- 9.8 and 90.1 +/- 36.4 pmol/10(6) cells for L-dT and L-dC, respectively. Furthermore, a choline derivative of L-dCDP was detected at concentrations of 15.8 +/- 1.8 and 25.6 +/- 0.1 pmol/10(6) cells in human hepatocytes and HepG2 cells, respectively. In HepG2 cells exposed to L-dC, the 5'-monophosphate and 5'-triphosphate derivatives of beta-L-2'-deoxyuridine (L-dUMP and L-dUTP, respectively) were also observed, reaching intracellular concentrations of 6.7 +/- 0.4 and 18.2 +/- 1.0 pmol/10(6) cells, respectively. In human hepatocytes, L-dUMP and L-dUTP were detected at concentrations of 5.7 +/- 2.4 and 43.5 +/- 26.8 pmol/10(6) cells, respectively. It is likely that deamination of L-dCMP by deoxycytidylate deaminase leads to the formation of L-dUMP, as the parent compound, L-dC, was not a substrate for deoxycytidine deaminase. The intracellular half-lives of L-dTTP, L-dCTP, and L-dUTP were at least 15 h, with intracellular concentrations of each metabolite remaining above their respective 50% inhibitory concentrations for the woodchuck hepatitis virus DNA polymerase for as long as 24 h after removal of the drug from cell cultures. Exposure of HepG2 cells to L-dT in combination with L-dC led to concentrations of the activated metabolites similar to those achieved with either agent alone. These results suggest that the potent anti-HBV activities of L-dT and L-dC are associated with their extensive phosphorylation.
Scaling question answering to the web (2001)

The wealth of information on the web makes it an attractive resource for seeking quick answers to simple, factual questions such as “who was the first American in space?” or “what is the second tallest mountain in the world?” Yet today's most advanced web search services (e.g., Google and AskJeeves) make it surprisingly tedious to locate answers to such questions. In this paper, we extend question-answering techniques, first studied in the information retrieval literature, to the web and experimentally evaluate their performance.First we introduce Mulder, which we believe to be the first general-purpose, fully-automated question-answering system available on the web. Second, we describe Mulder's architecture, which relies on multiple search-engine queries, natural-language parsing, and a novel voting procedure to yield reliable answers coupled with high recall. Finally, we compare Mulder's performance to that of Google and AskJeeves on questions drawn from the TREC-8 question answering track. We find that Mulder's recall is more than a factor of three higher than that of AskJeeves. In addition, we find that Google requires 6.6 times as much user effort to achieve the same level of recall as Mulder.
The integrality of speech in multimodal interfaces (1998)

A framework of complementary behavior has been proposed which maintains that direct-manipulation and speech interfaces have reciprocal strengths and weaknesses. This suggests that user interface performance and acceptance may increase by adopting a multimodal approach that combines speech and direct manipulation. This effort examined the hypothesis that the speed, accuracy, and acceptance of multimodal speech and direct-manipulation interfaces will increase when the modalities match the perceptual structure of the input attributes. A software prototype that supported a typical biomedical data collection task was developed to test this hypothesis. A group of 20 clinical and veterinary pathologists evaluated the prototype in an experimental setting using repeated measures. The results of this experiment supported the hypothesis that the perceptual structure of an input task is an important consideration when designing a multimodal computer interface. Task completion time, the number of speech errors, and user acceptance improved when interface best matched the perceptual structure of the input attributes.
Intravascular irreversible electroporation: Theoretical and experimental feasibility study (2008)

Irreversible electroporation (IRE) employs microsecond scale, mega-volt/m electric field pulses to impair the cell membrane. IRE is emerging as a valuable new minimally invasive technique. Of central importance in using IRE is the existence of electric fields, which while impairing the cell membrane, do not cause thermal Joule heating induced damage to the tissue. Our recent studies suggest that IRE could become an important technique to ablate vascular smooth muscle cells of the arterial wall and attenuate restenosis following angioplasty. This study was done to support the use of IRE in treatment of restenosis and is a fundamental investigation on the electric field parameters that can produce non-thermal IRE ablation of cells on the arterial wall. The study combines time-dependant finite-element models of the electric field equation and of the bio-heat equation with Henriques and Moritz thermal damage integral to evaluate the range of non-thermal IRE fields for use in blood vessels. The theoretical analysis is supported by temperature measurements during intravascular IRE of rodent carotid arteries, showing no significant temperature rise.
Characterising quantum dot concentrators (2002)

Luminescent collectors have advantages over geometric concentrators in that tracking is unnecessary and both direct and diffuse radiation can be collected. However, their development has been limited by the performance of luminescent dyes. The authors have recently proposed a novel concentrator in which the dyes are replaced by quantum dots (QDs). The advantages over dyes are: the absorption threshold can be tuned by choice of dot diameter, the red-shift between absorption and luminescence is related to the spread of dot sizes and high luminescence quantum efficiency (QE) has been observed. In this paper, the authors discuss how they have adapted a thermodynamic model to allow for re-absorption in QDs. They find that the amount of overlap of the absorption and luminescence has a strong effect on the efficiency. They show how to use the model to characterise the QDs and the concentrator by measuring the luminescence as a function of position.
Interactive navigation of multiple agents in crowded environments (2008)

We present a novel approach for interactive navigation and planning of multiple agents in crowded scenes with moving obstacles. Our formulation uses a precomputed roadmap that provides macroscopic, global connectivity for wayfinding and combines it with fast and localized navigation for each agent. At runtime, each agent senses the environment independently and computes a collision-free path based on an extended Velocity Obstacles concept. Furthermore, our algorithm ensures that each agent exhibits no oscillatory behaviors. We have tested the performance of our algorithm in several challenging scenarios with a high density of virtual agents. In practice, the algorithm performance scales almost linearly with the number of agents and can run at interactive rates on multi-core processors.