gebhart/patrepeval huggingface dataset:
Apoptosis Through Targeted Activation of Caspase8 (“ATTAC-mice”): Novel Mouse Models of Inducible and Reversible Tissue Ablation (2005)

Recent studies identifying obesity as a significant and increasingly more common cause of morbidity and mortality have intensified research efforts aimed at increasing our understanding of adipose tissue biology. These efforts have culminated in the discovery of several adipokines, or adipose tissue-derived hormones, that have been implicated in the regulation of multiple physiological functions, as well as the realization that adipose tissue dysfunction plays an important role in the pathogenesis of diseases such as obesity and diabetes. To better understand the role of adipose tissue in these physiological/pathological events, several studies have employed transgenic strategies to eliminate adipose tissue. However, these mouse models of congenital lipoatrophy/lipodystrophy exhibit severe metabolic and somatic cell dysfunction. To circumvent this limitation, we have designed and characterized the first inducible fatless mouse. The FAT-ATTAC mouse is a transgenic model whereby expression of a myristoylated caspase 8-FKBP fusion protein enables selective ablation of adipocytes via induction of apoptosis that occurs upon treatment with a chemical dimerizer. The FAT-ATTAC mouse model not only has the advantage that adipocyte ablation be induced at any time during development, but it is also fully reversible, as adipose tissue regenerates after cessation of dimerizer treatment. The inducibility of this fatless mouse model holds potential for revealing novel physiological roles for adipose tissue as well as its contribution to the etiology and pathogenesis of various disease states. Here we describe several ongoing areas of research employing the FAT-ATTAC mouse; in addition we describe potential uses of the targeted transgenic apoptotic approach to study other cell types of interest.
Abstract 4812: Collagen regulation of Snail expression in pancreatic cancer involves TGF-β1 signaling (2010)

Abstract Pancreatic cancer, the fourth leading cause of cancer death in the U.S., is associated with pronounced desmoplastic reaction; however, the role of this collagen-rich fibrotic reaction in pancreatic cancer progression is poorly understood. Previously, we had shown that the collagen increased expression of the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP). Now we show that collagen can also increase expression of the zinc-finger transcription factor Snail to enhance pancreatic cancer invasion. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3D collagen gels induced Snail. As we had previously published that TGF-β1 increases Snail levels, we examined the contribution of TGF-β1 signaling to collagen-induced Snail expression. Inhibiting TGF-β1 signaling with siRNA against TGF-β1 receptor type I (TbRI) or with a highly specific inhibitor of TbRI kinase activity attenuated the effect of collagen on Snail levels. To further examine the role of Snail in PDAC progression, we generated Snail-inducible PDAC cells lines. Expression of Snail in PDAC cells grown in 3D collagen gels enhanced invasion, which was blocked in the presence of the MMP inhibitor GM6001. Overexpression of Snail in PDAC cells increased MT1-MMP, while siRNA against Snail decreased MT1-MMP and also attenuated collagen-induced MT1-MMP expression. Snail expression of MT1-MMP requires ERK1/2 signaling and blocking ERK1/2 phosphorylation inhibited Snail-induced invasion in 3D collagen gels. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that collagen-rich milieu can increase the expression of Snail, and suggests that the desmoplastic reaction actively contributes to PDAC progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4812.
ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation (2012)

Deposition of uric acid crystals in joints causes the acute and chronic inflammatory disease known as gout and prolonged airway exposure to silica crystals leads to the development of silicosis, an irreversible fibrotic pulmonary disease. Aluminum salt (Alum) crystals are frequently used as vaccine adjuvant. The mechanisms by which crystals activate innate immunity through the Nlrp3 inflammasome are not well understood. Here, we show that uric acid, silica and Alum crystals trigger the extracellular delivery of endogenous ATP, which just precedes the secretion of mature interleukin-1β (IL-1β) by macrophages, both events depending on purinergic receptors and connexin/pannexin channels. Interestingly, not only ATP but also ADP and UTP are involved in IL-1β production upon these Nlrp3 inflammasome activators through multiple purinergic receptor signaling. These findings support a pivotal role for nucleotides as danger signals and provide a new molecular mechanism to explain how chemically and structurally diverse stimuli can activate the Nlrp3 inflammasome.
Glutathione S-transferase Pi mediates proliferation of androgen-independent prostate cancer cells (2008)

Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the 'transgenic rat adenocarcinoma in prostate' (TRAP) model, to analyze their gene expression using microarrays. Among the overexpressed genes in androgen-independent prostate cancers compared with the androgen-dependent tumors, glutathione S-transferase pi (GST-pi) was included. In line with this, human prostate cancer cell lines PC3 and DU145 (androgen independent) had higher expression of GST-pi compared with LNCaP (androgen dependent) as determined by semiquantitative reverse transcription-polymerase chain reaction analysis. To investigate the roles of GST-pi expression in androgen-independent human prostate cancers, GST-pi was knocked down by a small interfering RNA (siRNA), resulting in significant decrease of the proliferation rate in the androgen-independent PC3 cell line. In vivo, administration of GST-pi siRNA-atelocollagen complex decreased GST-pi protein expression, resulting in enhanced numbers of TdT mediated dUTP-biotin nick-end labering (TUNEL)-positive apoptotic cells. These findings suggest that GST-pi might play important roles in proliferation of androgen-independent human prostate cancer cells.
A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines (2017)

<h3>Background</h3> Clinical success with chimeric antigen receptor (CAR)- based immunotherapy for leukemia has been accompanied by the associated finding that antigen-escape variants of the disease are responsible for relapse. To target hematologic malignancies with a chimeric antigen receptor (CAR) that targets two antigens with a single vector, and thus potentially lessen the chance of leukemic escape mutations, a tandem-CAR approach was investigated. <h3>Methods</h3> Antigen binding domains from the FMC63 (anti-CD19) and Leu16 (anti-CD20) antibodies were linked in differing configurations to transmembrane and T cell signaling domains to create tandem-CARs. Expression on the surface of primary human T cells was induced by transduction with a single lentiviral vector (LV) encoding the tandem-CAR. Tandem-CARs were compared to single antigen targeting CARs in vitro and in vivo, and to an admixture of transduced cells expressing each CAR in vivo in immunodeficient (NSG) disease-bearing mice. <h3>Results</h3> Tandem constructs efficient killed the Raji leukemia cell line both in vitro and in vivo. Tandem CARs generated less cytokine than the CD20 CAR, but similar to CD19 CARs, on their own. In co-culture experiments at low effector to target ratios with both single- and tandem- CAR-T cells, a rapid down-modulation of full-length CD19 expression was seen on leukemia targets. There also was a partial down-modulation of CD22, and to a lesser degree, of CD20. Our data also highlight the extreme sensitivity of the NALM-6 cell line to general lymphocyte-mediated cytotoxicity. While single and tandem constructs were effective in vivo in a standard setting, in a high-disease burden setting, the tandem CAR proved both effective and less toxic than an admixture of transduced T cell populations expressing single CARs. <h3>Conclusion</h3> Tandem CARs are equally effective in standard disease models to single antigen specificity CARs, and may be both more effective and less toxic in a higher disease burden setting. This may be due to optimized cell killing with more moderate cytokine production. The rapid co-modulation of CD19, CD20, and CD22 may account for the ability to rapidly evolve escape mutants by selecting for leukemic clones that not require these target antigens for continued expansion.
Seizures Are Regulated by Ubiquitin-specific Peptidase 9 X-linked (USP9X), a De-Ubiquitinase (2015)

Epilepsy is a common disabling disease with complex, multifactorial genetic and environmental etiology. The small fraction of epilepsies subject to Mendelian inheritance offers key insight into epilepsy disease mechanisms; and pathologies brought on by mutations in a single gene can point the way to generalizable therapeutic strategies. Mutations in the PRICKLE genes can cause seizures in humans, zebrafish, mice, and flies, suggesting the seizure-suppression pathway is evolutionarily conserved. This pathway has never been targeted for novel anti-seizure treatments. Here, the mammalian PRICKLE-interactome was defined, identifying prickle-interacting proteins that localize to synapses and a novel interacting partner, USP9X, a substrate-specific de-ubiquitinase. PRICKLE and USP9X interact through their carboxy-termini; and USP9X de-ubiquitinates PRICKLE, protecting it from proteasomal degradation. In forebrain neurons of mice, USP9X deficiency reduced levels of Prickle2 protein. Genetic analysis suggests the same pathway regulates Prickle-mediated seizures. The seizure phenotype was suppressed in prickle mutant flies by the small-molecule USP9X inhibitor, Degrasyn/WP1130, or by reducing the dose of fat facets a USP9X orthologue. USP9X mutations were identified by resequencing a cohort of patients with epileptic encephalopathy, one patient harbored a de novo missense mutation and another a novel coding mutation. Both USP9X variants were outside the PRICKLE-interacting domain. These findings demonstrate that USP9X inhibition can suppress prickle-mediated seizure activity, and that USP9X variants may predispose to seizures. These studies point to a new target for anti-seizure therapy and illustrate the translational power of studying diseases in species across the evolutionary spectrum.
The Sym35 Gene Required for Root Nodule Development in Pea Is an Ortholog of Nin from Lotus japonicus (2003)

Comparative phenotypic analysis of pea (Pisum sativum) sym35 mutants and Lotus japonicus nin mutants suggested a similar function for the PsSym35 and LjNin genes in early stages of root nodule formation. Both the pea and L. japonicus mutants are non-nodulating but normal in their arbuscular mycorrhizal association. Both are characterized by excessive root hair curling in response to the bacterial microsymbiont, lack of infection thread initiation, and absence of cortical cell divisions. To investigate the molecular basis for the similarity, we cloned and sequenced the PsNin gene, taking advantage of sequence information from the previously cloned LjNin gene. An RFLP analysis on recombinant inbred lines mapped PsNin to the same chromosome arm as the PsSym35 locus and direct evidence demonstrating that PsNin is the PsSym35 gene was subsequently obtained by cosegregation analysis and sequencing of three independent Pssym35 mutant alleles. L. japonicus and pea root nodules develop through different organogenic pathways, so it was of interest to compare the expression of the two orthologous genes during nodule formation. Overall, a similar developmental regulation of the PsNin and LjNin genes was shown by the transcriptional activation in root nodules of L. japonicus and pea. In the indeterminate pea nodules, PsNin is highly expressed in the meristematic cells of zone I and in the cells of infection zone II, corroborating expression of LjNin in determinate nodule primordia. At the protein level, seven domains, including the putative DNA binding/dimerization RWP-RK motif and the PB1 heterodimerization domain, are conserved between the LjNIN and PsNIN proteins.
Efficient adaptive voltage scaling system through on-chip critical path emulation (2004)

Conventional voltage scaling techniques rely on the characterization and monitoring of a unique critical path. However, the uniqueness of the critical path is a difficult requirement to establish in modern VLSI technologies due to the growing impact of process variations and interconnect parasitics on delay. This paper presents an on-chip critical path emulator architecture which tracks the changing critical path. The ability to emulate the actual critical path recovers most of the large margin added by conventional systems to guarantee a robust operation at all conditions. Due to the reduced margin, the proposed architecture is up to 45% and 21% more energy efficient compared to conventional open-loop and closed-loop voltage scaling systems respectively.
Service oriented architecture for VoIP conferencing (2006)

Abstract Most current Voice/Video over IP (VoIP) systems are either highly centralized or dependent on IP multicast. We propose the Global Multimedia Collaboration System as a scalable, integrated and service‐oriented VoIP conferencing system, based on a SOAP‐based collaboration framework and advanced messaging oriented middleware. This system can provide media and session services to heterogeneous endpoints including H.323, SIP, Access Grid, and RealPlayer as well as accommodating diverse clients such as cellular phones. We suggest that our approach opens up new opportunities for extending classic VoIP systems by using these new technologies designed for scalable Internet based service‐oriented computing. Copyright © 2006 John Wiley &amp; Sons, Ltd.
Agricultural Research: Benefits and Beneficiaries of Alternative Funding Mechanisms (1999)

Abstract This article analyzes alternative funding mechanisms for agricultural research and the benefits and beneficiaries of these approaches. Although other mechanisms exist, the discussion focuses on public formula and competitive grants programs, private‐sector contracts and grants, and revenue from sale of intellectual property rights (IPRs) or new products embodying innovations. Over the past two decades, agricultural research has been criticized for the noncompetitive nature of research fund allocations. Considerable evidence exists that the system has performed well for society. We conclude that the private sector should be permitted to carry out research that it finds profitable to undertake with minimal competition from the public sector. The public research institutions should focus on general and pretechnology science programs that complement private research‐and‐development (R&amp;D) activities and conduct applied research in areas in which innovations are socially beneficial but not privately profitable. The mechanism for channeling public funds to researchers (e.g., formula, competitive grants, or earmarks) can be expected to affect the types of benefits/impacts of agricultural research conducted and the efficiency of the research activity. Issues remain about the emphasis on process versus substance in the R&amp;D funding debate. However, available evidence does not suggest the elimination of traditional funding mechanisms for public agricultural research.
The 9-decalyl and related cations. V. Generation of cis - and trans -2-t-Butyl-9-decalyl cations through π-routes by acetolysis (1978)

The synthesis and solvolytic behaviour (in buffered acetic acid) of 4- (5?-t-butylcyclohex-1'-enyl)but-1-yl p-nitrobenzenesulfonate (6) and 3- (cyclohex-1'-enylmethyl)-4,4-dimethylpentyl p-nitrobenzene-sulfonate (7) are described. Kinetic and product studies have shown that p-bond participation occurs in the acetolysis of both compounds. The rate enhancements, compared with saturated analogues, are c. 46 and 8290 for (6) and (7). The considerably greater rate enhancement observed for (7) is a manifestation of the 'gem-dialkyl' effect and is explained in terms of the effect of the t-butyl group on the conformations that the side chain might adopt. &amp;nbsp;&amp;nbsp;&amp;nbsp; The acetolyses of (6) and (7) give rise to cyclized products (c. 97 and 100%) arising from both cis- and trans-2-t-butyl-9-decalyl cations (2) and (3). The compositions of the products, which also include compounds formed from the cis-cation (55) obtained by a 1,2-hydride shift in (2), show that (6) and (7) do not react via the same cationic species. &amp;nbsp;&amp;nbsp;&amp;nbsp; Ion-pairs of an undefined nature are implicated in the reactions. Entirely consistent evidence was not obtained for the hypothesis that the counter-ion, behaving as a base, probably plays a significant role in olefin formation from the cis- and trans-cations (2) and (3) in ion- pairs that might be formed initially from (6) and (7).
Engineering of Escherichia coli central metabolism for aromatic metabolite production with near theoretical yield (1994)

Escherichia coli and many other microorganisms synthesize aromatic amino acids through the condensation reaction between phosphoenolpyruvate (PEP) and erythrose 4-phosphate to form 3-deoxy-D-arabinoheptulosonate 7-phosphate (DAHP). It has been shown that overexpression of transketolase increases the production of DAHP in an aroB mutant strain (unable to further metabolize DAHP) with elevated DAHP synthase. However, the yield (percent conversion) of DAHP from glucose is still low. Stoichiometric analysis shows that many enzymes compete for intracellular PEP. In particular, the phosphotransferase system, responsible for glucose transport in E. coli, uses PEP as a phosphate donor and converts it to pyruvate, which is less likely to recycle back to PEP. This stoichiometric limitation greatly reduces the yield of aromatic metabolites. To relieve this limitation, we overexpressed PEP synthase in the presence of glucose and showed that it increased the final concentration and the yield of DAHP by almost twofold, to a near theoretical maximum. The PEP synthase effect is not observed without overproduced transketolase, suggesting that erythrose 4-phosphate is the first limiting metabolite. This result demonstrates the utility of pathway analysis and the limitation of central metabolites in the high-level overproduction of desired metabolites.
Statistical similarity search applied to content-based video copy detection. (2005)

Abstract—Content-based copy detection (CBCD) is one of the emerging multimedia applications for which there is a need of a concerted effort from the database community and the computer vision community. Recent methods based on interest points and local fingerprints have been proposed to perform robust CBCD of images and video. They include two steps: the search of similar fingerprints in the database and a voting strategy that merges all the local results in order to make a global decision. In most image or video retrieval systems, the search of similar features in the database is performed by a geometrical query in a multidimensional index structure. Recently, the paradigm of approximate knearest neighbors query has shown that trading quality for time can be widely profitable in that context. In this paper, we propose a new approximate search paradigm dedicated to local fingerprints and we describe the original indexing structure we have developped to compute efficiently the corresponding queries. We consider that the distribution of the relevant fingerprints around a query can be modeled by the distribution of the distorsion vector between a referenced fingerprint and a candidate one. Experimental results show that these statistical queries allow high performance gains compared to classical ǫ-range queries. By studying the influence of this approximate search on a complete CBCD scheme based on local video fingerprints, we also show that trading quality for time during the search does not degrade seriously the global robustness of the system, even with very large databases including more than 10,000 hours of video. I.
Recombinant polyclonal antibodies for cancer therapy (2005)

Although monoclonal antibodies are increasingly used for cancer therapy, remissions are only temporary due to emergence of tumor cell escape variants that are no longer affected by the antibody. The emergence of escape variants could be minimized by multi-targeting of tumor cells with polyclonal antibodies, which would also be more efficient than monoclonal antibodies at mediating effector functions for target destruction. A technology for generating recombinant polyclonal antibodies for cancer therapy has been developed based on the construction and selection of tumor-reactive Fab phage display libraries. The selected Fabs are mass-converted to full-length polyclonal antibody libraries (PCALs) of any isotype and any species. Prototypic PCALs generated against human colorectal cancer cell lines showed that libraries of diverse recombinant antibodies, enriched for reactivity to the cancer cells compared to normal human cells, can be obtained. The success of recombinant polyclonal antibodies as cancer therapeutics will depend on the ability to generate, characterize, and mass-produce PCALs with high ratios of cancer-to-normal reactivities that cross-react with many cancers of the same type.
Effects of a dual inhibitor of tumor necrosis factor-α and interleukin-1 on lipopolysaccharide-induced lung injury in rats: Involvement of the p38 mitogen-activated protein kinase pathway (2001)

FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.
New Approach to Radial Expansive Force Measurement of Self Expandable Esophageal Metal Stents (2001)

The accurate measurement of radial expansive force is crucial for optimal design and implantation of self expandable esophageal metal stents. In the present study, a new method of measurement under experimental conditions simulating actual stent implantation has been developed. This method offers precise and reproducible measurements and can be applied to a wide variety of stent types. In particular, the method enables one to measure expansive pressure as well as the true radial expansive force up to the radial compression ratio of 72%, covering the range of compression often encountered in a partially obstructed lumen. The test results for various kinds of metal stents are presented and compared. Based on these results, three important points of observation critical in explaining and predicting the expansion characteristics of stents have been reported. Further understanding and characterization of these findings will be necessary for developing new stents with outstanding clinical efficacy.