gebhart/patrepeval huggingface dataset:
Identification, activation, and selectivein vivoablation of mouse NK cells via NKp46 (2007)

Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.
Determinants governing the CYP74 catalysis: Conversion of allene oxide synthase into hydroperoxide lyase by site‐directed mutagenesis (2008)

Bioinformatics analyses enabled us to identify the hypothetical determinants of catalysis by CYP74 family enzymes. To examine their recognition, two mutant forms F295I and S297A of tomato allene oxide synthase LeAOS3 (CYP74C3) were prepared by site-directed mutagenesis. Both mutations dramatically altered the enzyme catalysis. Both mutant forms possessed the activity of hydroperoxide lyase, while the allene oxide synthase activity was either not detectable (F295I) or significantly reduced (S297A) compared to the wild-type LeAOS3. Thus, both sites 295 and 297 localized within the "I-helix central domain" ("oxygen binding domain") are the primary determinants of CYP74 type of catalysis.
Vitamin K-Dependent Protein Production in Transgenic Animals (1997)

Vitamin K-dependent proteins are currently purified from pooled human plasma or produced in mammalian cell culture systems by recombinant DNA technology. Transgenic animals may provide an additional expression system for the production of these therapeutic proteins. Mice have been used to test hybrid genes which direct the expression of recombinant factor IX and Protein C to the mammary gland. Transgenic livestock have also been created that secrete into milk fully active Protein C at 0.3 mg/mL, and factor IX at 0.2 mg/mL. Thus, it is feasible to develop genetically manipulated livestock for the industrial production of vitamin K-dependent proteins.
Why Women Have More Alzheimer's Disease Than Men: Gender and Mitochondrial Toxicity of Amyloid-β Peptide (2010)

The main risk factors for developing Alzheimer's disease (AD) are age and gender. The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-beta toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females. Since estrogenic compounds protect against mitochondrial toxicity of amyloid-beta, estrogenic action may be important in protecting cells from amyloid-beta toxicity and suggests a possible treatment or prevention strategy for AD. Unfortunately, to date, clinical trials with Ginkgo biloba and other estrogenic therapies have not proved successful in treating AD. As such, more experiments and clinical trials are indeed warranted to find conditions in which estrogenic compounds may be useful to prevent or treat AD.
Stage-specific tissue and cell interactions play key roles in mouse germ cell specification (2001)

Primordial germ cells (PGCs) in mice have been recognized histologically as alkaline phosphatase (AP) activity-positive cells at 7.2 days post coitum (dpc) in the extra-embryonic mesoderm. However, mechanisms regulating PGC formation are unknown, and an appropriate in vitro system to study the mechanisms has not been established. Therefore, we have developed a primary culture of explanted embryos at pre- and early-streak stages, and have studied roles of cell and/or tissue interactions in PGC formation. The emergence of PGCs from 5.5 dpc epiblasts was observed only when they were co-cultured with extra-embryonic ectoderm, which may induce the conditions required for PGC formation within epiblasts. From 6.0 dpc onwards, PGCs emerged from whole epiblasts as did a fragment of proximal epiblast that corresponds to the area containing presumptive PGC precursors without neighboring extra-embryonic ectoderm and visceral endoderm. Dissociated epiblasts at these stages, however, did not give rise to PGCs, indicating that interactions among a cluster of a specific number of proximal epiblast cells is needed for PGC differentiation. In contrast, we observed that dissociated epiblast cells from a 6.5-b (6.5+15-16 hours) to 6.75 dpc embryo that had undergone gastrulation gave rise to PGCs. Our results demonstrate that stage-dependent tissue and cell interactions play key roles in PGC determination.
A note on the evaluation of generative models (2015)

Probabilistic generative models can be used for compression, denoising, inpainting, texture synthesis, semi-supervised learning, unsupervised feature learning, and other tasks. Given this wide range of applications, it is not surprising that a lot of heterogeneity exists in the way these models are formulated, trained, and evaluated. As a consequence, direct comparison between models is often difficult. This article reviews mostly known but often underappreciated properties relating to the evaluation and interpretation of generative models with a focus on image models. In particular, we show that three of the currently most commonly used criteria---average log-likelihood, Parzen window estimates, and visual fidelity of samples---are largely independent of each other when the data is high-dimensional. Good performance with respect to one criterion therefore need not imply good performance with respect to the other criteria. Our results show that extrapolation from one criterion to another is not warranted and generative models need to be evaluated directly with respect to the application(s) they were intended for. In addition, we provide examples demonstrating that Parzen window estimates should generally be avoided.
Role of cloned carotenoid genes expressed in Escherichia coli in protecting against inactivation by near-UV light and specific phototoxic molecules (1988)

Genes controlling carotenoid synthesis were cloned from Erwinia herbicola and expressed in an Escherichia coli strain. Carotenoids protect against high fluences of near-UV (NUV; 320 to 400 nm) but not against far-UV (200-300 nm). Protection of E. coli cells was not observed following treatment with either psoralen or 8-methoxypsoralen plus NUV. However, significant protection of cells producing carotenoids was observed with three photosensitizing molecules activated by NUV (alpha-terthienyl, harmine, and phenylheptatriyne) which are thought to have the membrane as an important lethal target. Protection of carotenoid-producing cells against inactivation was not observed with acridine orange plus visible light but was seen with toluidine blue O plus visible light.
Technological Developments in Regenerative Medicine (2004)

組織・臓器の損傷ならびに難病の根本的な修復・再生を行う「再生医療」の研究開発が進みつつある。従来の薬物治療は人体自身の治癒能力や再生能力を支援するだけであったし,臓器移植は臓器提供者が極端に少ない現状では難病治療の主軸になりえない。そこで,主として自分自身の細胞を培養し,組織・臓器を形成する技術が着目された。本稿では,再生医療の最近の進歩と高分子基盤材料の役割の紹介を通じて再生医療の現状と可能性を考える。
IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo (2015)

A novel approach for the treatment of ovarian cancer includes immunotherapy with genetically engineered T cells targeted to ovarian cancer cell antigens. Using retroviral transduction, T cells can be created that express an artificial T cell receptor (TCR) termed a chimeric antigen receptor (CAR). We have generated a CAR, 4H11-28z, specific to MUC-16<sup>ecto</sup> antigen, which is the over-expressed on a majority of ovarian tumor cells and is the retained portion of MUC-16 after cleavage of CA-125. We previously demonstrated that T cells modified to express the 4H11-28z CAR eradicate orthotopic human ovarian cancer xenografts in SCID-Beige mice. However, despite the ability of CAR T cells to localize to tumors, their activation in the clinical setting can be inhibited by the tumor microenvironment, as is commonly seen for endogenous antitumor immune response. To potentially overcome this limitation, we have recently developed a construct that co-expresses both MUC16<sup>ecto</sup> CAR and IL-12 (4H11-28z/IL-12). <i>In vitro</i>, 4H11-28z/IL-12 CAR T cells show enhanced proliferation and robust IFNγ secretion compared to 4H11-28z CAR T cells. In SCID-Beige mice with human ovarian cancer xenografts, IL-12 secreting CAR T cells exhibit enhanced antitumor efficacy as determined by increased survival, prolonged persistence of T cells, and higher systemic IFNγ. Furthermore, in anticipation of translating these results into a phase I clinical trial which will be the first to study IL-12 secreting CAR T cells in ovarian cancer, an elimination gene has been included to allow for deletion of CAR T cells in the context of unforeseen or off-tumor on-target toxicity.
Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction. (1988)

Binding experiments indicate that mitochondrial aspartate aminotransferase can associate with the alpha-ketoglutarate dehydrogenase complex and that mitochondrial malate dehydrogenase can associate with this binary complex to form a ternary complex. Formation of this ternary complex enables low levels of the alpha-ketoglutarate dehydrogenase complex, in the presence of the aminotransferase, to reverse inhibition of malate oxidation by glutamate. Thus, glutamate can react with the aminotransferase in this complex without glutamate inhibiting production of oxalacetate by the malate dehydrogenase in the complex. The conversion of glutamate to alpha-ketoglutarate could also be facilitated because in the trienzyme complex, oxalacetate might be directly transferred from malate dehydrogenase to the aminotransferase. In addition, association of malate dehydrogenase with these other two enzymes enhances malate dehydrogenase activity due to a marked decrease in the Km of malate. The potential ability of the aminotransferase to transfer directly alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex in this multienzyme system plus the ability of succinyl-CoA, a product of this transfer, to inhibit citrate synthase could play a role in preventing alpha-ketoglutarate and citrate from accumulating in high levels. This would maintain the catalytic activity of the multienzyme system because alpha-ketoglutarate and citrate allosterically inhibit malate dehydrogenase and dissociate this enzyme from the multienzyme system. In addition, citrate also competitively inhibits fumarase. Consequently, when the levels of alpha-ketoglutarate and citrate are high and the multienzyme system is not required to convert glutamate to alpha-ketoglutarate, it is inactive. However, control by citrate would be expected to be absent in rapidly dividing tumors which characteristically have low mitochondrial levels of citrate.
Miniature, solid-state gas compressor (1987)

A concept for a miniature, solid-state gas compressor is examined. The device operates by the phased activation of voltage-driven, electrostrictive ceramic blocks along a compression channel wherein a confined elastomer provides a motion-amplifying medium for peristaltically closing the compression channel. The device is also self-valving. Model estimates based on the nonlinear electromechanical parameters for paraelectric BaTiO3 suggest that a small (∼5×5×9-cm3), lightweight (∼1-kg) device would supply ∼0.3 cm3 per cycle at a compression ratio of 25:1 employing modest electric fields (∼20 kV/cm). At 500 Hz this corresponds to 38 mW of ideal Joule–Thompson refrigeration at 4.2 K using He gas. The efficiency of the device is estimated to be ∼85% (not including the power supply). A three-cell mechanical simulator of the concept was built and tested, and it was demonstrated that compression and self-valving can be achieved by peristaltically extruding an elastomer against a gas channel. An electronic power supply to drive the electrostrictive ceramics was designed, and a three-cell supply was built and tested which demonstrated that voltages up to 150 V could be switched at frequencies up to 10 kHz using small, inexpensive components. A critique of practical considerations is given, and it is concluded that the concept is feasible but additional research is required in elastomeric materials and in fabricating relatively large ceramic capacitors (∼2×2×1 cm3). Currently available electrostrictive actuators are inadequate.
Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase (2015)

Hepatocellular carcinoma is the second leading cause of cancer death worldwide. DNA microarray analysis identified the ornithine aminotransferase (OAT) gene as a prominent gene overexpressed in hepatocellular carcinoma (HCC) from Psammomys obesus. In vitro studies demonstrated inactivation of OAT by gabaculine (1), a neurotoxic natural product, which suppressed in vitro proliferation of two HCC cell lines. Alpha-fetoprotein (AFP) secretion, a biomarker for HCC, was suppressed by gabaculine in both cell lines, but not significantly. Because of the active site similarity between GABA aminotransferase (GABA-AT) and OAT, a library of 24 GABA-AT inhibitors was screened to identify a more selective inhibitor of OAT. (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidene)cyclopentane-1-carboxylic acid (2) was found to be an inactivator of OAT that only weakly inhibits GABA-AT, l-aspartate aminotransferase, and l-alanine aminotransferase. In vitro administration of 2 significantly suppressed AFP secretion in both Hep3B and HepG2 HCC cells; in vivo, 2 significantly suppressed AFP serum levels and tumor growth in HCC-harboring mice, even at 0.1 mg/kg. Overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth. This is the first demonstration of suppression of HCC by an OAT inactivator.
RECENT APPROACHES TO INTRACELLULAR DELIVERY OF DRUGS AND DNA AND ORGANELLE TARGETING (2006)

Intracellular delivery of various drugs, including DNA, and drug carriers can sharply increase the efficiency of various treatment protocols. However, the receptor-mediated endocytosis of drugs, drug carriers, and DNA results in their lysosomal delivery and significant degradation. The problem can be solved and therapy efficacy still further increased if the approaches for direct intracytoplasmic delivery that bypass the endocytic pathway are developed. This is especially important for many anticancer drugs (proapoptotic drugs whose primary action site is the mitochondrial membrane) and gene therapy (nuclear or mitochondrial genomes should be targeted). This review considers several current approaches for intracellular drug delivery: the use of pH-sensitive liposomes, the use of cell-penetrating proteins and peptides, and the use of immunoliposomes targeting intracellular antigens. Among intracellular targets, nuclei (gene therapy), mitochondria (proapoptotic cancer therapy and targeting of the mitochondrial genome), and lysosomes (lysosomal targeting of enzymes for the therapy of the lysosomal storage diseases) are considered. Examples of successful intracellular and organelle-specific delivery of biologically active molecules, including DNA, are presented; unanswered questions, challenges, and future trends are also discussed.
“La desesperación de la tinta”: García Lorca and the Failure of the Word (2011)

Abstract This article looks at some of the ways in which Federico García Lorca framed a problem that surfaces insistently in his writing of the 1920s, namely the disassociation between what he wanted to express and what he believed he was able to express. This problem is the source of both the frustration he voiced on various occasions at the time and the various innovations he incorporated into his own creative work, particularly his interest in the nonverbal communication of the drawn or cinematic image. The discussion centers on the sensation of loss and corruption that characterizes a good deal of García Lorca's writing and is associated with his feeling of being banished from a childhood paradise of purity and innocence in which words retained their power to communicate effectively. Attention is devoted to the different ways in which García Lorca seeks to overcome or at least to represent the limitations of language and the failure of the word and highlights the significance of the allusions to ink, as a metaphor for writing, that appear in a variety of contexts.
Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells (2008)

We report that angiotensin-converting enzyme (ACE), a critical physiologic regulator of blood pressure, angiogenesis, and inflammation, is a novel marker for identifying hemangioblasts differentiating from human embryonic stem cells (hESC). We demonstrate that ACE+CD45-CD34+/- hemangioblasts are common yolk sac (YS)-like progenitors for not only endothelium but also both primitive and definitive human lymphohematopoietic cells. Thrombopoietin and basic fibroblast growth factor are identified as critical factors for the proliferation of human hemangioblasts. The developmental sequence of human embryoid body hematopoiesis is remarkably congruent to the timeline of normal human YS development, which occurs during weeks 2 to 6 of human gestation. Furthermore, ACE and the renin-angiotensin system (RAS) directly regulate hemangioblast expansion and differentiation via signaling through the angiotensin II receptors AGTR1 and AGTR2. ACE enzymatic activity is required for hemangioblast expansion, and differentiation toward either endothelium or multipotent hematopoietic progenitors is dramatically augmented after manipulation of angiotensin II signaling with either AGTR1- or AGTR2-specific inhibitors. The RAS can therefore be exploited to direct the hematopoietic or endothelial fate of hESC-derived hemangioblasts, thus providing novel opportunities for human tissue engineering. Moreover, the initial events of human hematoendotheliogenesis can be delineated in a manner previously impossible because of inaccessibility to early human embryonic tissues.
Selective MR imaging of silicone with the three-point Dixon technique. (1993)

Selective magnetic resonance (MR) imaging of silicone with the three-point Dixon technique was evaluated. This technique, which conventionally allows separation of lipid and water signals, was modified to allow calculation of a silicone-only image and a lipid-water image. Imaging of fat and silicone implant phantoms was performed with a 1.5-T imager and was optimized in vivo in two volunteers who had breast reconstruction or augmentation. Six additional volunteers were then imaged to evaluate selective MR imaging of silicone. With an optimum frequency shift of 105 Hz, a repetition time of 1,000 msec, and an echo time of 28 msec, the modified three-point Dixon technique produced a silicone-only image containing 97.0% +/- 1.0 (standard deviation) of the total silicone signal, 2.6% +/- 0.5 of the fat signal, and 16.6% +/- 6.4 of the water signal. The silicone-fat contrast-to-noise ratio was 47.9 +/- 12.1. This method may be potentially useful in the evaluation of implant-related complications such as rupture.
Protocol-Independent Adaptive Replay of Application Dialog. (2006)

For many applications—including recognizing malware variants, determining the range of system versions vulnerable to a given attack, testing defense mechanisms, and filtering multi-step attacks—it can be highly useful to mimic an existing system while interacting with a live host on the network. We present RolePlayer, a system which, given examples of an application session, can mimic both the client side and the server side of the session for a wide variety of application protocols. A key property of RolePlayer is that it operates in an application-independent fashion: the system does not require any specifics about the particular application it mimics. It instead uses byte-stream alignment algorithms to compare different instances of a session to determine which fields it must change to successfully replay one side of the session. Drawing only on knowledge of a few low-level syntactic conventions (such as representing IP addresses using “dotted quads”), and contextual information such as the domain names of the participating hosts, RolePlayer can heuristically detect and adjust network addresses, ports, cookies, and length fields embedded within the session, including sessions that span multiple, concurrent connections on dynamically assigned ports. We have successfully used RolePlayer to replay both the client and server sides for a variety of network applications, including NFS, FTP, and CIFS/SMB file transfers, as well as the multi-stage infection processes of the Blaster and W32.Randex.D worms. 1