gebhart/patrepeval huggingface dataset:
Differential regulation of Ia expression and antigen presentation by listeriolysin-producing versus non-producing strains of Listeria monocytogenes (1996)

Listeria monocytogenes is an intracellular bacterial pathogen. A single gene product, listeriolysin (LLO), is critical for the induction of protective immunity. We now show that listeria that produce functional LLO augment Ia expression by macrophages and are better presented to a Th1, CD4+ anti-listeria T cell line. We used two genetically engineered strains of listeria which differed only in their ability (Ly+) or inability (Ly-) to produce functional LLO. Ia-negative murine macrophages ingested either Ly+ or Ly-, and then were stimulated by interferon-gamma (IFN-gamma). Increasing numbers of live Ly+, but not Ly-, augmented IFN-gamma-induced Ia expression. Ly+ by itself did not induce Ia expression. Heat-killed Ly+ and Ly- did not augment IFN-gamma-induced Ia expression. The abundance of Ia on the macrophage cell surface is one major determinant of antigen presentation to CD4+ T cells. Consistent with their ability to augment la expression, Ly+ were better presented than Ly- to a CD4+, Th1, anti-listeria T cell line. When macrophages and T cells were from different inbred mouse strains, antigen presentation required identity at the class II region of the MHC gene complex. This indicated that antigen presentation occurred via Ia molecules. The increased ability of macrophages to present Ly+ is a product of the macrophage-listeria interaction, not a property of the T cell tine 86. If Ia-negative macrophages ingested Listeria and were then stimulated by IFN-gamma, Ly+ was presented more efficiently than Ly-. On the other hand, if Ia-positive macrophages ingested Listeria, then Ly+ and Ly- were presented equally well to T cells. Altogether our data is consistent with the hypothesis that macrophages interact differently with Ly+, and that this contributes to the ability of only live Ly+ to induce protective immunity.
Pancreatic islet volume distribution: direct measurement in preparations stained by perfusion in situ (1984)

The islets of Langerhans in normal mice were analyzed and quantitated morphologically after selective in situ perfusion staining with dithizone of the isolated pancreas. Total islet area and number of islets were determined in a texture-analyzing system on projected images of each islet. Islets varied considerably in size and in shape and did not conform with ideal spheroids or ellipsoids. In order to derive methods for estimation of the total number and total volume of islets, a distributional study of the areas was carried out. The size distribution of the islets of Langerhans was not of a known simple type, and was fitted best with a (power)-generalized inverse Gaussian distribution.
Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia (2009)

The limit of acceptable toxicity for standard chemotherapy has been reached in AML. Therefore, new therapeutic strategies are needed. Targeting the PI3K/Akt/mTOR signaling network with small molecule inhibitors, alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit selective inhibitors of the PI3K/Akt/mTOR pathway that show effectiveness and safety in the clinical setting are currently underway.
Instant immunity through chemically programmable vaccination and covalent self-assembly (2009)

The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology. Reactive immunization was used to create a reservoir of covalent polyclonal antibodies in 3 mouse strains that were subsequently engrafted with syngeneic CT26 colon or B16F10 melanoma tumors. Upon administration of designed integrin alpha(v)beta(3) and alpha(v)beta(5) adapter ligands, the induced covalent polyclonal antibodies self-assembled with the adapter ligands and the animals mounted an instant, chemically programmed, polyclonal response against the implanted tumors. Significant therapeutic responses were observed without recourse to adjuvant therapy. The chemically programmed immune responses were driven by antibody-dependent cellular cytotoxicity and complement-directed cytotoxicity. We suggest that this type of chemistry-driven approach to vaccinology is underexplored and may provide routes to vaccines to protect against diseases that have proven intractable to biology-driven vaccine approaches.
Podoplanin: emerging functions in development, the immune system, and cancer (2012)

Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer.
Myofibroblast Transdifferentiation in Obliterative Bronchiolitis: TGF-β Signaling Through Smad3-Dependent and -Independent Pathways (2006)

We have shown that Smad3, an intracellular signal transducer for transforming growth factor-beta1 (TGF-beta1), is required to elicit the full histological manifestations of obliterative airway disease in a tracheal transplant model. This suggests that chronic allograft rejection results in TGF-beta1-induced Smad3 activation that leads to airway obliteration through fibroproliferation and increased matrix deposition. In other systems, these latter events are causally related to the transdifferentiation of fibroblasts into myofibroblasts, but their role in obliterative bronchiolitis (OB) after lung transplantation is unknown. We confirmed the presence of myofibroblasts inside affected airways associated with experimental OB using immunohistochemistry. Studying airway fibroblasts in vitro, we observed increased myofibroblast transdifferentiation in response to TGF-beta1, evidenced by increased alpha-smooth muscle actin mRNA and protein expression. In Smad3-null fibroblasts, TGF-beta1 induction of myofibroblast transdifferentiation was greatly diminished but not abolished, suggesting the presence of Smad3-independent pathways. Further studies revealed that small molecule inhibitors of p38 (SB203580) and MEK/ERK (U1026) further reduced the remaining effect of TGF-beta1 in Smad3-deficient fibroblasts. Together, these studies suggest that in chronic allograft rejection, TGF-beta1 stimulates myofibroblast transdifferentiation through Smad3-dependent and -independent signals, contributing to the excessive matrix deposition that characterizes obliterative bronchiolitis.
The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm (2001)

An organizer population has been identified in the anterior end of the primitive streak of the mid-streak stage embryo, by the expression of Hnf3beta, Gsc(lacZ) and Chrd, and the ability of these cells to induce a second neural axis in the host embryo. This cell population can therefore be regarded as the mid-gastrula organizer and, together with the early-gastrula organizer and the node, constitute the organizer of the mouse embryo at successive stages of development. The profile of genetic activity and the tissue contribution by cells in the organizer change during gastrulation, suggesting that the organizer may be populated by a succession of cell populations with different fates. Fine mapping of the epiblast in the posterior region of the early-streak stage embryo reveals that although the early-gastrula organizer contains cells that give rise to the axial mesoderm, the bulk of the progenitors of the head process and the notochord are localized outside the early gastrula organizer. In the mid-gastrula organizer, early gastrula organizer derived cells that are fated for the prechordal mesoderm are joined by the progenitors of the head process that are recruited from the epiblast previously anterior to the early gastrula organizer. Cells that are fated for the head process move anteriorly from the mid-gastrula organizer in a tight column along the midline of the embryo. Other mid-gastrula organizer cells join the expanding mesodermal layer and colonize the cranial and heart mesoderm. Progenitors of the trunk notochord that are localized in the anterior primitive streak of the mid-streak stage embryo are later incorporated into the node. The gastrula organizer is therefore composed of a constantly changing population of cells that are allocated to different parts of the axial mesoderm.
Separating agreement from execution for byzantine fault tolerant services (2003)

We describe a new architecture for Byzantine fault tolerant state machine replication that separates agreement that orders requests from execution that processes requests. This separation yields two fundamental and practically significant advantages over previous architectures. First, it reduces replication costs because the new architecture can tolerate faults in up to half of the state machine replicas that execute requests. Previous systems can tolerate faults in at most a third of the combined agreement/state machine replicas. Second, separating agreement from execution allows a general privacy firewall architecture to protect confidentiality through replication. In contrast, replication in previous systems hurts confidentiality because exploiting the weakest replica can be sufficient to compromise the system. We have constructed a prototype and evaluated it running both microbenchmarks and an NFS server. Overall, we find that the architecture adds modest latencies to unreplicated systems and that its performance is competitive with existing Byzantine fault tolerant systems.
Induction of nm23 Gene Expression in Human Colonic Neoplasms and Equal Expressions in Colon Tumors of High and Low Metastatic Potential (1991)

Levels of expression of the murine nm23 gene inversely correlate with metastatic potential in several rodent tumor model systems. Expression of the human nm23 homologue also is lower in human breast cancers of high metastatic potential than in breast cancers of low metastatic potential. In the present study, we examined changes in nm23 expression during colon carcinogenesis as found in 18 matched pairs of normal and neoplastic human colon tissues. We found that a 0.8-kilo-base nm23 transcript was expressed in all samples of morphologically normal colon mucosa. In 16 of 18 colon neoplasms, nm23 expression was further increased in the neoplastic, compared with the morphologically normal, colon mucosa from the same individual. Expression of nm23 was elevated over normal mucosa in 3 of 3 polyps, in 2 of 3 nonmetastatic cancers, and in 11 of the 12 cancers that were metastatic at the initial presentation. The levels of nm23 expressed were similar in the 12 metastatic colon neoplasms and in the 6 colon neoplasms of lower clinical stage. In addition, nm23 expression was maintained in culture in each of 12 cell lines initiated from human colon neoplasms and did not differ between lines established from neoplasms of high or low metastatic capability. We concluded that nm23 was expressed in normal colon mucosa. Expression of nm23 increased during early stages of colon carcinogenesis and remained increased in metastatic colon cancer. Therefore, in the colon, tissue-specific events dissociate nm23 expression from loss of tumor metastatic competence.
Task force suggests AIDS care financing alternatives (1988)

Work Group IX: Financial Issues in the Care of Children with HIV Infection Recommendations 1.) Because reliable data are scarce, we can make only rough estimates of the health care costs of pediatric HIV infection. Given the limitations of the current surveillance definition of AIDS and the underreporting, a projection of 10,000 pediatric cases with symptomatic HIV infection by 1991 seems probable. A number of studies has found hospital utilization of 30 to 40 days per year per child. For those children who cannot be discharged because of extraordinary placement and care problems, the figures are much higher.
Impact of Altered Gibberellin Metabolism on Biomass Accumulation, Lignin Biosynthesis, and Photosynthesis in Transgenic Tobacco Plants (2004)

Gibberellins (GAs) are involved in regulation of many aspects during plant development. To investigate the impact of altered GA levels on plant growth and metabolism, transgenic tobacco (Nicotiana tabacum) plants have been engineered to express either a GA20-oxidase (AtGA20-ox) or a GA2-oxidase (AtGA2-ox) gene from Arabidopsis under control of the cauliflower mosaic virus 35S promoter. Resulting plants were characterized by elongated or stunted shoot growth, respectively, indicating changes in the content of bioactive GAs. In accordance with the effect on plant growth, biomass production was increased or decreased in AtGA20-ox or AtGA2-ox plants, respectively, and was found to be positively correlated with the rate of photosynthesis as determined at the whole plant level. Differences in dry matter accumulation were most likely due to changes in lignin deposition as indicated by histochemical staining and quantitative measurements. Altered lignification of transgenic plants was paralleled by up- or down-regulation of the expression of lignin biosynthetic genes. Short-term GA3 feeding of excised petioles induced lignin formation in the absence of a transcriptional activation of pathway-specific genes. Thus, short-term GA treatment mediates lignin deposition most likely by polymerization of preformed monomers, whereas long-term effects on lignification involve elevated production of precursors by transcriptional stimulation of the biosynthetic pathway. Interestingly, analysis of stem cross sections revealed a differential effect of GA on the formation of xylem and pith cells. The number of lignified vessels was increased in AtGA20-ox plants pointing to a stimulation of xylem formation while the number of pith cells declined indicating a negative regulation.
VII. Colours in metal glasses, in metallic films, and in metallic solutions.—II (1906)

Abstract This paper is an extension of a previous memoir on the “Colours in Metal Glasses and in Metallic Films”; it is concerned with the application of mathematical analysis, akin to that already there developed, to the explanation and coordination of the colours which certain metals are, under a great variety of circumstances, capable of causing. From observations on gold and copper ruby glasses, it has been shown that the first stage in the formation of a crystal of those metals is the small sphere; and from observations on the growth of sulphur crystals in CS2, Vogelsang arrived at the conclusion that the small sphere is always the first stage in the formation of a crystal. He remarked, however, that it is by no means necessary that each of the small spheres, formed as crystallisation commences, should give rise to a separate crystal: the small spheres tend to coagulate, forming first rows and then groups of other and more complicated shapes, until the crystal is ultimately formed. To the intermediate bodies he gives the name of crystallites.
Cardiac Mitochondrial NADP+-isocitrate Dehydrogenase Is Inactivated through 4-Hydroxynonenal Adduct Formation (2003)

Mitochondrial NADP+-isocitrate dehydrogenase activity is crucial for cardiomyocyte energy and redox status, but much remains to be learned about its role and regulation. We obtained data in spontaneously hypertensive rat hearts that indicated a partial inactivation of this enzyme before hypertrophy development. We tested the hypothesis that cardiac mitochondrial NADP+-isocitrate dehydrogenase is a target for modification by the lipid peroxidation product 4-hydroxynonenal, an aldehyde that reacts readily with protein sulfhydryl and amino groups. This hypothesis is supported by the following in vitro and in vivo evidence. In isolated rat heart mitochondria, enzyme inactivation occurred within a few minutes upon incubation with 4-hydroxynonenal and was paralleled by 4-hydroxynonenal/NADP+-isocitrate dehydrogenase adduct formation. Enzyme inactivation was prevented by the addition of its substrate isocitrate or a thiol, cysteine or glutathione, suggesting that 4-hydroxynonenal binds to a cysteine residue near the substrate's binding site. Using an immunoprecipitation approach, we demonstrated the formation of 4-hydroxynonenal/NADP+-isocitrate dehydrogenase adducts in the heart and their increased level (210%) in 7-week-old spontaneously hypertensive rats compared with control Wistar Kyoto rats. To the best of our knowledge, this is the first study to demonstrate that mitochondrial NADP+-isocitrate dehydrogenase is a target for inactivation by 4-hydroxynonenal binding. Furthermore, the pathophysiological significance of our finding is supported by in vivo evidence. Taken altogether, our results have implications that extend beyond mitochondrial NADP+-isocitrate dehydrogenase. Indeed, they emphasize the implication of post-translational modifications of mitochondrial metabolic enzymes by 4-hydroxynonenal in the early oxidative stress-related pathophysiological events linked to cardiac hypertrophy development.
Gene Therapy in the Inner Ear Using Adenovirus Vectors (2009)

Therapies for the protection and regeneration of auditory hair cells are of great interest given the significant monetary and lifestyle impact of hearing loss. The past decade has seen tremendous advances in the use of adenoviral vectors to achieve these aims. Preliminary data demonstrated the functional capacity of this technique as adenoviral-induced expression of neurotrophic and growth factors protected hair cells and spiral ganglion neurons from ototoxic insults. Subsequent efforts confirmed the feasibility of adenoviral transfection of cells in the auditory neuroepithelium via cochleostomy into the scala media. Most recently, efforts have focused on regeneration of depleted hair cells. Mammalian hearing loss is generally considered a permanent insult as the auditory epithelium lacks a basal layer capable of producing new hair cells. Recently, the transcription factor Atoh1 has been found to play a critical role in hair cell differentiation. Adenoviral-mediated overexpression of Atoh1 in culture and in vivo have shown the ability to regenerate auditory and vestibular hair cells by causing transdifferentiation of neighboring epithelial-supporting cells. Functional recovery of both the auditory and vestibular systems has been documented following adenoviral induced Atoh1 overexpression.
Predicting the Behavior of Techno-Social Systems (2009)

We live in an increasingly interconnected world of techno-social systems, in which infrastructures composed of different technological layers are interoperating within the social component that drives their use and development. Examples are provided by the Internet, the World Wide Web, WiFi communication technologies, and transportation and mobility infrastructures. The multiscale nature and complexity of these networks are crucial features in understanding and managing the networks. The accessibility of new data and the advances in the theory and modeling of complex networks are providing an integrated framework that brings us closer to achieving true predictive power of the behavior of techno-social systems.
Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound (2017)

OBJECTIVE Ultrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal. METHODS Ten Yorkshire swine ( Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage. RESULTS LIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage. CONCLUSIONS These results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.
Binding of the NG2 Proteoglycan to Type VI Collagen and Other Extracellular Matrix Molecules (1996)

Previous studies have suggested that the NG2 proteoglycan interacts with type VI collagen. We have further characterized this interaction using a solid phase binding assay in which purified NG2 was shown to bind to pepsin-solubilized type VI collagen. In addition, NG2 bound a recombinant alpha2 (VI) collagen chain but did not appreciably bind to the recombinant alpha1 (VI) chain or the N-terminal domain of alpha3 (VI) (N9-N2). Binding of NG2 to type VI collagen was shown to be concentration-dependent and saturable and to depend mainly on the NG2 core protein, since chondroitinase-treated NG2 bound the collagen as well as undigested samples. In addition, the binding studies revealed several other possible ligands for NG2, including type II collagen, type V collagen, tenascin, and laminin. Binding of the proteoglycan to these molecules was also shown to be mediated by domains contained within the NG2 core protein. The ability of NG2 to bind to these extracellular matrix molecules was compared with that of the chondroitin sulfate proteoglycan decorin, revealing an almost identical binding pattern of the two proteoglycans to the different collagen types. In addition, decorin was found to effectively inhibit the ability of NG2 to bind to collagen, thus suggesting that the two proteoglycans may bind to some of the same regions on the collagen substrates. In contrast, decorin did not bind tenascin and was ineffective in inhibiting the binding of NG2 to tenascin or laminin, indicating that NG2 may bind these two molecules using a separate domain that is distinct from its collagen binding region.