gebhart/patrepeval huggingface dataset:
Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. (2009)

Boehringer Ingelheim Corp is developing the novel, xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor linagliptin for the potential treatment of type 2 diabetes mellitus. In vitro assays suggested that linagliptin was a potent DPP-4 inhibitor, with good selectivity for DPP-4 compared with other DPPs and proteases. The inhibition of DPP-4 by linagliptin was also demonstrated in vivo, resulting in increased glucagon-like peptide 1 levels and improved glucose tolerance in both healthy animals and models of disease. Furthermore, linagliptin exhibited prolonged pharmacodynamic activity, with long-lasting DPP-4 inhibition across different species. The prolonged DPP-4 inhibition observed in preclinical models has translated to humans; linagliptin demonstrated approximately 80% inhibition of DPP-4 activity at daily doses as low as 5 mg in phase II clinical trials. The effects were sustained, and no signs or symptoms of hypoglycemia were observed, even at high doses of up to 600 mg. The low therapeutic dose of linagliptin, the long-lasting inhibition of DPP-4 activity and the good safety/tolerability profile exhibited thus far suggest that linagliptin may be superior to competitors. The results from ongoing phase III clinical trials will provide further information on such aspects; however, from the available data, linagliptin appears to have promise for market success.
Small and Neutral TcvO BAT, Bisaminoethanethiol (N2S2) Complexes for Developing New Brain Imaging Agents (1998)

Bisaminoethanethiol (BAT) ligands with various gem-dimethyl and amide groups were prepared, and the corresponding neutral Tc-99m complexes were prepared and evaluated for their relative stabilities by ligand-exchange reactions. It was demonstrated that technetium complexes containing gem-dimethyl substituents have higher lipophilicities, whereas those with an amide group possess greater stability, which enhances ligand-exchange reaction. The most interesting observation was that the brain uptake in rats is not determined only by lipophilicity. Apparently, Tc-99m complexes with an amide functional group display lower brain uptakes in rats compared to those without an amide group. The brain uptake was strongly influenced by substituents on the BAT ligand. These factors are critically important and should be taken into consideration when designing Tc-99m-labeled agents for CNS receptor imaging.
Patterns of clinical disease associated with antibodies to nuclear ribonucleoprotein. (1978)

Forty-three patients were studied whose sera were monospecific for nuclear ribonucleoprotein by double immunodiffusion. Thirty-four patients had features typical of systemic lupus erythematosus of which 30 fulfilled the American Rheumatism Association criteria. Clinical features such as rashes, serositis and hematological abnormalities occurred with a frequency expected in SLE. Raynaud's phenomenon occurred in 60%, but other features of mixed connective tissue disease were uncommon. Clinical evidence of renal disease occurred in only four patients. In our experience a good prognosis is related more to the presence of anti-nRNP alone in the serum than to any specific set of clinical findings.
In vitro method for the generation of protein libraries using PCR amplification of a single DNA molecule and coupled transcription/translation (1998)

A novel in vitro method for the generation of a protein library has been developed using the polymerase chain reaction (PCR) amplification of a single DNA molecule followed by in vitro coupled transcription/translation. DNA template encoding green fluorescent protein of a jellyfish Aequorea victoria was extensively diluted to one molecule per well, and then amplified by a total of 80 cycles of PCR with nested primers. The exact number of origins in the amplified DNA fragment was then estimated by directly sequencing a part of the fragment, at which an individual template molecule was marked by PCR with a primer containing three randomized bases. Since the sequences obtained in 91 independent amplifications were diversified statistically, each amplified fragment was likely originated from a single DNA molecule. In addition, the amplified fragments served as a template for in vitro coupled transcription/translation using T7 RNA polymerase and Escherichia coli S30 extract. These results suggest that the library obtained by the PCR amplification of a single DNA molecule diluted from a variety of DNA pools is potentially useful in high-throughput generation of protein libraries.
E- and A-type cyclins as markers for cancer diagnosis and prognosis (2003)

Cyclin-dependent kinase (CDK)2 interacting cyclins perform essential functions for DNA replication and cellular proliferation. The human genome encodes two E-type cyclins (E and E2) and two A-type cyclins (A1 and A2). Dysregulation of the CDK2-bound cyclins plays an important role in the pathogenesis of cancer. Cyclin A2 is associated with cellular proliferation and can be used for molecular diagnostics as a proliferation marker. In addition, cyclin A2 expression is associated with a poor prognosis in several types of cancer. Cyclin A1 is a tissue-specific cyclin that is highly expressed in acute myeloid leukemia and in testicular cancer. High levels of cyclin E expression are found in many types of cancer. Overexpression of cyclin E at the mRNA level can be based on gene amplification and transcriptional mechanisms. In addition, proteolytically cleaved forms of cyclin E that show oncogenic functions have been described. Cyclin E plays a critical role for G1/S transition. Its overexpression is not only associated with proliferation but rather indicates a more malignant phenotype which is likely to be linked to the induction of chromosomal instability. These biological functions of cyclin E relate to a poor prognosis when high cyclin E levels are found. The link between cyclin E and poor prognosis is well established in breast and lung cancer but is likely to be observed in other cancers as well. The second E-type cyclin, cyclin E2, has been shown to be overexpressed in breast cancers although the potential role as a diagnostic or prognostic marker is unknown. This review provides an overview of the potential of cyclins E and A as markers for diagnosis and prognosis in human cancer.
Infliximab therapy for sarcoidosis (lupus pernio) (2004)

Sarcoidosis is a chronic granulomatous disease of unknown aetiology in which the primary cytokine tumour necrosis factor (TNF)-alpha appears to play a major role. Older immune-modulating drugs including corticosteroids, antimalarials and thalidomide, as well as cytotoxic drugs with immune modulatory effects, have been used to control disease. We present a patient with severe mutilating cutaneous sarcoidosis (lupus pernio) who had showed only partial response to courses of a wide spectrum of immune modulators and cytotoxic therapies, and who had developed significant side-effects due to prolonged high-dose corticosteroids. However, the patient's cutaneous disease responded rapidly to the TNF-alpha inhibitor infliximab.
Genetic disruption of PPAR δ decreases the tumorigenicity of human colon cancer cells (2001)

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that have been implicated in a variety of biologic processes. The PPARdelta isotype was recently proposed as a downstream target of the adenomatous polyposis coli (APC)/beta-catenin pathway in colorectal carcinogenesis. To evaluate its role in tumorigenesis, a PPARdelta null cell line was created by targeted homologous recombination. When inoculated as xenografts in nude mice, PPARdelta -/- cells exhibited a decreased ability to form tumors compared with PPARdelta +/- and wild-type controls. These data suggest that suppression of PPARdelta expression contributes to the growth-inhibitory effects of the APC tumor suppressor.
CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication (2012)

The HIV-1 genome enters cells inside a shell comprised of capsid (CA) protein. Variation in CA sequence alters HIV-1 infectivity and escape from host restriction factors. However, apart from the Cyclophilin A-binding loop, CA has no known interfaces with which to interact with cellular cofactors. Here we describe a novel protein-protein interface in the N-terminal domain of HIV-1 CA, determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence. The interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Mutation of the interface prevents binding to and restriction by CPSF6-358, a truncated cytosolic form of the RNA processing factor, cleavage and polyadenylation specific factor 6 (CPSF6). Furthermore, mutations that prevent CPSF6 binding also relieve dependence on nuclear entry cofactors TNPO3 and RanBP2. These results suggest that the HIV-1 capsid mediates direct host cofactor interactions to facilitate viral infection.
Research Resource: Transcriptional Response to Glucocorticoids in Childhood Acute Lymphoblastic Leukemia (2011)

Glucocorticoids (GC) induce apoptosis in lymphoblasts and are thus essential in the treatment of acute lymphoblastic leukemia (ALL). Their effects result from gene regulations via the GC receptor (NR3C1/GR), but it is unknown how these changes evolve, what the primary GR targets are, and to what extent responses differ between ALL subtypes and nonlymphoid malignancies. We delineated the transcriptional response to GC on the exon level in a time-resolved manner in a precursor B- and a T childhood ALL model employing Exon microarrays and combined this with genome-wide NR3C1-binding site detection using chromatin immunoprecipitation-on-chip technology. This integrative approach showed that the response was strongly influenced by kinetics and extent of GR autoinduction in both models. Although remarkable differences between the ALL systems were apparent, we defined a set of common response genes enriched in apoptosis-related processes. Globally, GR binding was higher for GC-induced vs. -repressed genes, suggesting that GR mediates gene repression by interaction with distant enhancers or by cross talk with other transcription factors. Exon level analysis defined several new GC-regulated transcript variants of genes, including ATP4B, GPR98, TBCD, and ZBTB16. Our study provides unprecedented insight into the transcriptional response to GC in ALL cells, essential to understand this biologically and clinically important phenomenon. We found evidence of cell type-specific as well as common responses, possibly related to apoptosis induction, and detected induction of novel transcript variants by GC in the investigated systems. Finally, we implemented a bioinformatic framework that might be useful for high-density microarray analyses to identify alternative transcript variant expression.
Towards Evaluating the Robustness of Neural Networks (2017)

Neural networks provide state-of-the-art results for most machine learning tasks. Unfortunately, neural networks are vulnerable to adversarial examples: given an input x and any target classification t, it is possible to find a new input x' that is similar to x but classified as t. This makes it difficult to apply neural networks in security-critical areas. Defensive distillation is a recently proposed approach that can take an arbitrary neural network, and increase its robustness, reducing the success rate of current attacks' ability to find adversarial examples from 95% to 0.5%. In this paper, we demonstrate that defensive distillation does not significantly increase the robustness of neural networks by introducing three new attack algorithms that are successful on both distilled and undistilled neural networks with 100% probability. Our attacks are tailored to three distance metrics used previously in the literature, and when compared to previous adversarial example generation algorithms, our attacks are often much more effective (and never worse). Furthermore, we propose using high-confidence adversarial examples in a simple transferability test we show can also be used to break defensive distillation. We hope our attacks will be used as a benchmark in future defense attempts to create neural networks that resist adversarial examples.
Pore structure and surface area of silica SBA-15: influence of washing and scale-up (2011)

The removal of the surfactant (EO(20)PO(70)EO(20)) by washing before final calcination is a critical step in the synthesis of silica SBA-15. In contrast to washing with pure water or ethanol, washing with water and ethanol may, depending on the quantity of solvent used, alter the homogeneity and order of the pores, but also lead to an increase of the surface area of SBA-15. A reduction of solvent volume and a controlled washing protocol allow the synthesis of high surface area SBA-15 materials with a narrow monomodal pore size distribution. For larger batch sizes the influence of the quantity of solvent on the quality of the SBA-15 is reduced.
Semaphorins and neuropilins: new players in the neuroendocrine control of the intrathymic T‐cell migration in humans (2012)

Cell migration is a key event for proper intrathymic T-cell differentiation, and several ligand-receptor interactions contribute to the well-co ordinated movement of developing thymocytes within the thymic lobules. Herein we summarize recent data that place semaphorin 3A (Sema3A) and its receptor neuropilin 1 (NRP1) as further players in the physiological process of cell migration in the human thymus. These molecules, as well as class A plexins (necessary for the intracellular signalling transduction triggered by Sema3A-NRP1 ligation), are constitutively expressed by both developing thymocytes and components of the thymic microenvironment, including epithelial and dendritic cells. Functionally, Sema3A decreases the adhesion of human thymocytes on thymic epithelial cell monolayers and exerts per se a dose-dependent chemorepulsive effect on human thymocytes. Moreover, Sema3A inhibits chemoattractant migratory responses induced by other ligands, including fibronectin, laminin and CXCL12 (chemokine CXC motif ligand 12). These data should be placed in the context of the concept that migration of developing T cells is a multivectorial system, in which the resulting migration vector derives from a balance of several simultaneous and/or sequential ligand-receptor pair interactions. Accordingly, semaphorins and neuropilins can be considered as further players in the system.
Magnetic Resonance Analysis of Mouse Embryos with Altered Gene Expression (1996)

Techniques to assess and analyze phenotypes of experimentally altered animals have not kept pace with our ability to manipulate the genome. Assessment of the shape, position, and timing of the appearance of anatomical structures is indispensable to identifying and understanding the mechanisms of normal and abnormal morphogenesis. Tools are needed to effectively diagnose the condition of the hundreds of experimentally altered animals being produced. Magnetic resonance (MR) microscopy is a non-destructive technique capable of generating three-dimensional images of developing structures from whole embryos. It facilitates the evaluation of complex anatomical structures by allowing them to be studied in any plane of sectioning for cut-away views and from any angle for surface views. MR microscopy has been used to assess the following mutant mouse embryos and mouse embryos with altered gene expression: Splotch, Curly-tail, Loop-tail, TS 16, HOX 2.2 transgenic, MARKS knockout, LH-2 knockout, and Dlx-2 knockout. Imaging was performed on a modified 9.4 Tesla GE NMR Instruments Omega system with echo times of 6 ms and repetition times of 200 ms.
Extensive post-transcriptional regulation of microRNAs and its implications for cancer (2006)

MicroRNAs (miRNAs) are short, noncoding RNAs that post-transcriptionally regulate gene expression. While hundreds of mammalian miRNA genes have been identified, little is known about the pathways that regulate the production of active miRNA species. Here we show that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by the enzyme Drosha. An analysis of gene expression in primary tumors indicates that the widespread down-regulation of miRNAs observed in cancer is due to a failure at the Drosha processing step. These data uncover a novel regulatory step in miRNA function and provide a mechanism for miRNA down-regulation in cancer.
Structure−Activity Relationships of Water-Soluble Cationic Methacrylate/Methacrylamide Polymers for Nonviral Gene Delivery (1999)

A number of water-soluble cationic carriers was evaluated as transfectant. Almost all studied cationic methacrylate/methacrylamide polymers were able to condense the structure of plasmid DNA, yielding polymer/plasmid complexes (polyplexes) with a size of 0.1-0.3 micron and a slightly positive zeta-potential, which can be taken up by cells, e.g., via endocytosis. However, the transfection efficiency and the cytotoxicity of the polymers differed widely: the highest transfection efficiency and cytotoxicity were observed for poly[2-(dimethylamino)ethyl methacrylate], p(DMAEMA). Assuming that polyplexes enter cells via endocytosis, p(DMAEMA) apparently has advantageous properties to escape the endosome. A possible explanation is that, due to its average pK(a) value of 7.5, p(DMAEMA) is partially protonated at physiological pH and might behave as a proton sponge. This might cause a disruption of the endosome, which results in the release of both the polyplexes and cytotoxic endosomal/lysosomal enzymes into the cytosol. On the other hand, the analogues of p(DMAEMA) studied here have a higher average pKa value and have, consequently, a higher degree of protonation and a lower buffering capacity. This might be associated with a lower tendency to destabilize the endosome, resulting in both a lower transfection efficiency and a lower cytotoxicity. Furthermore, molecular modeling showed that, of all studied polymers, p(DMAEMA) has the lowest number of interactions with DNA. We therefore hypothesized that the superior transfection efficiency of p(DMAEMA) containing polyplexes can be ascribed to an intrinsic property of p(DMAEMA) to destabilize endosomes combined with an easy dissociation of the polyplex once present in the cytosol and/or the nucleus.
HUMAN CYTOTOXIC T LYMPHOCYTE RESPONSES TO EPSTEIN-BARR VIRUS INFECTION (1997)

Epstein-Barr virus (EBV) provides one of the most informative systems with which to study cytotoxic T lymphocyte (CTL) responses in humans. The virus establishes a highly immunogenic growth-transforming infection of B lymphocytes, associated with the coordinate expression of six virus-coded nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMPs 1 and 2). This elicits both primary and memory CT8+ CTL responses that are markedly skewed toward HLA allele-specific epitopes drawn from the EBNA3A, 3B, 3C subset of latent proteins, with reactivities to other antigens being generally much less frequent. This hierarchy of immunodominance among the different latent proteins may at least partly reflect their differential accessibility to the HLA class I-processing pathway. Furthermore, CTLs to some of the immunodominant epitopes involve highly conserved T cell receptor (TCR) usage, a level of focusing which evidence suggests could have immunopathological consequences from cross-reactive recognition of other target structures. EBV is associated with a range of human tumors, and there is increasing interest in the possibility of targeting such malignancies using virus-specific CTLs. The dramatic reversal of EBV-driven lymphoproliferations in bone marrow transplant patients following CTL infusion demonstrates the potential of this approach, and here we discuss prospects for its extension to other EBV-positive tumors in which the immunodominant EBNA3A, 3B, 3C proteins are not expressed.
T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. (1980)

The results of this paper are consistent with the hypothesis that progressive growth of the Meth A fibrosarcoma evokes the generation of a T-cell-mediated mechanism of immunosuppression that prevents this highly immunogenic tumor from being rejected by its immunocompetent host. It was shown that it is possible to cause the regression of large, established Meth A tumors by intravenous infusion of tumor-sensitized T cells from immune donors, but only if the tumors are growing in T-cell-deficient recipients. It was also shown that the adoptive T-cell-mediated regression of tumors in such recipients can be prevented by prior infusion of splenic T cells from T-cell-intact, tumor-bearing donors. The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression. Because the presence of suppressor T cells generated in response to the Meth A did not suppress the capacity of Meth A-bearing mice to generate and express immunity against a tumor allograft, it is obvious that they were not in a state of generalized immunosuppression.
The role of dendritic cell subsets in selection between tolerance and immunity (2002)

Dendritic cells (DC) are considered nature's adjuvants. They are potent stimulators of naive T cells and key inducers of primary immune responses. In recent times it has become clear that they can also play a central role in the development of T cell tolerance. Further complicating our understanding of DC function is the realization that DC can no longer be viewed as a homogeneous cell type. Rather, they exist as a complex mixture of strikingly different cell populations. The mechanisms that drive the conflicting immunological outcomes of tolerance and immunity have been the subject of intense scrutiny in recent years, most recently in terms of how the various DC subsets are involved in these events. Here we review recent experiments that provide insights into how DC subsets control the outcome of T cell activation and in so doing select between immunity and tolerance induction.
Post‐Metalation Structural Insights into the Use of Alkali‐Metal‐Mediated Zincation for Directed ortho‐Metalation of a Tertiary Aromatic Amide (2006)

Catch me if you can: Invisible using standard electrophilic substitution detection methods, two distinct ortho-metalated “intermediates” generated by alkali-metal-mediated zincation of N,N-diisopropylbenzamide are structurally elucidated.