gebhart/patrepeval huggingface dataset:
Efficient Synthesis of Isofagomine and Noeuromycin (2001)

Starting from D-arabinose the synthesis of the very strong glycosidase inhibitors isofagomine (2) and noeuromycin (3) was achieved in six and seven steps, respectively. Keystep in the reaction sequence is the application of an efficient C-4 oxidation method to benzyl alpha-D-arabino-pyranoside. Subsequent Henry reaction of the obtained aldoketose with nitromethane provided the required branched carbohydrate precursors, which gave access to 2 and 3 in 17-21% overall yield.
Inhibition of autophagy enhances the effects of the AKT inhibitor MK‐2206 when combined with paclitaxel and carboplatin in BRAF wild‐type melanoma (2014)

This study investigates the mechanism of action behind the long-term responses (12-16 months) of two BRAF WT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6 days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs.
3D Traffic Scene Understanding From Movable Platforms (2013)

In this paper, we present a novel probabilistic generative model for multi-object traffic scene understanding from movable platforms which reasons jointly about the 3D scene layout as well as the location and orientation of objects in the scene. In particular, the scene topology, geometry, and traffic activities are inferred from short video sequences. Inspired by the impressive driving capabilities of humans, our model does not rely on GPS, lidar, or map knowledge. Instead, it takes advantage of a diverse set of visual cues in the form of vehicle tracklets, vanishing points, semantic scene labels, scene flow, and occupancy grids. For each of these cues, we propose likelihood functions that are integrated into a probabilistic generative model. We learn all model parameters from training data using contrastive divergence. Experiments conducted on videos of 113 representative intersections show that our approach successfully infers the correct layout in a variety of very challenging scenarios. To evaluate the importance of each feature cue, experiments using different feature combinations are conducted. Furthermore, we show how by employing context derived from the proposed method we are able to improve over the state-of-the-art in terms of object detection and object orientation estimation in challenging and cluttered urban environments.
Optimizing the "one big switch" abstraction in software-defined networks (2013)

Software Defined Networks (SDNs) support diverse network policies by offering direct, network-wide control over how switches handle traffic. Unfortunately, many controller platforms force applications to grapple simultaneously with end-to-end connectivity constraints, routing policy, switch memory limits, and the hop-by-hop interactions between forwarding rules. We believe solutions to this complex problem should be factored in to three distinct parts: (1) high-level SDN applications should define their end-point connectivity policy on top of a "one big switch" abstraction; (2) a mid-level SDN infrastructure layer should decide on the hop-by-hop routing policy; and (3) a compiler should synthesize an effective set of forwarding rules that obey the user-defined policies and adhere to the resource constraints of the underlying hardware. In this paper, we define and implement our proposed architecture, present efficient rule-placement algorithms that distribute forwarding policies across general SDN networks while managing rule-space constraints, and show how to support dynamic, incremental update of policies. We evaluate the effectiveness of our algorithms analytically by providing complexity bounds on their running time and rule space, as well as empirically, using both synthetic benchmarks, and real-world firewall and routing policies.
Autodeimination of Protein Arginine Deiminase 4 Alters Protein–Protein Interactions but Not Activity (2011)

The protein arginine deiminases (PAD), which catalyze the hydrolysis of peptidyl-arginine to form peptidyl-citrulline, play important roles in a variety of cell signaling pathways, including apoptosis, differentiation, and transcriptional regulation. In addition to these important cellular roles, PAD activity is dysregulated in multiple human diseases [e.g., rheumatoid arthritis (RA), cancer, and colitis], and significantly, PAD inhibition with Cl-amidine has been shown to reduce disease severity in the collagen-induced arthritis model of RA. Although these enzymes play important roles in human cell signaling and disease, the mechanisms that regulate PAD activity under both physiological and pathological conditions are poorly understood. One possible mechanism for regulating PAD activity is autodeimination, to which PAD4 has been shown by us and others to be subjected in vitro and in vivo. Herein, we demonstrate that PAD4 autodeimination does not alter the activity, substrate specificity, or calcium dependence of this isozyme. However, the results of these studies indicate a novel role for autodeimination in modulating the ability of PAD4 to interact with histone deacetylase 1 (HDAC1), citrullinated histone H3 (Cit H3), and protein arginine methyltransferase 1 (PRMT1).
Docetaxel Accumulates in Lymphatic Circulation Following Subcutaneous Delivery Compared to Intravenous Delivery in Rats (2016)

Subcutaneous docetaxel achieves lymphatic accumulation greater than that of i.v. delivery.
Microstrip antennas : the analysis and design of microstrip antennas and arrays (1995)

"This anthology combines 15 years of microstrip antenna technology research into one significant volume and includes a special introductory tutorial by the co-editors. Covering theory, design and modeling techniques and methods, this source book is an excellent reference tool for engineers who want to become more familiar with microstrip antennas and microwave systems. Proven antenna designs, novel solutions to practical design problemsand relevant papers describing the theory of operation and analysis of microstrip antennas are contained within this convenient reference."
Severe CD4 T Cell-Mediated Immunopathology in Murine Schistosomiasis Is Dependent on IL-12p40 and Correlates with High Levels of IL-17 (2005)

C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high levels of IFN-gamma. We explored the cause of the severe immunopathology by using IL-12p40(-/-) and IL-12p35(-/-) mice. SEA/CFA-immunized IL-12p40(-/-) mice, incapable of making IL-12 or IL-23, were completely resistant to high pathology, and their SEA-stimulated lymphoid cells failed to secrete significant IFN-gamma or IL-17. In contrast, SEA/CFA-immunized IL-12p35(-/-) mice, able to make IL-23 but not IL-12, developed severe lesions that correlated with high levels of IL-17, low IFN-gamma, and an expansion of activated CD4 T cells with a CD44(high)/CD62L(low) memory phenotype. In vivo administration of neutralizing anti-IL-17 mAb markedly inhibited hepatic granulomatous inflammation. Importantly, CBA mice, a naturally high pathology strain, also displayed elevated IL-17 levels comparable to those seen in the SEA/CFA-immunized BL/6 mice, and their lesions were similarly reduced by in vivo treatment with anti-IL-17. Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis.
Update on Inflammation in Chronic Kidney Disease (2015)

Chronic inflammation should be regarded as a common comorbid condition in CKD and especially in dialysis patients. A number of interventions have been proven to be safe and effective in well-designed clinical studies. This includes such inexpensive approaches as modification of physical activity and dietary supplementation. Further investigations are needed to evaluate the effects of these interventions on hard outcomes, as well as to better understand the role of inflammation in selected CKD populations (e.g., in children).
Studies on the Synthesis of the 2-Aminothiazole Derivatives. III (1961)

Examination was made on the reactivity of active methylene in asymmetric, straight-chain ketone of the formula R-CH2COCH2-R′, in the synthesis of 2-aminothiazole by reaction with thiourea and iodine, using a basic catalyst. Contrary to the use of an acid catalyst, the use of a basic catalyst was found to result in different reactivity of the methylene according to the nature of R and R′. When R is hydrogen and R′ is a straight-chain bond, the methylene on the side of R′-CH2- is more reactive when the catalyst is a weak base, as in the case of an acid base, and both methyl and methylene react when the catalyst is a strong base, affording a mixture of the two kinds of product. However, CH3CO(CH2)5CH3 is an exception and its methyl group undergoes the reaction to form 2-amino-4-hexylthiazole. When the R′-CH2- has a branched bond, chiefly the methylene undergoes the reactiton with a weak base and the methyl preferentially reacts when the catalyst is a strong acid. When R is a methyl and R′ is a straight-chain alkyl, the methylene of R′-CH2-undergoes the reaction, but when R′ is a branched alkyl, the compound undergoes resinification and objective substance is not obtained.
Human monoclonal antibodies to the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 enhance HIV-1 infection in vitro. (1990)

Three of 16 human monoclonal antibodies (hu-mAbs) enhanced human immunodeficiency virus type 1 (HIV-1) infection of MT-2 target cells by means of a mechanism that is dependent on complement. Enhanced infections are characterized by an increase in cytopathic effects and antigen synthesis as well as an increase in the production of progeny virus as detected by release of reverse transcriptase activity and infectious virus into the culture medium. Analyses by radioimmunoprecipitation, Western blot, and ELISA using the pENV9 envelope fragment localize the antigenic specificities of these three hu-mAbs to the N-terminal two-thirds of the transmembrane protein gp41. Competitive binding experiments indicate that the hu-mAbs are reactive with immunodominant epitopes of gp41 recognized by sera from essentially all HIV-1-infected subjects. Combination dose-effect experiments demonstrate that these hu-mAbs can act synergistically in vitro to enhance HIV-1 infection. These data demonstrate that hu-mAbs directed against the HIV-1 transmembrane glycoprotein gp41 can enhance HIV-1 infection in vitro. The availability of these reagents allows for the mapping of enhancing epitopes on HIV-1 and provides a means for studying whether deletion of such enhancing epitopes from candidate HIV-1 vaccines might improve the protective immune response to HIV-1 in immunized humans and chimpanzees.
A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy (2001)

In temporal-lobe epilepsy, surgery is superior to prolonged medical therapy. Randomized trials of surgery for epilepsy are feasible and appear to yield precise estimates of treatment effects.
IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer (2018)

Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.
Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat (1997)

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the 5HT1B/1D agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-producing structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. Cats were anaesthetized with alpha-chloralose (60 mg/kg, intraperitoneally), paralysed (gallamine 6 mg/kg, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation and spontaneous activity of the same cells. The electrode was a custom-made seven barrel glass microelectrode with the central barrel containing a tungsten recording wire. Signals were amplified and monitored on-line using a custom-written sampling program. Cells were recorded that were activated by electrical stimulation of the sinus and were also spontaneously activated. Cells fired with latencies consistent with A delta and C fibres, generally firing three or four times per stimulus (0.3 Hz, 250 microseconds duration, 100 V) delivered to the sinus. Both evoked and spontaneous firing could be inhibited by iontophoresis of ergometrine (9/10 cells), sumatriptan (2/3 cells) and zolmitriptan (9/15 cells) but not by saline (3/10 cells). These data are the first demonstration of inhibition of second order trigeminal neurons by direct local application of 5HT1B/1D agonists. Although intravenous administration of these compounds has demonstrated inhibition of sinus evoked firing in previous studies, it is not possible using the intravenous route to be clear at which anatomical site inhibition is taking place, whereas microiontophoresis offers a clear locus of action. These data demonstrate that the second order trigeminal nucleus synapse in the brainstem and upper cervical cord is the most likely site of action for brain penetrant anti-migraine drugs of the 5HT1B/1D class.
Acylation of a Plasmodium falciparum merozoite surface antigen via sn-1,2-diacyl glycerol. (1985)

The 195-kDa merozoite protein synthesized in schizonts of Plasmodium falciparum (Holder, A. A., and Freeman, R. R. (1982) J. Exp. Med. 156, 1528-1538) contains ester-linked fatty acid. Enzymatic treatment of the purified acylated protein established that the lipid is present as sn-1,2-diacyl glycerol, most probably linked to a phosphodiester at the 3-position of glycerol. The phosphodiglyceride is not directly esterified to an amino acid residue on the polypeptide backbone. The 195-kDa protein is processed to three fragments (83, 42, and 19 kDa) on the surface of free merozoites (Holder, A. A., and Freeman, R. R. (1984) J. Exp. Med. 160, 624-629), of which only the 42-kDa polypeptide is acylated.
IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance (2014)

Chronic inflammation has long been associated with the development of cancer. Among the various signaling pathways within cancer cells that can incite the expression of inflammatory molecules are those that activate IL-1 receptor-associated kinases (IRAK). The IRAK family is comprised of four family members, IRAK-1, IRAK-2, IRAK-3 (also known as IRAK-M), and IRAK-4, which play important roles in both positively and negatively regulating the expression of inflammatory molecules. The wide array of inflammatory molecules that are expressed in response to IRAK signaling within the tumor microenvironment regulate the production of factors which promote tumor growth, metastasis, immune suppression, and chemotherapy resistance. Based on published reports we propose that dysregulated activation of the IRAK signaling pathway in cancer cells contributes to disease progression by creating a highly inflammatory tumor environment. In this article, we present both theoretical arguments and reference experimental data in support of this hypothesis.
The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production (2008)

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glia cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may influence neuronal cell survival. Recent studies have demonstrated that glia cell-mediated neuroinflammation is also related to the pathophysiology of schizophrenia. In the present study, anti-inflammatory and neuroprotective effects of antipsychotics were investigated using cultured brain cells as a model. The results showed that spiperone significantly decreased the production of nitric oxide in lipopolysaccharide-stimulated BV-2 microglia cells, primary microglia and primary astrocyte cultures. Spiperone also significantly inhibited nitric oxide production in adenosine 5'-triphosphate (ATP)-stimulated primary microglia cultures. Spiperone markedly decreased the production of tumor necrosis factor-alpha in BV-2 microglia cells. Spiperone attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha at mRNA levels in BV-2 microglia cells. Spiperone inhibited nuclear translocation and DNA binding of the p65 subunit of nuclear factor kappa B (NF-kappaB), inhibitor of kappa B (IkappaB) degradation, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated BV-2 microglia cells. Moreover, spiperone was neuroprotective, as the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture. These results imply that the antipsychotic spiperone has anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation.
Both RadA and RadB Are Involved in Homologous Recombination inPyrococcus furiosus (2000)

RecA and Rad51 proteins are essential for homologous recombination in Bacteria and Eukarya, respectively. Homologous proteins, called RadA, have been described for Archaea. Here we present the characterization of two RecA/Rad51 family proteins, RadA and RadB, from Pyrococcus furiosus. The radA and radB genes were not induced by DNA damage resulting from exposure of the cells to gamma and UV irradiation and heat shock, suggesting that they might be constitutively expressed in this hyperthermophile. RadA had DNA-dependent ATPase, D-loop formation, and strand exchange activities. In contrast, RadB had a very weak ATPase activity that is not stimulated by DNA. This protein had a strong binding affinity for DNA, but little strand exchange activity could be detected. A direct interaction between RadA and RadB was detected by an immunoprecipitation assay. Moreover, RadB, but not RadA, coprecipitated with Hjc, a Holliday junction resolvase found in P. furiosus, in the absence of ATP. This interaction was suppressed in the presence of ATP. The Holliday junction cleavage activity of Hjc was inhibited by RadB in the absence, but not in the presence, of ATP. These results suggest that RadB has important roles in homologous recombination in Archaea and may regulate the cleavage reactions of the branch-structured DNA.
Multigenic Dissection and Prognostic Modeling of Overt Stroke in Sickle Cell Anemia. (2004)

Abstract Stroke is a major vascular complication of sickle cell anemia, more frequent in patients under the age of 20 years. Transcranial Doppler (TCD) flow studies can predict the likelihood of stroke in children with sickle cell anemia, but only 10% of individuals with abnormal TCD values will have stroke, and stroke will occur in some individuals with normal TCD. Therefore, more precise means of prognosis would be welcome so that prophylactic treatments like transfusions or hydroxyurea can be targeted to individuals at highest risk. Using Bayesian networks (BNs), we analyzed 235 single nucleotide polymorphisms (SNPs) in 80 candidate genes in 1398 unrelated subjects with sickle cell anemia enrolled in the Cooperative Study of Sickle Cell Disease. Bayesian networks are a novel generation of multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. These modules can be learned from data and then can be used to describe how changes in some variables affect other variables and ultimately the risk for the phenotype of interest. Bayesian networks provide a coherent framework within which genotypes, phenotypes and environmental factors can be seamlessly integrated into a comprehensive genomic landscape. We found that 25 SNPs on 11 genes and 4 clinical variables - including α thalassemia and fetal hemoglobin - interact in a complex network of dependency to modulate the risk of stroke. This network of interactions includes three genes (TGFBR2, TGFBR3, BMP6) with a functional role in the TGF-beta pathway and one gene (SELP) already associated with stroke in the general population. We validated our results in a different population by predicting the occurrence of stroke in a set of 114 subjects not included in the original study: 7 stroke patients and 107 control patients, a proportion consistent with the phenotype distribution in the original cohort study. Our model predicted the correct outcome for all 7 stroke patients, and for 105 of 107 non-stroke patients, with 100% true positive rate and 98.14% true negative rate, and an overall predictive accuracy of 98.2%. Our results support the hypothesis that stroke in sickle cell anemia patients is a complex trait caused by the interaction of multiple genes, and the predictive accuracy of our model is a step toward the development of additional prognostic tests to allow us to more precisely identify sickle cell anemia patients at risk for stroke. The presence in our model of genes already associated with stroke, such as SELP, suggests that some genetic factors predisposing to stroke are shared by both sickle cell anemia patients and stroke victims in the general population, and that our model may offer some insights into the genetic basis of the third leading cause of death in the United States.