gebhart/patrepeval huggingface dataset:
A Unified Deep Learning Architecture for Abuse Detection (2019)

Hate speech, offensive language, sexism, racism, and other types of abusive behavior have become a common phenomenon in many online social media platforms. In recent years, such diverse abusive behaviors have been manifesting with increased frequency and levels of intensity. Despite social media's efforts to combat online abusive behaviors this problem is still apparent. In fact, up to now, they have entered an arms race with the perpetrators, who constantly change tactics to evade the detection algorithms deployed by these platforms. Such algorithms, not disclosed to the public for obvious reasons, are typically custom-designed and tuned to detect only one specific type of abusive behavior, but usually miss other related behaviors. In the present paper, we study this complex problem by following a more holistic approach, which considers the various aspects of abusive behavior. We focus on Twitter, due to its popularity, and analyze user and textual properties from different angles of abusive posting behavior. We propose a deep learning architecture, which utilizes a wide variety of available metadata, and combines it with automatically-extracted hidden patterns within the text of the tweets, to detect multiple abusive behavioral norms which are highly inter-related. The proposed unified architecture is applied in a seamless and transparent fashion without the need for any change of the architecture but only training a model for each task (i.e., different types of abusive behavior). We test the proposed approach with multiple datasets addressing different abusive behaviors on Twitter. Our results demonstrate high performance across all datasets, with the AUC value to range from 92% to 98%.
Mast Cell Stabilization Improves Survival by Preventing Apoptosis in Sepsis (2010)

Inhibiting single cytokines produced modest effects in clinical trials, in part because the cytokines were not specific for sepsis, and sepsis may require cellular strategies. Previous studies reported that mast cells (MCs) fight infections in early sepsis. In this study, we report that MC stabilizers restrain serum TNF levels and improve survival in wild-type but not in MC-deficient mice. Yet, MC depletion in knockout mice attenuates serum TNF but does not improve survival in sepsis. Serum HMGB1 was the only factor correlating with survival. MC stabilizers inhibit systemic HMGB1 levels and rescue mice from established peritonitis. MC stabilizers fail to inhibit HMGB1 secretion from macrophages, but they prevent apoptosis and caspase-3 activation in sepsis. These results suggest that MC stabilization provides therapeutic benefits in sepsis by inhibiting extracellular release of HMGB1 from apoptotic cells. Our study provides the first evidence that MCs have major immunological implications regulating cell death in sepsis and represent a pharmacological target for infectious disorders in a clinically realistic time frame.
A Marked Change of Receptor Affinity of the 2-Methyl-5-(3-hydroxyphenyl)morphans upon Attachment of an (E)-8-Benzylidene Moiety: Synthesis and Evaluation of a New Class of .sigma. Receptor Ligands (1994)

The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding enantiomers of 5 and 6 were obtained in > 99% optical purity from the optical isomers of 4, resolved with the O,O'-dibenzoyltartaric acids. The absolute configurations of the enantiomers of 4 were determined by conversion, via Clemmensen reduction, to the enantiomers of 1, the configurations of which are known. The determination of the regioisomer and configurational isomer of 5, with respect to the introduced benzylidene group, was determined from a single-crystal X-ray analysis. 1H NMR data was used to confirm that 6 possessed the same configuration as 5. Radioreceptor binding studies in rat and guinea pig brain preparations revealed that (-)-(1S,5S)-5 displayed an 11-fold decrease in affinity for the opioid mu receptor and an increase in affinity for sigma receptors of 81-fold (low nanomolar affinity) relative to the ketone precursor (+)-(1S,5S)-4. An analogous, albeit less dramatic, trend was seen with compound (-)-(1S,5S)-6. Compounds (-)-(1S,5S)-5 and (-)-(1S,5S)-6 are distinct from the typical sigma-opiates in that they have very low affinity for either PCP sites or muscarinic receptors. The high affinity and selectivity of these novel sigma receptor ligands suggests that they will be valuable for the elucidation of the functional roles of sigma receptors.
Characterization of Cyanobacterial Hydrocarbon Composition and Distribution of Biosynthetic Pathways (2014)

Cyanobacteria possess the unique capacity to naturally produce hydrocarbons from fatty acids. Hydrocarbon compositions of thirty-two strains of cyanobacteria were characterized to reveal novel structural features and insights into hydrocarbon biosynthesis in cyanobacteria. This investigation revealed new double bond (2- and 3-heptadecene) and methyl group positions (3-, 4- and 5-methylheptadecane) for a variety of strains. Additionally, results from this study and literature reports indicate that hydrocarbon production is a universal phenomenon in cyanobacteria. All cyanobacteria possess the capacity to produce hydrocarbons from fatty acids yet not all accomplish this through the same metabolic pathway. One pathway comprises a two-step conversion of fatty acids first to fatty aldehydes and then alkanes that involves a fatty acyl ACP reductase (FAAR) and aldehyde deformylating oxygenase (ADO). The second involves a polyketide synthase (PKS) pathway that first elongates the acyl chain followed by decarboxylation to produce a terminal alkene (olefin synthase, OLS). Sixty-one strains possessing the FAAR/ADO pathway and twelve strains possessing the OLS pathway were newly identified through bioinformatic analyses. Strains possessing the OLS pathway formed a cohesive phylogenetic clade with the exception of three Moorea strains and Leptolyngbya sp. PCC 6406 which may have acquired the OLS pathway via horizontal gene transfer. Hydrocarbon pathways were identified in one-hundred-forty-two strains of cyanobacteria over a broad phylogenetic range and there were no instances where both the FAAR/ADO and the OLS pathways were found together in the same genome, suggesting an unknown selective pressure maintains one or the other pathway, but not both.
An epitope common to gangliosides O-acetyl-GD3 and GD3 recognized by antibodies in melanoma patients after active specific immunotherapy. (1989)

GD3 is a major ganglioside of human melanoma and was shown to be an effective target for passive immunotherapy with murine monoclonal antibodies. It was noted earlier that GD3 neither purified nor in melanoma cell vaccine (MCV), could elicit an antibody response in melanoma patients. In this study, we demonstrate that melanoma patients who received MCV had autoantibodies against a derivative of GD3, O-acetylated GD3 (O-AcGD3), a minor ganglioside expressed on human melanoma cells, and that the antibodies cross-reacted with GD3. Thin layer chromatographic immunostaining revealed that all of the sera containing antibodies against O-AcGD3 also reacted to GD3. None of the other sera responded only to GD3, although the MCV contained 7- to 12-fold higher GD3 than O-AcGD3. Furthermore, the antibody activity was completely abolished by absorption with animal erythrocytes expressing either O-acetyl disialogangliosides or GD3, indicating that the antibodies recognize an epitope commonly shared by GD3 and O-AcGD3. The antibodies bound only to the sialyloligosaccharide moiety but not to the ceramide portion of GD3 after endoglycosylceramidase treatment. The antibodies failed to bind to GD3 after neuraminidase treatment. These results indicate that the sialyloligosaccharides of the gangliosides are important components of the epitope. Periodate oxidation abolished reactivity of the antibodies to GD3 but not that to O-AcGD3, revealing that the glycerol side chain of the sialic acids in both GD3s was an important structure of the epitope. The binding of the antibodies to melanoma cell surface gangliosides was confirmed by an absorption with a GD3- and O-AcGD3-positive melanoma cell line. These results in the light of previous reports on the inability of GD3 to elicit immune response in humans suggest that anti-GD3 antibodies found in the melanoma patients were induced by immunization with O-AcGD3 and O-AcGD3 present in the MCV would serve as an antigen source for GD3-targeted active specific immunotherapy of melanoma.
Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain (2001)

Traumatic injury to rat brain induced by controlled cortical impact (CCI) results in chronic neuronal death in the hippocampus. In the normal brain, glutamate transporters actively clear the glutamate released synaptically to prevent receptor overactivation and excitotoxicity. Glutamate transporter 1 (GLT-1) is the most abundant and active glutamate transporter, which mediates the bulk of glutamate uptake. CCI injury significantly decreased GLT-1 mRNA (by 49-66%, P < 0.05) and protein (by 29-44%, P < 0.05) levels in the ipsilateral hippocampus, compared with either the respective contralateral hippocampus or the sham-operated control, 24-72 h after the injury. CCI injury in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) exacerbated the hippocampal neuronal death and mortality, compared with the GLT-1 sense/random ODN-infused controls. At 7 days after the injury, hippocampal neuronal numbers were significantly lower in the CA1 (reduced by 32%, P < 0.05), CA2 (by 45%, P < 0.01), CA3 (by 68%, P < 0.01) and dentate gyrus (by 31%, P < 0.05) in GLT-1 antisense ODN-infused rats, compared with the GLT-1 sense/random ODN-infused controls. This study suggested a role for GLT-1 dysfunction in promoting the hippocampal neuronal death after traumatic brain injury.
Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women (2000)

Chronic nicotinic acid (NA) ingestion effectively lowers lipid levels, but adverse effects on glucose metabolism have been reported. Our goal was to investigate acute and chronic effects of NA on lipolysis and glucose metabolism in women. Healthy normolipidemic volunteers (n = 5) were studied twice; four-day hospital stays were separated by 1 mo, during which time subjects took increasing doses of NA to 2 g/day (500 mg, 4 times). In the second study, 500 mg of NA was given at 0800. Rates of appearance (R(a)) of free fatty acid (FFA), glycerol, and glucose were determined by isotope dilution (of [1,2,3,4-(13)C(4)]palmitate, [2-(13)C(1)]glycerol, and [U-(13)C(6)]glucose). Mass isotopomer distribution analysis was used to measure gluconeogenesis and glycogenolysis. Fasting FFA concentrations ([FFA]), R(a) FFA, and R(a) glycerol were nonsignificantly elevated after 1 mo. Acute NA induced a significant reduction followed by a rebound overshoot of [FFA], R(a) FFA, and R(a) glycerol. Whole body fat oxidation fell initially and then increased back to basal levels; endogenous glucose production (EGP) increased in parallel with carbohydrate oxidation and then returned to basal values. The increased EGP was due entirely to increased glycogenolysis, not gluconeogenesis. We conclude that chronic effects of NA on FFA metabolism are complex (acute suppression followed by overshoot of R(a) FFA and [FFA] on top of a trend toward basal elevations), that responses after NA are consistent with operation of a glucose-fatty acid cycle in peripheral tissues, and that secondary effects on EGP were through changes in glycogenolysis, not gluconeogenesis.
RBFOX1 regulates both splicing and transcriptional networks in human neuronal development (2012)

RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.
Synthesis of Monofunctional Curcumin Derivatives, Clicked Curcumin Dimer, and a PAMAM Dendrimer Curcumin Conjugate for Therapeutic Applications (2007)

Curcumin, the primary active ingredient in the spice turmeric, was converted to reactive monofunctional derivatives (carboxylic acid/azide/alkyne). The derivatives were employed to produce a 3 + 2 azide-alkyne "clicked" curcumin dimer and a poly(amidoamine) (PAMAM) dendrimer-curcumin conjugate. The monofunctional curcumin derivatives retain biological activity and are efficient for labeling and dissolving amyloid fibrils. The curcumin dimer selectively destroys human neurotumor cells. The synthetic methodology developed affords a general strategy for attaching curcumin to various macromolecular scaffolds.
Survival of athymic (nu/nu) mice after Theiler's murine encephalomyelitis virus infection by passive administration of neutralizing monoclonal antibody (1989)

Little or no antiviral immune response is mounted in athymic nude mice infected with the Daniels strain of Theiler's murine encephalomyelitis virus. In these athymic mice, increasing levels of infectious virus could be detected in the central nervous system. Seventy-five percent (9 of 12) of the nude mice were moribund or dead by 4 weeks postinfection. In contrast, treatment of Theiler's virus-infected nude mice with a neutralizing monoclonal antibody (H7-2) against the viral protein VP-1 resulted in a dramatic reduction of infectious virus within the central nervous system. All antibody-treated nude animals survived beyond 4 weeks postinfection. Monoclonal antibody titers could be maintained by passive transfer in treated nude mice at levels comparable to those of polyclonal antibody titers found in heterozygous infected nu/+ littermates. Areas of demyelination were detected in the untreated animals as early as 7 days after infection with little or no remyelination present. In approximately one-half of the antibody-treated nude animals, no demyelinating lesions were found. However, the rest of these treated mice were found to have areas of both demyelination and remyelination. Thus, anti-Theiler's murine encephalomyelitis virus antibody against VP-1 can play a dramatic role in the survival of mice, clearance of virus, limiting viral spread, and altering the pattern of disease in the absence of a functional T-cell response.
Regulation of Sindbis virus RNA replication: uncleaved P123 and nsP4 function in minus-strand RNA synthesis, whereas cleaved products from P123 are required for efficient plus-strand RNA synthesis (1994)

Nonstructural proteins of Sindbis virus, nsP1, nsP2, nsP3, and nsP4, as well as intermediate polyproteins, are produced from two precursor polyproteins, P123 and P1234, by a proteolytic enzyme encoded in the C-terminal half of nsP2. We studied the requirements for and the functions of the intermediate and mature processing products for Sindbis virus RNA synthesis by using site-directed mutants which have a defect(s) in processing the 1/2, 2/3, or 3/4 cleavage sites either singly or in various combinations. A mutant defective in cleaving both the 1/2 and 2/3 sites, which makes only uncleavable P123 and mature nsP4 as final products, produced 10(-3) as much virus as did the wild-type virus after 10 h at 30 degrees C and was nonviable at 40 degrees C. A mutant defective in processing the 2/3 site, which makes nsP1, nsP4, and P23 as well as precursor P123, grew 10(-1) as efficiently as wild-type virus at 30 degrees C and 10(-3) as efficiently at 40 degrees C. Early minus-strand RNA synthesis by these mutants was as efficient as that by wild-type virus, whereas plus-strand RNA synthesis was substantially decreased compared with that by wild-type virus. A mutant defective in processing the 3/4 site was nonviable at either 30 or 40 degrees C. The 3/4 site mutant could be complemented by the mutant unable to cleave either the 1/2 or 2/3 site, which can provide mature nsP4. We interpret these results to signify that (i) mature nsP4 is required for RNA replication, (ii) nsP4 and uncleaved P123 function in minus-strand RNA synthesis, and (iii) cleavage of P123 is required for efficient plus-strand RNA synthesis. We propose that Sindbis virus RNA replication is regulated by differential proteolysis of P123. Early in infection, nsP4 and uncleaved P123 form transient minus-strand RNA replication complexes which vanish upon cleavage of P123. Later in infection, an elevated level of viral proteinase activity eliminates de novo synthesis of P123, and no further synthesis of minus-strand RNA is possible. In contrast, nsP4 and cleavage products from P123 form plus-strand RNA replication complexes which are stable and remain active throughout the infection cycle.
Autism spectrum disorders (2006)

Some children are less socially interactive and communicative than others. When the combination of social and communication problems takes on the quality of a clinically severely impairing condition one needs to consider the possibility of a disorder of social interaction, particularly one that may fall under the diagnostic umbrella of 'autism spectrum disorders'.
Common molecular scaffold for two unrelated RGD molecules (1995)

The sequence arginine-glycine-aspartic acid (RGD) is important for recognition of cell adhesion proteins by cell surface receptors (integrins). This tripeptide sequence is present in a number of proteins including fibronectin, vitronectin, von Willebrand factor and fibrinogen. Specific and selective binding of the RGD sequence by different receptors suggests that the conformational orientation of the tripeptide is critical for stereochemical recognition. The crystal structures of two proteins that contain the RGD signal were determined: (i) the cell-binding type III module of fibronectin (FNIII10) and (ii) an anti-receptor antibody fragment (OPG2) that is a functional RGD ligand mimic with an RYD recognition site in the variable (VH) domain. Both of these modules are folded into beta-barrels with two layers of antiparallel beta-sheets enclosing a hydrophobic core. Since these molecules each contain the RGD (RYD) sequence, there is a unique opportunity for direct structural comparison. The comparison has defined a common molecular scaffold in these two unrelated molecules. Within this framework, the RGD (RYD) sites are located in structurally related loops in the two modules, i.e. at one end of the scaffold in a long loop connecting the last two strands in one of the beta-sheets. This shared scaffold is used for the stereochemical presentation of the RGD site for receptor recognition.
Coherent intrinsic images from photo collections (2012)

An intrinsic image is a decomposition of a photo into an illumination layer and a reflectance layer, which enables powerful editing such as the alteration of an object's material independently of its illumination. However, decomposing a single photo is highly under-constrained and existing methods require user assistance or handle only simple scenes. In this paper, we compute intrinsic decompositions using several images of the same scene under different viewpoints and lighting conditions. We use multi-view stereo to automatically reconstruct 3D points and normals from which we derive relationships between reflectance values at different locations, across multiple views and consequently different lighting conditions. We use robust estimation to reliably identify reflectance ratios between pairs of points. From these, we infer constraints for our optimization and enforce a coherent solution across multiple views and illuminations. Our results demonstrate that this constrained optimization yields high-quality and coherent intrinsic decompositions of complex scenes. We illustrate how these decompositions can be used for image-based illumination transfer and transitions between views with consistent lighting.
A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. (2017)

e14040 Background: NKTR-214 is a CD-122-biased agonist that targets the IL-2 pathway and is designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T regulatory cells within the tumor microenvironment. In a phase 1 monotherapy trial, pts treated with NKTR-214 demonstrated a substantial increase in CD8+ T and NK cells within the tumor microenvironment even when pretreated with multiple prior immunotherapeutic agents (abstract submitted). Based on this biomarker data and a favorable safety profile, a trial combining NKTR-214 and nivolumab was initiated. Methods: This is an on-going phase 1/2 study of NKTR-214 plus nivolumab in Pts with either melanoma (Mel), NSCLC, renal, bladder, or TNBC. Pts who are immunotherapy naïve or checkpoint therapy relapse/refractory are being studied separately. NKTR-214 and nivolumab are administered IV on a q2w or q3w schedule. Cohort 1 received NKTR-214 0.006 mg/kg q3w with nivolumab 240 mg q2w. Blood and tumor tissue were collected to measure immune activation using flow cytometry, immunohistochemistry, T cell clonality and gene expression analyses. Results: As of February 7, 2017, 5 Pts have been treated with the combination and all Pts were naïve to checkpoint inhibitors. There have been no dose limiting toxicities, no drug-related or immune related grade 3-5 adverse events (TRAEs) and no Pts have discontinued treatment. The most common TRAEs were pruritis and rash. Radiographic scans were available for 2 Pts. On treatment, Pt 1 with Mel had a mixed radiographic response at 1st scan, a ~40% decrease in LDH and a robust tumor immune cell infiltrate at week 3 the majority being newly proliferating CD8+ T cells expressing PD-1. Pt 2 with Mel had an unconfirmed complete response per RECIST 1.1 after 6 weeks of treatment; follow up tumor response data will be presented. Conclusions: Preliminary data demonstrate that NKTR-214 and nivolumab combination therapy is well tolerated with early evidence of clinical activity. Updated safety, pharmacokinetics, tumor response and biomarker data will be presented. Clinical trial information: NCT02983045.
Facile synthesis of stapled, structurally reinforced peptide helices via a photoinduced intramolecular 1,3-dipolar cycloaddition reaction (2009)

We report the first use of a photoinduced 1,3-dipolar cycloaddition reaction in "stapling" peptide sidechains to reinforce a model peptide helical structure with moderate to excellent yields; the resulting pyrazoline "staplers" exhibit unique fluorescence useful in a cell permeability study.