nils-herrmann/clean_scirepeval huggingface dataset:
Role of Side Chains in b Sheet Self Assembly into Peptide Fibrils. IR and VCD Spectroscopic Studies of Glutamic Acid Containing Peptides.
Venue: Langmuir the ACS journal of surfaces and colloids

Poly(glutamic acid) at low pH self assembles after incubation at higher temperature into fibrils composed of antiparallel sheets that are stacked in a b2 type structure whose amide carbonyls have bifurcated H bonds involving the side chains from the next sheet. Oligomers of Glu can also form such structures, and isotope labeling has provided insight into their out of register antiparallel structure Biomacromolecules 2013 14 3880 3891 In this paper we report IR and VCD spectra and transmission electron micrograph (TEM) images for a series of alternately sequenced oligomers, Lys (Aaa Glu)5 Lys NH2, where Aaa was varied over a variety of polar, aliphatic, or aromatic residues. Their spectral and TEM data show that these oligopeptides self assemble into different structures, both local and morphological, that are dependent on both the nature of the Aaa side chains and growth conditions employed. Such alternate peptides substituted with small or polar residues, Ala and Thr, do not yield fibrils; but with b branched aliphatic residues, Val and Ile, that could potentially pack with Glu side chains, these oligopeptides do show evidence of b2 stacking. By contrast, for Leu, with longer side chains, only b1 stacking is seen while with even larger Phe side chains, either b form can be detected separately, depending on preparation conditions. These structures are dependent on high temperature incubation after reducing the pH and in some cases after sonication of initial fibril forms and reincubation. Some of these fibrillar peptides, but not all, show enhanced VCD, which can offer evidence for formation of long, multistrand, often twisted structures. Substitution of Glu with residues having selected side chains yields a variety of morphologies, leading to both b1 and b2 structures, that overall suggests two different packing modes for the hydrophobic side chains depending on size and type.
Assessing bisphenol A (BPA) exposure risk from long term dietary intakes in Taiwan.
Venue: The Science of the total environment

Dietary intake is the major bisphenol A (BPA) exposure route in humans, and is a cause of BPA related adverse effects. The large scale exposure risk of humans to BPA through dietary sources in Taiwan is less well studied. The aim of this study was to assess the average daily dose (ADD) and hazardous quotient (HQ) of BPA exposure risk from long term dietary intake of BPA, as well as BPA concentrations in different age sex groups in Taiwan. We reanalyzed the BPA concentrations of regular daily food sources (rice, poultry, livestock, seafood, protein, fruits, and vegetables) and used a national dietary survey to estimate the contribution of variance to ADDs and potential human health effect for different age sex groups. This study found that the daily consumption of chicken, pork/beef, and seafood were estimated to be 33.77 (Male)/22.65 (Female) 91.70 (M)/66.35 (F) and 54.15 (M)/40.78 (F) g/day, respectively. The highest BPA ADD was found in the 6 9 years age group (95% CI=0.0006 0.0027 mg/kg bw/day) whereas the lowest BPA ADD was in the =65 years age group (0.0002 0.0020 mg/kg bw/day) Based on the latest EFSA guidelines (0.004 mg/kg bw/day) the 97.5 percentile HQ of BPA intake in different age sex groups in Taiwan posed no risks through dietary intake. However, a combination of multiple exposure routes and long term exposure in specific populations may be of concern in the future.
Dietary Protein, Metabolism, and Aging.
Venue: Annual review of biochemistry

Dietary restriction (DR) a moderate reduction in food intake, improves health during aging and extends life span across multiple species. Specific nutrients, rather than overall calories, mediate the effects of DR, with protein and specific amino acids (AAs) playing a key role. Modulations of single dietary AAs affect traits including growth, reproduction, physiology, health, and longevity in animals. Epidemiological data in humans also link the quality and quantity of dietary proteins to long term health. Intricate nutrient sensing pathways fine tune the metabolic responses to dietary AAs in a highly conserved manner. In turn, these metabolic responses can affect the onset of insulin resistance, obesity, neurodegenerative disease, and other age related diseases. In this review we discuss how AA requirements are shaped and how ingested AAs regulate a spectrum of homeostatic processes. Finally, we highlight the resulting opportunity to develop nutritional strategies to improve human health during aging.
A REVIEW ON PHYTOCHEMICAL AND PHARMACOLOGICAL STUDIES OF ALBIZIA JULIBRISSIN: AN ORNAMENTAL PLANT

The present investigation reviews Albizia species to tap out the shelf of bioactive constituents that possess pharmacological properties specially considering Albizia julibrissin. Albizia julibrissin (Persian silk tree, pink silk tree) is a species of tree in the family Fabaceae, The species is usually called "silk tree" or "mimosa" in the United States. It is widely planted in India as an ornamental plant in parks and gardens, grown for its leaf texture and flowers.Now Albizia julibrissin flower extract are showing significant antidepressant, reduction in both its spontaneous activity and passive activities, antidiabetic, antiinflammatory and anti obesity properties. It is also well known remedy for insomnia in Chinese medicine as well as shows an important and very significant in vitro anti tumor activity. Hence its extract and essential oil are widely used for dysphoria induced wakefulness, depression, forgetfulness, and dreaminess. The evidence of these amazing Albizia julibrissin effects can be identified from its pharmacological action though not much dimension has been explored, Albizia julibrissin can be beneficial for future research and can be of great medicinal use.
Characterization of Flavonoids from Albizia amara Leaves and their Biological Activity on Microbes

Phytochemical screening of methanol extract of leaves of Albizia Amara revealed the presence of secondary metabolites: saponins, alkaloids, tannins, glycosides and flavonoids. Powdered shadedried leaves (1kg) of A. amara. were extracted with 95% ethanol at room temperature for 48 hours, The crude extract was suspended in water and partitioned with organic solvents in order of increasing polarity, petroleum ether, chloroform ethyl acetate and n butanol, three compounds were isolated from n butanol fraction. These compounds were isolated by chromatographic techniques and identified via spectroscopic tools: IR, UV, 1HNMR and Mass spectroscopy. The isolated compounds were tested for antimicrobial potential against four bacterial strains: Gram positive (Staphylococus aureus and Bacillus subtilis) gram negative (Pseudomonas aeruginosa and Escherichia coli) and two Fungal species (Candida albicans and Aspergillus niger) Agar well diffusion method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) at concentrations of 100 mg /ml to 6.25mg /ml. Compounds II and III showed significant antimicrobial activity at 100mg/ml and 50mg/ml. Compound I exhibited promising activity at these doses. The results of the Table 4 suggests that these flavonoids could serve as leads for further optimization.
Soil carbon and nitrogen and barley yield responses to repeated additions of compost and slurry
Venue: The Journal of Agricultural Science

The yields of spring barley during a medium term (7 years) compost and slurry addition experiment and the soil carbon (C) and nitrogen (N) contents, bacterial community structure, soil microbial biomass and soil respiration rates have been determined to assess the effects of repeated, and in some cases very large, organic amendments on soil and crop parameters. For compost, total additions were equivalent to up to 119 t C/ha and 1*7 t N/ha and for slurry they were 25 t C/ha and 0*35 t N/ha over 7 years, which represented very large additions compared to control soil C and N contents (69 t C/ha and 0*3 t N/ha in the 0 30 cm soil depth) There was an initial positive response to compost and slurry addition on barley yield, but over the experiment the yield differential between the amounts of compost addition declined, indicating that repeated addition of compost at a lower rate over several years had the same cumulative effect as a large single compost application. By the end of the experiment it was clear that the addition of compost and slurry increased soil C and N contents, especially towards the top of the soil profile, as well as soil respiration rates. However, the increases in soil C and N contents were not proportional to the amount of C and N added, suggesting either that: (i) a portion of the added C and N was more vulnerable to loss; (ii) that its addition rendered another C or N pool in the soil more susceptible to loss; or (iii) that the C inputs from additional crop productivity did not increase in line with the organic amendments. Soil microbial biomass was depressed at the highest rate of organic amendment, and whilst this may have been due to genuine toxic or inhibitory effects of large amounts of compost, it could also be due to the inaccuracy of the substrate induced respiration approach used for determining soil biomass when there is a large supply of organic matter. At the highest compost addition, the bacterial community structure was significantly altered, suggesting that the amendments significantly altered soil community dynamics.
Two decades of no till in the Oberacker long term field experiment: Part I. Crop yield, soil organic carbon and nutrient distribution in the soil profile

This is the first in a series of papers describing the impact of two decades of no till in the Oberacker long term field experiment in Switzerland. The experiment was established in 1994 on a sandy loam and compares two tillage systems, conventional tillage with mouldboard ploughing (MP) and no till (NT) Crops are grown in a six year rotation, namely peas (Pisum sativum L. winter wheat (Triticum aestivum L. field beans (Phaseolus vulgaris L. winter barley (Hordeum vulgare L. sugar beet (Beta vulgaris L. silage maize (Zea mays L. This study investigated the impact of the two tillage systems on (i) nutrient distribution and storage in the soil profile, (ii) the depth distribution of soil organic carbon and (iii) crop productivity. Soil samples were collected layer by layer following cultivation layers and natural soil horizons in a metal frame (0.5 m x 0.5 m cross sectional area) down to 0.5 m depth. The layer boundaries were approximately 0.02, 0.05, 0.15, 0.25, 0.30, 0.40, and 0.50 m for NT, and 0.15, 0.25, 0.30, 0.40, and 0.50 m for MP. Soil organic carbon (SOC) total nitrogen (TotN) phosphorus (P) calcium (Ca) potassium (K) magnesium (Mg) pH, and bulk density were measured for each layer. The nutrient distribution was rather uniform within the plough layer in MP. In NT, there was strong stratification, with higher nutrient concentrations in the upper layers for TotN, K and Mg. This was associated with crop residue retention on the surface and reduced plant uptake due to low pH. In contrast, the distribution of P and Ca in NT was rather uniform in the 0 30 cm layer, with a trend towards maximum concentrations at around 20 cm depth. Total storage of nutrients per ha in the whole soil profile was similar in NT and MP for all nutrients. SOC stocks did not differ between NT and MP, although the depth distribution of SOC concentration was significantly different. The long term average crop yield was slightly higher in NT than in MP, but the difference was not significant. Crop yield was significantly higher in NT for winter cereals (winter wheat, winter barley) and legumes (field beans and peas) but lower for root and tuber crops (sugar beet, potatoes) It can be assumed that the high crop yields in NT in the Oberacker long term field experiment are due to the well balanced crop rotation.
Soft Hair on Black Holes.
Venue: Physical review letters

It has recently been shown that Bondi van der Burg Metzner Sachs supertranslation symmetries imply an infinite number of conservation laws for all gravitational theories in asymptotically Minkowskian spacetimes. These laws require black holes to carry a large amount of soft (i.e. zero energy) supertranslation hair. The presence of a Maxwell field similarly implies soft electric hair. This Letter gives an explicit description of soft hair in terms of soft gravitons or photons on the black hole horizon, and shows that complete information about their quantum state is stored on a holographic plate at the future boundary of the horizon. Charge conservation is used to give an infinite number of exact relations between the evaporation products of black holes which have different soft hair but are otherwise identical. It is further argued that soft hair which is spatially localized to much less than a Planck length cannot be excited in a physically realizable process, giving an effective number of soft degrees of freedom proportional to the horizon area in Planck units.
Abstract LB 212: Therapeutic efficacy of the paradox breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS driven cancer models

KRAS is mutated in ~80% of pancreatic ductal adenocarcinoma (PDAC) ~35% of colorectal cancer (CRC) and ~20% of non small cell lung cancer (NSCLC) KRAS remains an intractable drug target and targeting the downstream pathway component is ineffective because feedback mechanisms or parallel pathways provide alternative routes to cell proliferation and/or survival. Here we show that a new panRAF/SRC inhibitor, CCT3833, is active in KRAS mutant PDAC, CRC and NSCLC. We demonstrate that CCT3833 inhibits tumor growth in several KRAS driven cancers via inhibition of RAF and SRC, eliciting therapeutic efficacy at well tolerated doses in mouse models of human cancer. CCT3833 has already entered clinical trials (NCT02437227) for BRAF mutant and BRAF inhibitor resistant melanomas and these new data show that it is also effective in KRAS mutant cancers, potentially providing a new therapeutic option for these patients.  Grazia Saturno, Filipa Lopes, Maria Romina Girotti, Ion Niculescu Duvaz, Dan Niculescu Duvaz, Alfonso Zambon, Lawrence Davies, Louise Johnson, Natasha Preece, Amaya Viros, Malin Pedersen, Robert McLeary, Ruth Knight, Rebecca Lee, Denys Holovanchuk, Paul Lorigan, Nathalie Dhomen, Richard Marais, Caroline Springer. Therapeutic efficacy of the paradox breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS driven cancer models.
Abstract 2818: An unbiased tumor cell panel profiling method to identify drug drug interactions reveals synergy between the CDK4 and CDK 6 inhibitor abemaciclib and the Raf dimer and pan Raf inhibitor LY3009120 in Ras mutant cancers

Drug sensitivity profiling across genomically characterized panels of tumor cells can identify the molecular determinants of drug response. By testing compound combinations in an unbiased format, the same methodology can be used to identify the genomic context of drug drug synergy. Based on this principle, we developed an unbiased combination screening protocol to identify synergistic interactions with LY3009120, a novel Raf dimer inhibitor that inhibits all three Raf isoforms (Peng et al. 2015,  Inhibitors of the Ras MAPK pathway have proven very effective in the treatment of BRAF mutant melanoma but are, in general, only partially effective in the treatment of BRAF mutant colorectal cancer and Ras mutant cancers. LY3009120 combined with various compounds was screened across panels of genomically characterized tumor cells. These screens identified a strong synergy with abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4 and CDK6) Statistical analysis of effects in over 500 cancer cell lines showed that mutations in BRAF or Ras family genes were strongly associated with sensitivity to this combination. Strong synergy was observed in skin, colorectal, lung and pancreatic cancers with Ras/Raf mutations, but was also observed in various cancer cells wild type for Ras pathway genes. This included tumor types sensitive to single agent abemaciclib, such as mantle cell lymphoma, ER+ breast cancers, certain leukemias, squamous non small cell lung cancer, and/or lung cancer with receptor tyrosine kinase activation. In vitro and in vivo analyses of the effects of the combination treatment on signaling pathways in KRAS mutant cancers led to potential mechanistic explanations for the differing efficacy of the combination, which manifests as regression of tumor xenografts in rodent models.  Xueqian Gong, Wenjuan Wu, Li Chun Chio, Susan Pratt, Constance King, Yue Webster, Maria Jose Lallena, Karsten Boehnke, Raquel Torres, Philip Iversen, Christoph Reinhard, Shih Hsun Chen, Richard Bechmann, Sheng Bin Peng, Sean Buchanan. An unbiased tumor cell panel profiling method to identify drug drug interactions reveals synergy between the CDK4 and CDK 6 inhibitor abemaciclib and the Raf dimer and pan Raf inhibitor LY3009120 in Ras mutant cancers.
An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.
Venue: Cancer cell

(Cancer Cell 30, 192 194; August 8, 2016) In the originally published version of this paper, the authors mistakenly used the word 'neuronal' when referring to glioma in four instances. The word 'neural' would more accurately describe the putative origin of gliomas and should have been used instead. This error has now been corrected in the original paper online. The authors apologize for this error and any confusion that may have resulted. a 2016 Elsevier Inc.
A Novel RAF Kinase Inhibitor with DFG Out Binding Mode: High Efficacy in BRAF Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation
Venue: Molecular Cancer Therapeutics

BI 882370 is a highly potent and selective RAF inhibitor that binds to the DFG out (inactive) conformation of the BRAF kinase. The compound inhibited proliferation of human BRAF mutant melanoma cells with 100x higher potency (1 10 nmol/L) than vemurafenib, whereas wild type cells were not affected at 1,000 nmol/L. BI 882370 administered orally was efficacious in multiple mouse models of BRAF mutant melanomas and colorectal carcinomas, and at 25 mg/kg twice daily showed superior efficacy compared with vemurafenib, dabrafenib, or trametinib (dosed to provide exposures reached in patients) To model drug resistance, A375 melanoma bearing mice were initially treated with vemurafenib; all tumors responded with regression, but the majority subsequently resumed growth. Trametinib did not show any efficacy in this progressing population. BI 882370 induced tumor regression; however, resistance developed within 3 weeks. BI 882370 in combination with trametinib resulted in more pronounced regressions, and resistance was not observed during 5 weeks of second line therapy. Importantly, mice treated with BI 882370 did not show any body weight loss or clinical signs of intolerability, and no pathologic changes were observed in several major organs investigated, including skin. Furthermore, a pilot study in rats (up to 60 mg/kg daily for 2 weeks) indicated lack of toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics. Our results indicate the feasibility of developing novel compounds that provide an improved therapeutic window compared with first generation BRAF inhibitors, resulting in more pronounced and long lasting pathway suppression and thus improved efficacy.
Increased Expression of miR 23a Mediates a Loss of Expression in the RAF Kinase Inhibitor Protein RKIP.
Venue: Cancer research

RAF kinase inhibitor protein (RKIP) is a seminal regulator of intracellular signaling and exhibits both antimetastatic and antitumorigenic properties. Decreased expression of RKIP has been described in several human malignancies, including acute myelogenous leukemia (AML) As the mechanisms leading to RKIP loss in AML are still unclear, we aimed to analyze the potential involvement of miRNAs within this study. miRNA microarray and qPCR data of more than 400 AML patient specimens revealed correlation between decreased expression of RKIP and increased expression of miR 23a, a member of the miR 23a/27a/24 2 cluster. In functional experiments, overexpression of miR 23a decreased RKIP mRNA and protein expression, whereas miR 23a inhibition caused the opposite effect. By using an RKIP 3' untranslated region luciferase reporter construct with and without mutation or deletion of the putative miR 23a binding site, we could show that RKIP modulation by miR 23a is mediated via direct binding to this region. Importantly, miR 23a overexpression induced a significant increase of proliferation in hematopoietic cells. Simultaneous transfection of an RKIP expression construct lacking the miR 23a binding sites reversed this phenotype, indicating that this effect is truly mediated via downregulation of RKIP. Finally, by analyzing more than 4,300 primary patient specimens via database retrieval from The Cancer Genome Atlas, we could highlight the importance of the miR 23a/RKIP axis in a broad range of human cancer entities. In conclusion, we have identified miR 23a as a negative regulator of RKIP expression in AML and have provided data that suggest the importance of our observation beyond this tumor entity. . (c)2016 AACR.
Abstract 1230: BGB 283: a novel RAF Dimer inhibitor, displays potent antitumor activity in HCC patient derived xenograft models

Liver cancer has the third highest mortality rate among all cancers in China and hepatocellular carcinoma (HCC) is the most common type of liver cancer. The mitogen activated protein kinase (MAPK) signaling pathway is often constitutively active in HCC. The growth of HCC requires the formation of new blood vessels. and VEGF is critical in this process. Sorafenib, a multikinase inhibitor that targets both RAF and VEGF receptor, is to date the only approved drug to treat advanced stages of HCC. Despite sorafenib extended the survival in patients with HCC, its clinical benefits remain modest and drug resistance is common. BGB283 is a second generation RAF inhibitor with unique RAF dimer and VEGFR inhibition activity. Thus, there is good rationale to test BGB 283 in HCC. In this study, we compared the in vitro and in vivo activities of BGB 283 and sorafinib in human HCC cell lines and patient derived HCC xenograft models. In the biochemical assays, BGB 283 demonstrated great potency for BRAF V600E, BRAF WT, CRAF(IC50 32, 69 and 6.5 nM, respectively) and for VEGFR family enzymes, VEGFR1, VEGFR2 and VEGFR3 (IC50 25, 14 and 58 nM, respectively) In the cellular assays, the anti proliferative effect of BGB 283 and sorafinib was evaluated in several HCC cell lines. A head to head comparison of in vivo anti tumor activities of BGB 283 and sorafinib were also evaluated in human primary HCC xenograft mouse models. The patient derived xenograft (PDX) HCC models were established in house using HCC patient surgical samples. Sorafinib was not active in 2 out of 7 models. Oral administration of BGB 283 resulted in significant tumor growth inhibition in all 7 models and was significantly more efficacious than sorafinib in 4 models and similar in the other 3 models. In conclusion, BGB 283 is a unique RAF dimer inhibitor with VEGFR inhibition activity. BGB 283 has also demonstrated better anti tumor activity than sorafinib in HCC PDX models, suggesting BGB 283 could be a promising drug candidate for treating HCC patients.