High beverage sugar as well as high animal protein intake at infancy may increase overweight risk at 8 years: a prospective longitudinal pilot study

<p>Abstract</p> <p>Background</p> <p>Combined effects of early exposure to beverage sugar and animal protein and later life overweight risk have not been studied.</p> <p>Methods</p> <p>A prospective longitudinal study was initiated in 2001 with 226 infants between 4 and 13 months of age. Dietary intake was assessed with a 2 day food record. Also information on infant body weight and socio-economic status was obtained at baseline. At 8 year follow-up in 2009, children were surveyed again. Main outcome measure was overweight at 8 years as defined by BMIsds > = +1.0. Also maternal BMI, present dietary intake and physical activity, were obtained by questionnaire and 2-day food record.</p> <p>Results</p> <p>At the 8 year follow up, 120 children (53%) were surveyed again. Of those, questionnaires and food records were completed for 63 children, for the other 57 children only weight and height at 8 years was available; 20 out of 120 children (17%) were self-reported overweight at 8 years of age. Unadjusted odds ratios (ORs; 95% CI) for overweight at 8 years were 1.10 (1.02, 1.18) for beverage sugar intake per one percent of energy intake and 4.06 (1.50, 11.00) for the highest tertile of animal protein intake at infancy compared to the lowest two tertiles. After adjustment for sex, age, infant weight, breastfed at intake assessment, and socio-economic status, odds ratios were 1.13 (1.03, 1.24) for beverage sugar, and 9.67 (2.56, 36.53) for highest tertile of animal protein intake. In the subgroup with completed questionnaire (n = 63) ORs were also adjusted for current maternal overweight, more than 2 months full breastfeeding, physical activity, and energy intake, but ORs remained significantly associated with overweight at 8 years.</p> <p>Conclusions</p> <p>A high intake of sugar containing beverages as well as animal protein in the first year of life may increase the risk of overweight at 8 years. The results of this pilot investigation should be confirmed in a larger cohort.</p

Varespladib Inhibits the Phospholipase A 2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes

Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib on snake venom PLA2s was investigated by nanofractionation analytics, which combined chromatography, mass spectrometry (MS), and bioassays. The venoms of the medically important snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus, Echis ocellatus, and Oxyuranus scutellatus were separated by liquid chromatography (LC) followed by nanofractionation and interrogation of the fractions by a coagulation assay and a PLA2 assay. Next, we assessed the ability of varespladib to inhibit the activity of enzymatic PLA2s and the coagulopathic toxicities induced by fractionated snake venom toxins, and identified these bioactive venom toxins and those inhibited by varespladib by using parallel recorded LC-MS data and proteomics analysis. We demonstrated here that varespladib was not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities (most profoundly anticoagulation) induced by venom toxins. While varespladib effectively inhibited PLA2 toxins responsible for anticoagulant effects, we also found some evidence that this inhibitory molecule can partially abrogate procoagulant venom effects caused by different toxin families. These findings further emphasize the potential clinical utility of varespladib in mitigating the toxic effects of certain snakebites

Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)—a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.</jats:p

Soil pH effects on the interactions between dissolved zinc, non-nano- and nano-ZnO with soil bacterial communities

Zinc oxide nanoparticles (ZnO NPs) are used in an array of products and processes, ranging from personal care products to antifouling paints, textiles, food additives, antibacterial agents and environmental remediation processes. Soils are an environment likely to be exposed to manmade nanoparticles due to the practice of applying sewage sludge as a fertiliser or as an organic soil improver. However, understanding on the interactions between soil properties, nanoparticles and the organisms that live within soil is lacking, especially with regards to soil bacterial communities. We studied the effects of nanoparticulate, non-nanoparticulate and ionic zinc (in the form of zinc chloride) on the composition of bacterial communities in soil with a modified pH range (from pH 4.5 to pH 7.2). We observed strong pH dependent effects on the interaction between bacterial communities and all forms of zinc, with the largest changes in bacterial community composition occurring in soils with low and medium pH levels (pH 4.8 and 5.9). The high pH soil (pH 7.2) was less susceptible to the effects of zinc exposure. At the highest doses of zinc (2500 mg/kg dw soil) both nano and non-nano particulate zinc applications elicited a similar response in the soil bacterial community, and this differed significantly to the ionic zinc salt treatment. The results highlight the importance of considering soil pH in nanotoxicology studies, although further work is needed to determine the exact mechanisms controlling the toxicity and fate and interactions of nanoparticles with soil microbial communities

Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions

The effect of nitrification inhibitor on N2O, NO and N2 emissions under different soil moisture levels in a permanent grassland soil

[EN] Emissions of gaseous forms of nitrogen from soil, such as nitrous oxide (N2O) and nitric oxide (NO), have shown great impact on global warming and atmospheric chemistry. Although in soil both nitrification and denitrification could cause N2O and NO emissions, most studies demonstrated that denitrification is the dominant process responsible for the increase of atmospheric N2O, while nitrification produces mostly NO. The use of nitrification inhibitors (NIs) has repeatedly been shown to reduce both N2O and NO emissions from agricultural soils; nevertheless, the efficiency of the mitigation effect varies greatly. It is generally assumed that nitrification inhibitors have no direct effect on denitrification. However, the indirect impact, due to the reduced substrate (nitrate) delivery to microsites where denitrification occurs, may have significant effects on denitrification product stoichiometry that may significantly lower soil borne N2O emissions. Soil-water status is considered to have a remarkable effect on the relative fluxes of nitrogen gases. The effect and mechanism of NI on N2O, NO and N-2 emission under different soil water-filled pore space (WFPS) is still not well explored. In the present study, we conducted a soil incubation experiment in an automated continuous-flow incubation system under a He/O-2 atmosphere. Ammonium sulfate was applied with and without NI (DMPP) to a permanent UK grassland soil under three different soil moisture conditions (50, 65, and 80% WFPS). With every treatment, glucose was applied to supply enough available carbon for denitrification. Emissions of CO2, N2O, NO and N-2 were investigated. Additionally, isotopic signatures of soil-emitted N2O were analyzed. Generally, higher WFPS led to higher N2O and NO emissions, while N-2 emissions were only detected at high soil moisture condition (80% WFPS). Different processes were responsible for N2O and NO emission in different phases of the incubation period. The application of DMPP did significantly reduce both N2O and NO emissions at all three soil moisture conditions. Furthermore, DMPP application increased N-2 emissions and decreased the N2O/(N2O + N-2) product ratio at 80% WFPS. (C) 2017 Elsevier Ltd. All rights reserved.Rothamsted Research is sponsored by the BBSRC. This study was in part funded by BBSRC project BB/K001051/1 and supported by the Chinese Scholarship Council (scholarship no. give number 201306350130).Wu, D.; Cárdenas, LM.; Calvet, S.; Brüggemann, N.; Loick, N.; Liu, S.; Bol, R. (2017). The effect of nitrification inhibitor on N2O, NO and N2 emissions under different soil moisture levels in a permanent grassland soil. Soil Biology and Biochemistry. 113:153-160. https://doi.org/10.1016/j.soilbio.2017.06.007S15316011

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant