Biochemistry of Cone Snail toxin activation

posterCone snails use venom to capture prey for food and for defense against predators. The venom is composed of over 100 active peptides that target specific receptors in the nervous system. Several of these peptides have the potential to become medicine for treatment of pain, depression, seizures, and neurological disorders such as Alzheimer 019s disease and MS. In our efforts to understand how cone snails make toxins, we want to purify the Astacin-like protease thought to execute the final steps in toxin activation. Initial trials indicated that purification from bacteria expressing the protease would be challenging. We applied a sparse matrix search to find buffer conditions (pH, salt, metal ions, additives) that maximized yield of soluble Astacin-like protease

Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.

MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for 'retaining' O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer

Standardizing training for Pressurized Intraperitoneal Aerosol Chemotherapy.

PIPAC is a novel mode of intraperitoneal drug delivery for patients with peritoneal cancer (PC). PIPAC is a safe treatment with promising oncological results. Therefore, a structured training program is needed to maintain high standards and to guarantee safe implementation. An international panel of PIPAC experts created by means of a consensus meeting a structured 2-day training course including essential theoretical content and practical exercises. For every module, learning objectives were defined and structured presentations were elaborated. This structured PIPAC training program was then tested in five courses. The panel consisted of 12 experts from 11 different centres totalling a cumulative experience of 23 PIPAC courses and 1880 PIPAC procedures. The final program was approved by all members of the panel and includes 12 theoretical units (45 min each) and 6 practical units including dry-lab and live surgeries. The panel finalized and approved 21 structured presentations including the latest evidence on PIPAC and covering all mandatory topics. These were organized in 8 modules with clear learning objectives to be tested by 12 multiple-choice questions. Lastly, a structured quantifiable (Likert scale 1-5) course evaluation was created. The new course was successfully tested in five courses with 85 participants. Mean overall satisfaction with the content was rated at 4.79 (±0.5) with at 4.71 (±0.5) and at 4.61 (±0.7), respectively for course length and the balance between theory and practice. The proposed PIPAC training program contains essential theoretical background and practical training enabling the participants to safely implement PIPAC

Hawking radiation and thermodynamics of dynamical black holes in phantom dominated universe

The thermodynamic properties of dark energy-dominated universe in the presence of a black hole are investigated in the general case of a varying equation-of-state-parameter $w(a)$. We show that all the thermodynamics quantities are regular at the phantom divide crossing, and particularly the temperature and the entropy of the dark fluid are always positive definite. We also study the accretion process of a phantom fluid by black holes and the conditions required for the validity of the generalized second law of thermodynamics. As a results we obtain a strictly negative chemical potential and an equation-of-state parameter $w<-5/3.$Comment: 22 pages,3 figure

Staff experiences of working in a Sexual Assault Referral Centre: the impacts and emotional tolls of working with traumatised people

This study considers the impacts on staff of supporting people who have reported sexual violence and attend a Sexual Assault Referral Centre (SARC). This paper focuses on the staff’s perspectives of the stresses and emotional tolls they experience including the coping mechanisms they utilise. Semi- structured interviews were conducted with 12 staff, and a focus group was held with a further four staff of a SARC. The data were examined using thematic analysis. Findings indicated that staff experienced positive emotions connected to the meaningfulness of the work and team spirit as well as a range of unpleasant emotions. Staff also reported emotional numbing, in connection to the specificity, volume and sometimes unpredictable nature of the work. Coping mechanisms used by staff focused on the supportive connection to family, nature, and other team members; the value of clinical supervision; and the avoidance of topics related to work

Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol

Search for Yukawa Production of a Light Neutral Higgs Boson at LEP

Within a Two-Higgs-Doublet Model (2HDM) a search for a light Higgs boson in the mass range of 4-12 GeV has been performed in the Yukawa process e+e- -> b bbar A/h -> b bbar tau+tau-, using the data collected by the OPAL detector at LEP between 1992 and 1995 in e+e- collisions at about 91 GeV centre-of-mass energy. A likelihood selection is applied to separate background and signal. The number of observed events is in good agreement with the expected background. Within a CP-conserving 2HDM type II model the cross-section for Yukawa production depends on xiAd = |tan beta| and xihd = |sin alpha/cos beta| for the production of the CP-odd A and the CP-even h, respectively, where tan beta is the ratio of the vacuum expectation values of the Higgs doublets and alpha is the mixing angle between the neutral CP-even Higgs bosons. From our data 95% C.L. upper limits are derived for xiAd within the range of 8.5 to 13.6 and for xihd between 8.2 to 13.7, depending on the mass of the Higgs boson, assuming a branching fraction into tau+tau- of 100%. An interpretation of the limits within a 2HDM type II model with Standard Model particle content is given. These results impose constraints on several models that have been proposed to explain the recent BNL measurement of the muon anomalous magnetic moment.Comment: 24 pages, 9 figures, Submitted to Euro. Phys. J.

Determination of alpha_s using Jet Rates at LEP with the OPAL detector

Hadronic events produced in e+e- collisions by the LEP collider and recorded by the OPAL detector were used to form distributions based on the number of reconstructed jets. The data were collected between 1995 and 2000 and correspond to energies of 91 GeV, 130-136 GeV and 161-209 GeV. The jet rates were determined using four different jet-finding algorithms (Cone, JADE, Durham and Cambridge). The differential two-jet rate and the average jet rate with the Durham and Cambridge algorithms were used to measure alpha(s) in the LEP energy range by fitting an expression in which order alpah_2s calculations were matched to a NLLA prediction and fitted to the data. Combining the measurements at different centre-of-mass energies, the value of alpha_s (Mz) was determined to be alpha(s)(Mz)=0.1177+-0.0006(stat.)+-0.0012$(expt.)+-0.0010(had.)+-0.0032(theo.) \.Comment: 40 pages, 17 figures, Submitted to Euro. Phys. J.