A universal method for analyzing copolymer growth

Polymers consisting of more than one type of monomer, known as copolymers, are vital to both living and synthetic systems. Copolymerisation has been studied theoretically in a number of contexts, often by considering a Markov process in which monomers are added or removed from the growing tip of a long copolymer. To date, the analysis of the most general models of this class has necessitated simulation. We present a general method for analysing such processes without resorting to simulation. Our method can be applied to models with an arbitrary network of sub-steps prior to addition or removal of a monomer, including non-equilibrium kinetic proofreading cycles. Moreover, the approach allows for a dependency of addition and removal reactions on the neighbouring site in the copolymer, and thermodynamically self-consistent models in which all steps are assumed to be microscopically reversible. Using our approach, thermodynamic quantities such as chemical work; kinetic quantities such as time taken to grow; and statistical quantities such as the distribution of monomer types in the growing copolymer can be derived either analytically or numerically directly from the model definition

Associations Between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress

TeV scale mirage mediation in NMSSM

We study the next-to-minimal supersymmetric standard model. We consider soft supersymmetry breaking parameters, which are induced by the mirage mediation mechanism of supersymmetry breaking. We concentrate on the mirage mediation, where the so-called mirage scale is the TeV scale. In this scenario, we can realize the up-type Higgs soft mass of O(200) GeV, while other masses such as gaugino masses and stop masses are heavy such as 1 TeV or more. Cancellation between the effective \mu-term and the down-type Higgs soft mass ameliorates the fine-tuning in the electroweak symmetry breaking even for \mu=O(500) GeV. The mixing between the doublet and singlet Higgs bosons is suppressed by (\lambda/\kappa)/tan\beta. Then the lightest doublet Higgs mass naturally reaches 125 GeV lifted by the new quartic coupling. The higgsino and singlino are light and their linear combination is the lightest superparticle.Comment: 24 pages, 24 figures, Numerical analysis is replaced with the version calculated by NMSSMTools. Comments and references are added on the suppressed doublet-singlet mixing and cases in which the 125 GeV boson is the 2nd lightest CP-even scalar. The version accepted by JHE

May Measurement Month 2017: analysis of the blood pressure screening results in Argentina-Americas

Hypertension is a growing concern worldwide, causing over 10 million deaths each year. The prevalence of high blood pressure (BP) in Argentina is 36.3% and 38% of these are unaware of their disease. Half of the hypertensive patients are on pharmacological treatment and only a quarter of them are controlled. The International Society of Hypertension initiated the May Measurement Month (MMM) as a global campaign to raise awareness on high BP that may also serve as a temporary solution to the lack of global screening programs worldwide. A volunteer cross-sectional survey was carried out in May 2017 across 56 health centres. Blood pressure measurement, definition of hypertension and statistical analysis followed the MMM protocol. For this awareness campaign, the Argentine Society of Hypertension coined the slogan: 'Know and control your blood pressure'. A total of 32 346 individuals aged at least 18 years were screened during MMM17. After imputation, 16 263 (50.4%) were hypertensive. Of the 12 156 receiving antihypertensive medication 5400 (44.4%) still had uncontrolled BP. MMM17, called in our country 'Know and control your blood pressure', was the largest BP screening campaign done in Argentina. Almost 6 out of 10 hypertensive patients were either not on treatment or were not controlled to the BP goal. These results suggest that appropriate screening can help to identify a significant number of people with high BP

Tetrahydrobiopterin modulates ubiquitin conjugation to UBC13/UBE2N and proteasome activity by S-nitrosation

Nitric Oxide (NO) is an intracellular signalling mediator, which affects many biological processes via the posttranslational modification of proteins through S-nitrosation. The availability of NO and NOS-derived reactive oxygen species (ROS) from enzymatic uncoupling are determined by the NO synthase cofactor Tetrahydrobiopterin (BH4). Here, using a global proteomics “biotin-switch” approach, we identified components of the ubiquitin-proteasome system to be altered via BH4-dependent NO signalling by protein S-nitrosation. We show S-nitrosation of ubiquitin conjugating E2 enzymes, in particular the catalytic residue C87 of UBC13/UBE2N, leading to impaired polyubiquitylation by interfering with the formation of UBC13~Ub thioester intermediates. In addition, proteasome cleavage activity in cells also seems to be altered by S-nitrosation, correlating with the modification of cysteine residues within the 19S regulatory particle and catalytic subunits of the 20S complex. Our results highlight the widespread impact of BH4 on downstream cellular signalling as evidenced by the effect of a perturbed BH4-dependent NO-Redox balance on critical processes within the ubiquitin-proteasome system (UPS). These studies thereby uncover a novel aspect of NO associated modulation of cellular homeostasis

Probing natural SUSY from stop pair production at the LHC

We consider the natural supersymmetry scenario in the framework of the R-parity conserving minimal supersymmetric standard model (called natural MSSM) and examine the observability of stop pair production at the LHC. We first scan the parameters of this scenario under various experimental constraints, including the SM-like Higgs boson mass, the indirect limits from precision electroweak data and B-decays. Then in the allowed parameter space we study the stop pair production at the LHC followed by the stop decay into a top quark plus a lightest neutralino or into a bottom quark plus a chargino. From detailed Monte Carlo simulations of the signals and backgrounds, we find the two decay modes are complementary to each other in probing the stop pair production, and the LHC with $\sqrt{s}= 14$ TeV and 100 $fb^{-1}$ luminosity is capable of discovering the stop predicted in natural MSSM up to 450 GeV. If no excess events were observed at the LHC, the 95% C.L. exclusion limits of the stop masses can reach around 537 GeV.Comment: 19 pages, 10 figures, version accepted by JHE

Nut production in Bertholletia excelsa across a logged forest mosaic: implications for multiple forest use

Although many examples of multiple-use forest management may be found in tropical smallholder systems, few studies provide empirical support for the integration of selective timber harvesting with non-timber forest product (NTFP) extraction. Brazil nut (Bertholletia excelsa, Lecythidaceae) is one of the world’s most economically-important NTFP species extracted almost entirely from natural forests across the Amazon Basin. An obligate out-crosser, Brazil nut flowers are pollinated by large-bodied bees, a process resulting in a hard round fruit that takes up to 14 months to mature. As many smallholders turn to the financial security provided by timber, Brazil nut fruits are increasingly being harvested in logged forests. We tested the influence of tree and stand-level covariates (distance to nearest cut stump and local logging intensity) on total nut production at the individual tree level in five recently logged Brazil nut concessions covering about 4000 ha of forest in Madre de Dios, Peru. Our field team accompanied Brazil nut harvesters during the traditional harvest period (January-April 2012 and January-April 2013) in order to collect data on fruit production. Three hundred and ninety-nine (approximately 80%) of the 499 trees included in this study were at least 100 m from the nearest cut stump, suggesting that concessionaires avoid logging near adult Brazil nut trees. Yet even for those trees on the edge of logging gaps, distance to nearest cut stump and local logging intensity did not have a statistically significant influence on Brazil nut production at the applied logging intensities (typically 1–2 timber trees removed per ha). In one concession where at least 4 trees ha-1 were removed, however, the logging intensity covariate resulted in a marginally significant (0.09) P value, highlighting a potential risk for a drop in nut production at higher intensities. While we do not suggest that logging activities should be completely avoided in Brazil nut rich forests, when a buffer zone cannot be observed, low logging intensities should be implemented. The sustainability of this integrated management system will ultimately depend on a complex series of socioeconomic and ecological interactions. Yet we submit that our study provides an important initial step in understanding the compatibility of timber harvesting with a high value NTFP, potentially allowing for diversification of forest use strategies in Amazonian Perù

A locus at 19q13.31 significantly reduces the <em>ApoE</em> ε4 risk for Alzheimer\u27s Disease in African Ancestry

Copyright: \ua9 2022 Rajabli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention