Alien Registration- Farrell, Daniel P. (Millinocket, Penobscot County)

https://digitalmaine.com/alien_docs/7254/thumbnail.jp

Enhancement of the Physicochemical Properties of Pt(dien)(nucleobase) (2+) for HIVNCp7 Targeting

Physicochemical properties of coordination compounds can be exploited for molecular recognition of biomolecules. The inherent π-π stacking properties of [Pt(chelate)(N-donor)]2+([PtN4]) complexes were modulated by systematic variation of the chelate (diethylenetriamine and substituted derivatives) and N-donor (nucleobase or nucleoside) in the formally substitution-inert PtN4 coordination sphere. Approaches to target the HIV nucleocapsid protein HIVNCp7 are summarized building on (i) assessment of stacking interactions with simple tryptophan or tryptophan derivatives to (ii) the tryptophan-containing C-terminal zinc finger and (iii) to the full two-zinc finger peptide and its interactions with RNA and DNA. The xanthosine nucleoside was identified as having significantly enhanced stacking capability over guanosine. Correlation of the LUMO energies of the modified nucleobases with the DFT π-stacking energies shows that frontier orbital energies of the individual monomers can be used as a first estimate of the π-stacking strength to Trp. Cellular accumulation studies showed no significant correlation with lipophilicity of the compounds, but all compounds had very low cytotoxicity suggesting the potential for antiviral selectivity. The conceptual similarities between nucleobase alkylation and platination validates the design of formally substitution-inert coordination complexes as weak Lewis acid electrophiles for selective peptide targeting

Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

AbstractBackground: Erythropoietin (EPO), the hormone involved in red blood cell production, activates its receptor by binding to the receptor's extracellular domain and presumably dimerizing two receptor monomers to initiate signal transduction. EPO-mimetic peptides, such as EMP1, also bind and activate the receptor by dimerization. These mimetic peptides are not as potent as EPO, however. The crystal structure of the EPO receptor (EBP) bound to EMP1 reveals the formation of a complex consisting of two peptides bound to two receptors, so we sought to improve the biological activity of EPO-mimetic peptides by constructing covalent dimers of EMP1 and other peptide mimetics linked by polyethylene glycol (PEG).Results: The potency of the PEG-dimerized EPO peptide mimetics both in vitro and in vivo was improved up to 1,000-fold compared to the corresponding peptide monomers. The dinners were constructed using peptide monomers which have only one reactive amine per molecule, allowing us to conclude that the increase in potency can be attributed to a structure in which two peptides are linked through their respective amino termini to the difunctional PEG molecule. In addition, an inactive peptide was converted into a weak agonist by PEG-induced dimerization.Conclusions: The potency of previously isolated peptides that are modest agonists of the EPO receptor was dramatically increased by PEG-induced dimerization. The EPO receptor is thought to be dimerized during activation, so our results are consistent with the proposed 2:2 receptor : peptide stoichiometry. The conversion of an inactive peptide into an agonist further supports the idea that dimerization can mediate receptor activation

Mainstreaming domestic and gender-based violence into sociology and the criminology of violence

Sociological and criminological views of domestic and gender-based violencegenerally either dismiss it as not worthy of consideration, or focus on specificgroups of offenders and victims (male youth gangs, partner violence victims). Inthis paper, we take a holistic approach to violence, extending the definition fromthat commonly in use to encompass domestic violence and sexual violence. Weoperationalize that definition by using data from the latest sweep of the CrimeSurvey for England and Wales. By so doing, we identify that violence is currentlyunder-measured and ubiquitous; that it is gendered, and that other forms of violence (family violence, acquaintance violence against women) are equally ofconcern. We argue that violence studies are an important form of activity forsociologists

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Effect of Biodiversity Changes in Disease Risk: Exploring Disease Emergence in a Plant-Virus System

The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk) is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect), and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect). Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin) under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Assessing worst case scenarios in movement demands derived from global positioning systems during international rugby union matches: Rolling averages versus fixed length epochs

The assessment of competitive movement demands in team sports has traditionally relied upon global positioning system (GPS) analyses presented as fixed-time epochs (e.g., 5–40 min). More recently, presenting game data as a rolling average has become prevalent due to concerns over a loss of sampling resolution associated with the windowing of data over fixed periods. Accordingly, this study compared rolling average (ROLL) and fixed-time (FIXED) epochs for quantifying the peak movement demands of international rugby union match-play as a function of playing position. Elite players from three different squads (n = 119) were monitored using 10 Hz GPS during 36 matches played in the 2014–2017 seasons. Players categorised broadly as forwards and backs, and then by positional sub-group (FR: front row, SR: second row, BR: back row, HB: half back, MF: midfield, B3: back three) were monitored during match-play for peak values of high-speed running (>5 m·s-1; HSR) and relative distance covered (m·min-1) over 60–300 s using two types of sample-epoch (ROLL, FIXED). Irrespective of the method used, as the epoch length increased, values for the intensity of running actions decreased (e.g., For the backs using the ROLL method, distance covered decreased from 177.4 ± 20.6 m·min-1 in the 60 s epoch to 107.5 ± 13.3 m·min-1 for the 300 s epoch). For the team as a whole, and irrespective of position, estimates of fixed effects indicated significant between-method differences across all time-points for both relative distance covered and HSR. Movement demands were underestimated consistently by FIXED versus ROLL with differences being most pronounced using 60 s epochs (95% CI HSR: -6.05 to -4.70 m·min-1, 95% CI distance: -18.45 to -16.43 m·min-1). For all HSR time epochs except one, all backs groups increased more (p < 0.01) from FIXED to ROLL than the forward groups. Linear mixed modelling of ROLL data highlighted that for HSR (except 60 s epoch), SR was the only group not significantly different to FR. For relative distance covered all other position groups were greater than the FR (p < 0.05). The FIXED method underestimated both relative distance (~11%) and HSR values (up to ~20%) compared to the ROLL method. These differences were exaggerated for the HSR variable in the backs position who covered the greatest HSR distance; highlighting important consideration for those implementing the FIXED method of analysis. The data provides coaches with a worst-case scenario reference on the running demands required for periods of 60–300 s in length. This information offers novel insight into game demands and can be used to inform the design of training games to increase specificity of preparation for the most demanding phases of matches

Assessing worst case scenarios in movement demands derived from global positioning systems during international rugby union matches: Rolling averages versus fixed length epochs

The assessment of competitive movement demands in team sports has traditionally relied upon global positioning system (GPS) analyses presented as fixed-time epochs (e.g., 5±40 min). More recently, presenting game data as a rolling average has become prevalent due to concerns over a loss of sampling resolution associated with the windowing of data over fixed periods. Accordingly, this study compared rolling average (ROLL) and fixed-time (FIXED) epochs for quantifying the peak movement demands of international rugby union match-play as a function of playing position. Elite players from three different squads (n = 119) were monitored using 10 Hz GPS during 36 matches played in the 2014±2017 seasons. Players categorised broadly as forwards and backs, and then by positional sub-group (FR: front row, SR: second row, BR: back row, HB: half back, MF: midfield, B3: back three) were monitored during match-play for peak values of high-speed running (&gt;5 m∙s5 m∙s-1; HSR) and relative distance covered (m∙min-1) over 60±300 s using two types of sample-epoch (ROLL, FIXED). Irrespective of the method used, as the epoch length increased, values for the intensity of running actions decreased (e.g., For the backs using the ROLL method, distance covered decreased from 177.4 ± 20.6 m∙min-1 in the 60 s epoch to 107.5 ± 13.3 m∙min-1 for the 300 s epoch). For the team as a whole, and irrespective of position, estimates of fixed effects indicated significant between-method differences across all time-points for both relative distance covered and HSR. Movement demands were underestimated consistently by FIXED versus ROLL with differences being most pronounced using 60 s epochs (95% CI HSR: -6.05 to -4.70 m∙min-1, 95% CI distance: -18.45 to -16.43 m∙min-1). For all HSR time epochs except one, all backs groups increased more (p