A model for orientation effects in electron‐transfer reactions

A method for solving the single‐particle Schrödinger equation with an oblate spheroidal potential of finite depth is presented. The wave functions are then used to calculate the matrix element T_BA which appears in theories of nonadiabatic electron transfer. The results illustrate the effects of mutual orientation and separation of the two centers on TBA. Trends in these results are discussed in terms of geometrical and nodal structure effects. Analytical expressions related to T_BA for states of spherical wells are presented and used to analyze the nodal structure effects for T_BA for the spheroidal wells

sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data

Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline that analyzes CSR events and dynamics of B cells from single-cell RNA sequencing (scRNA-seq) experiments. Validated on both simulated and real data, sciCSR re-analyzes scRNA-seq alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline 'sterile' transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built to infer the dynamics and direction of CSR. Applying sciCSR on severe acute respiratory syndrome coronavirus 2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier time point in the collected time-course, the isotype distribution of B cell receptor repertoires of subsequent time points with high accuracy (cosine similarity ~0.9). Using processes specific to B cells, sciCSR identifies transitions that are often missed by conventional RNA velocity analyses and can reveal insights into the dynamics of B cell CSR during immune response

The effect of time constraint on anticipation, decision making, and option generation in complex and dynamic environments

Researchers interested in performance in complex and dynamic situations have focused on how individuals predict their opponent(s) potential courses of action (i.e., during assessment) and generate potential options about how to respond (i.e., during intervention). When generating predictive options, previous research supports the use of cognitive mechanisms that are consistent with long-term working memory (LTWM) theory (Ericsson and Kintsch in Phychol Rev 102(2):211–245, 1995; Ward et al. in J Cogn Eng Decis Mak 7:231–254, 2013). However, when generating options about how to respond, the extant research supports the use of the take-the-first (TTF) heuristic (Johnson and Raab in Organ Behav Hum Decis Process 91:215–229, 2003). While these models provide possible explanations about how options are generated in situ, often under time pressure, few researchers have tested the claims of these models experimentally by explicitly manipulating time pressure. The current research investigates the effect of time constraint on option-generation behavior during the assessment and intervention phases of decision making by employing a modified version of an established option-generation task in soccer. The results provide additional support for the use of LTWM mechanisms during assessment across both time conditions. During the intervention phase, option-generation behavior appeared consistent with TTF, but only in the non-time-constrained condition. Counter to our expectations, the implementation of time constraint resulted in a shift toward the use of LTWM-type mechanisms during the intervention phase. Modifications to the cognitive-process level descriptions of decision making during intervention are proposed, and implications for training during both phases of decision making are discussed

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies1 in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease2. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function3,4. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases

The school policy, social, and physical environment and change in adolescent physical activity: An exploratory analysis using the LASSO.

PURPOSE: We examined the association between the school policy, social and physical environment and change in adolescent physical activity (PA) and explored how sex and socioeconomic status modified potential associations. METHODS: Data from the GoActive study were used for these analyses. Participants were adolescents (n = 1765, mean age±SD 13.2±0.4y) from the East of England, UK. Change in longitudinal accelerometer assessed moderate-to-vigorous physical activity (MVPA) was the outcome. School policy, social and physical environment features (n = 267) were exposures. The least absolute shrinkage and selection operator variable selection method (LASSO) was used to determine exposures most relevant to the outcome. Exposures selected by the LASSO were added to a multiple linear regression model with estimates of change in min/day of MVPA per 1-unit change in each exposure reported. Post-hoc analyses, exploring associations between change in variables selected by the LASSO and change in MVPA, were undertaken to further explain findings. FINDINGS: No school policy or physical environment features were selected by the LASSO as predictors of change in MVPA. The LASSO selected two school social environment variables (participants asking a friend to do physical activity; friend asking a participant to do physical activity) as potential predictors of change in MVPA but no significant associations were found in subsequent linear regression models for all participants (β [95%CI] -1.01 [-2.73;0.71] and 0.65 [-2.17;0.87] min/day respectively). In the post-hoc analyses, for every unit increase in change in participants asking a friend to do PA and change in a friend asking participants to do PA, an increase in MVPA of 2.78 (1.55;4.02) and 1.80 (0.48;3.11) min/day was predicted respectively. CONCLUSIONS: The school social environment is associated with PA during adolescence. Further exploration of how friendships during adolescence may be leveraged to support effective PA promotion in schools is warranted

Evolution of Xylan Substitution Patterns in Gymnosperms and Angiosperms: Implications for Xylan Interaction with Cellulose.

The interaction between cellulose and xylan is important for the load-bearing secondary cell wall of flowering plants. Based on the precise, evenly spaced pattern of acetyl and glucuronosyl (MeGlcA) xylan substitutions in eudicots, we recently proposed that an unsubstituted face of xylan in a 2-fold helical screw can hydrogen bond to the hydrophilic surfaces of cellulose microfibrils. In gymnosperm cell walls, any role for xylan is unclear, and glucomannan is thought to be the important cellulose-binding polysaccharide. Here, we analyzed xylan from the secondary cell walls of the four gymnosperm lineages (Conifer, Gingko, Cycad, and Gnetophyta). Conifer, Gingko, and Cycad xylan lacks acetylation but is modified by arabinose and MeGlcA. Interestingly, the arabinosyl substitutions are located two xylosyl residues from MeGlcA, which is itself placed precisely on every sixth xylosyl residue. Notably, the Gnetophyta xylan is more akin to early-branching angiosperms and eudicot xylan, lacking arabinose but possessing acetylation on alternate xylosyl residues. All these precise substitution patterns are compatible with gymnosperm xylan binding to hydrophilic surfaces of cellulose. Molecular dynamics simulations support the stable binding of 2-fold screw conifer xylan to the hydrophilic face of cellulose microfibrils. Moreover, the binding of multiple xylan chains to adjacent planes of the cellulose fibril stabilizes the interaction further. Our results show that the type of xylan substitution varies, but an even pattern of xylan substitution is maintained among vascular plants. This suggests that 2-fold screw xylan binds hydrophilic faces of cellulose in eudicots, early-branching angiosperm, and gymnosperm cell walls.This work was supported by the Leverhulme Trust Centre for Natural Material Innovation (MBW, PD), The Low Carbon Energy University Alliance (AL), BBSRC Grant: BB/G016240/1 BBSRC Sustainable Bioenergy Centre cell wall sugars (TT, PD) and the Sao Paulo Research Foundation (RLS, CSP, MSS, TCFG) (Grants 2013/08293-7, 2014/10448-1 and 2015/25031-1)

The pattern of xylan acetylation suggests xylan may interact with cellulose microfibrils as a twofold helical screw in the secondary plant cell wall of Arabidopsis thaliana.

The interaction between xylan and cellulose microfibrils is important for secondary cell wall properties in vascular plants; however, the molecular arrangement of xylan in the cell wall and the nature of the molecular bonding between the polysaccharides are unknown. In dicots, the xylan backbone of β-(1,4)-linked xylosyl residues is decorated by occasional glucuronic acid, and approximately one-half of the xylosyl residues are O-acetylated at C-2 or C-3. We recently proposed that the even, periodic spacing of GlcA residues in the major domain of dicot xylan might allow the xylan backbone to fold as a twofold helical screw to facilitate alignment along, and stable interaction with, cellulose fibrils; however, such an interaction might be adversely impacted by random acetylation of the xylan backbone. Here, we investigated the arrangement of acetyl residues in Arabidopsis xylan using mass spectrometry and NMR. Alternate xylosyl residues along the backbone are acetylated. Using molecular dynamics simulation, we found that a twofold helical screw conformation of xylan is stable in interactions with both hydrophilic and hydrophobic cellulose faces. Tight docking of xylan on the hydrophilic faces is feasible only for xylan decorated on alternate residues and folded as a twofold helical screw. The findings suggest an explanation for the importance of acetylation for xylan-cellulose interactions, and also have implications for our understanding of cell wall molecular architecture and properties, and biological degradation by pathogens and fungi. They will also impact strategies to improve lignocellulose processing for biorefining and bioenergy.The work conducted by TT and NN was supported by a grant from the BBSRC: BB/G016240/1 BBSRC Sustainable Energy Centre Cell Wall Sugars Programme (BSBEC) to PD and DNB. The work of PD was supported by the European Community’s Seventh Framework Programme SUNLIBB (FP7/2007-2013) under the grant agreement #251132. The NMR facility infrastructure was supported by the BBSRC and the Wellcome Trust. TCFG thanks CNPq (Brazil) for a graduate fellowship (grant # 140978/2009-7). MSS thanks CEPROBIO (grant # 490022/2009- 0) and FAPESP for funding (grant #2013/08293-7).This is the accepted version of the following article: "Busse-Wicher, M; Gomes, T.C.F; Tryfona, T; Nikolovski, N; Stott, K; Grantham, N.J; Bolam, D.N; Skaf, M.S; Dupree, P. (2014) "The pattern of xylan acetylation suggests xylan may interact with cellulose microfibrils as a two-fold helical screw in the secondary plant cell wall of Arabidopsis thaliana." The Plant Journal. Accepted article [electronic] 10.1111/tpj.12575", which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/tpj.12575/abstrac

Stereotyping starlings are more 'pessimistic'.

Negative affect in humans and animals is known to cause individuals to interpret ambiguous stimuli pessimistically, a phenomenon termed 'cognitive bias'. Here, we used captive European starlings (Sturnus vulgaris) to test the hypothesis that a reduction in environmental conditions, from enriched to non-enriched cages, would engender negative affect, and hence 'pessimistic' biases. We also explored whether individual differences in stereotypic behaviour (repetitive somersaulting) predicted 'pessimism'. Eight birds were trained on a novel conditional discrimination task with differential rewards, in which background shade (light or dark) determined which of two covered dishes contained a food reward. The reward was small when the background was light, but large when the background was dark. We then presented background shades intermediate between those trained to assess the birds' bias to choose the dish associated with the smaller food reward (a 'pessimistic' judgement) when the discriminative stimulus was ambiguous. Contrary to predictions, changes in the level of cage enrichment had no effect on 'pessimism'. However, changes in the latency to choose and probability of expressing a choice suggested that birds learnt rapidly that trials with ambiguous stimuli were unreinforced. Individual differences in performance of stereotypies did predict 'pessimism'. Specifically, birds that somersaulted were more likely to choose the dish associated with the smaller food reward in the presence of the most ambiguous discriminative stimulus. We propose that somersaulting is part of a wider suite of behavioural traits indicative of a stress response to captive conditions that is symptomatic of a negative affective state

A cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of the GoActive intervention to increase physical activity among adolescents aged 13-14 years.

INTRODUCTION: Adolescent physical activity promotion is rarely effective, despite adolescence being critical for preventing physical activity decline. Low adolescent physical activity is likely to last into adulthood, increasing health risks. The Get Others Active (GoActive) intervention is evidence-based and was developed iteratively with adolescents and teachers. This intervention aims to increase physical activity through increased peer support, self-efficacy, group cohesion, self-esteem and friendship quality, and is implemented using a tiered-leadership system. We previously established feasibility in one school and conducted a pilot randomised controlled trial (RCT) in three schools. METHODS AND ANALYSIS: We will conduct a school-based cluster RCT (CRCT) in 16 secondary schools targeting all year 9 students (n=2400). In eight schools, GoActive will run for two terms: weekly facilitation support from a council-funded intervention facilitator will be offered in term 1, with more distant support in term 2. Tutor groups choose two weekly activities, encouraged by older adolescent mentors and weekly peer leaders. Students gain points for trying new activities; points are entered into a between-class competition. Outcomes will be assessed at baseline, interim (week 6), postintervention (week 14-16) and 10-month follow-up (main outcome). The primary outcome will be change from baseline in daily accelerometer-assessed moderate-to-vigorous physical activity. Secondary outcomes include accelerometer-assessed activity intensities on weekdays/weekends; self-reported physical activity and psychosocial outcomes; cost-effectiveness and cost-utility analyses; mixed-methods process evaluation integrating information from focus groups and participation logs/questionnaires. ETHICS AND DISSEMINATION: Ethical approval for the conduct of the study was gained from the University of Cambridge Psychology Research Ethics Committee. Given the lack of rigorously evaluated interventions, and the inclusion of objective measurement of physical activity, long-term follow-up and testing of causal pathways, the results of a CRCT of the effectiveness and cost-effectiveness of GoActive are expected to add substantially to the limited evidence on adolescent physical activity promotion. Workshops will be held with key stakeholders including students, parents, teachers, school governors and government representatives to discuss plans for wider dissemination of the intervention. TRIAL REGISTRATION NUMBER: ISRCTN31583496

Role of the employment status and education of mothers in the prevalence of intestinal parasitic infections in Mexican rural schoolchildren

<p><b>Background:</b> Intestinal parasitic infections are a public health problem in developing countries such as Mexico. As a result, two governmental programmes have been implemented: a) "National Deworming Campaign" and b) "Opportunities" aimed at maternal care. However, both programmes are developed separately and their impact is still unknown. We independently investigated whether a variety of socio-economic factors, including maternal education and employment levels, were associated with intestinal parasite infection in rural school children.</p> <p><b>Methods:</b> This cross-sectional study was conducted in 12 rural communities in two Mexican states. The study sites and populations were selected on the basis of the following traits: a) presence of activities by the national administration of albendazole, b) high rates of intestinal parasitism, c) little access to medical examination, and d) a population having less than 2,500 inhabitants. A total of 507 schoolchildren (mean age 8.2 years) were recruited and 1,521 stool samples collected (3 per child). Socio-economic information was obtained by an oral questionnaire. Regression modelling was used to determine the association of socio-economic indicators and intestinal parasitism.</p> <p><b>Results:</b> More than half of the schoolchildren showed poliparasitism (52%) and protozoan infections (65%). The prevalence of helminth infections was higher in children from Oaxaca (53%) than in those from Sinaloa (33%) (p < 0.0001). Giardia duodenalis and Hymenolepis nana showed a high prevalence in both states. Ascaris lumbricoides, Trichuris trichiura and Entamoeba hystolitica/dispar showed low prevalence. Children from lower-income families and with unemployed and less educated mothers showed higher risk of intestinal parasitism (odds ratio (OR) 6.0, 95% confidence interval (CI) 1.6–22.6; OR 4.5, 95% CI 2.5–8.2; OR 3.3, 95% CI 1.5–7.4 respectively). Defecation in open areas was also a high risk factor for infection (OR 2.4, 95% CI 2.0–3.0).</p> <p><b>Conclusion:</b> Intestinal parasitism remains an important public health problem in Sinaloa (north-western Mexico) and Oaxaca (south-eastern Mexico). Lower income, defecation in open areas, employment status and a lower education level of mothers were the significant factors related to these infections. We conclude that mothers should be involved in health initiatives to control intestinal parasitism in Mexico.</p&gt