Quantifying evolutionary constraints on B cell affinity maturation

The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on B cell receptors using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.Comment: Previously entitled "Substitution and site-specific selection driving B cell affinity maturation is consistent across individuals

Abundance-weighted phylogenetic diversity measures distinguish microbial community states and are robust to sampling depth

In microbial ecology studies, the most commonly used ways of investigating alpha (within-sample) diversity are either to apply count-only measures such as Simpson's index to Operational Taxonomic Unit (OTU) groupings, or to use classical phylogenetic diversity (PD), which is not abundance-weighted. Although alpha diversity measures that use abundance information in a phylogenetic framework do exist, but are not widely used within the microbial ecology community. The performance of abundance-weighted phylogenetic diversity measures compared to classical discrete measures has not been explored, and the behavior of these measures under rarefaction (sub-sampling) is not yet clear. In this paper we compare the ability of various alpha diversity measures to distinguish between different community states in the human microbiome for three different data sets. We also present and compare a novel one-parameter family of alpha diversity measures, BWPD_\theta, that interpolates between classical phylogenetic diversity (PD) and an abundance-weighted extension of PD. Additionally, we examine the sensitivity of these phylogenetic diversity measures to sampling, via computational experiments and by deriving a closed form solution for the expectation of phylogenetic quadratic entropy under re-sampling. In all three of the datasets considered, an abundance-weighted measure is the best differentiator between community states. OTU-based measures, on the other hand, are less effective in distinguishing community types. In addition, abundance-weighted phylogenetic diversity measures are less sensitive to differing sampling intensity than their unweighted counterparts. Based on these results we encourage the use of abundance-weighted phylogenetic diversity measures, especially for cases such as microbial ecology where species delimitation is difficult.Comment: Submitted to Peer

Whole genome sequence analysis reveals the broad distribution of the RtxA type 1 secretion system and four novel putative type 1 secretion systems throughout the Legionella genus.

Type 1 secretion systems (T1SSs) are broadly distributed among bacteria and translocate effectors with diverse function across the bacterial cell membrane. Legionella pneumophila, the species most commonly associated with Legionellosis, encodes a T1SS at the lssXYZABD locus which is responsible for the secretion of the virulence factor RtxA. Many investigations have failed to detect lssD, the gene encoding the membrane fusion protein of the RtxA T1SS, in non-pneumophila Legionella, which has led to the assumption that this system is a virulence factor exclusively possessed by L. pneumophila. Here we discovered RtxA and its associated T1SS in a novel Legionella taurinensis strain, leading us to question whether this system may be more widespread than previously thought. Through a bioinformatic analysis of publicly available data, we classified and determined the distribution of four T1SSs including the RtxA T1SS and four novel T1SSs among diverse Legionella spp. The ABC transporter of the novel Legionella T1SS Legionella repeat protein secretion system shares structural similarity to those of diverse T1SS families, including the alkaline protease T1SS in Pseudomonas aeruginosa. The Legionella bacteriocin (1-3) secretion systems T1SSs are novel putative bacteriocin transporting T1SSs as their ABC transporters include C-39 peptidase domains in their N-terminal regions, with LB2SS and LB3SS likely constituting a nitrile hydratase leader peptide transport T1SSs. The LB1SS is more closely related to the colicin V T1SS in Escherichia coli. Of 45 Legionella spp. whole genomes examined, 19 (42%) were determined to possess lssB and lssD homologs. Of these 19, only 7 (37%) are known pathogens. There was no difference in the proportions of disease associated and non-disease associated species that possessed the RtxA T1SS (p = 0.4), contrary to the current consensus regarding the RtxA T1SS. These results draw into question the nature of RtxA and its T1SS as a singular virulence factor. Future studies should investigate mechanistic explanations for the association of RtxA with virulence

Cognitive-behaviour therapy and skilled motor performance in adults with chronic tic disorder

The first aim of the present study was to compare performance of people with tic disorders (TD) and controls on executive function and a range of skilled motor tests requiring complex performance, guided movements, hand co-ordination, and fine control of steadiness. The second aim was to investigate the effect of cognitive behaviour therapy (CBT) on motor performance. A total of 55 patients with TD were recruited at baseline from participants in a behavioural management programme. A comparison group of 55 patients suffering from a variety of habit disorders (HD) involving complex manual movements, were matched on age and level of education to 34 non-psychiatric controls. Participants were evaluated pre- and post-treatment and post-waitlist with a neuropsychological evaluation focusing on executive function (Wisconsin Card Sorting Test, WCST) and skilled motor performance (Purdue Pegboard, Hole Steadiness Test, and the Groove Test). Results revealed WCST scores in the normal range, while motor performance differed significantly on the Purdue Pegboard Tests in both TD and HD as compared to the control group. Cognitive-behavioural treatment selectively improved motor performance in both clinical groups compared to waitlist control, and this improvement related to clinical outcome measures

Improving thermal and electrical efficiency in photovoltaic thermal systems for sustainable cooling system integration

Research into photovoltaic thermal systems is important in solar technologies as photovoltaic thermal systems are designed to produce both electrical and thermal energy, this can lead to improved performance of the overall system. The performance of photovoltaic thermal systems is based on several factors that include photovoltaic thermal materials, design, ambient temperature, inlet and outlet fluid temperature and photovoltaic cell temperature. The aim of this study is to investigate the effect of photovoltaic thermal outlet water temperatures and solar cell temperature on both electrical and thermal efficiency for different range of inlet water temperature. To achieve this, a mathematical model of a photovoltaic thermal system was developed to calculate the anticipated system performance. The factors that affect the efficiency of photovoltaic thermal collectors were discussed and the outlet fluid temperature from the photovoltaic thermal is investigated in order to reach the highest overall efficiency for the solar cooling system. An average thermal and electrical efficiency of 65% and 13.7%, respectively, was achieved and the photovoltaic thermal mathematical model was validated with experimental data from literature

Increased hypoglycemia associated with renal failure during continuous intravenous insulin infusion and specialized nutritional support

Objective: To evaluate glycemic control for critically ill, hyperglycemic trauma patients with renal failure who received concurrent intensive insulin therapy and continuous enteral (EN) or parenteral nutrition (PN). Methods: Adult trauma patients with renal failure, who were given EN or PN concurrently with continuous graduated intravenous regular human insulin (RHI) infusion for at least 3 days were evaluated. Our conventional RHI algorithm was modified for those with renal failure by allowing greater changes in blood glucose concentrations (BG) before the infusion rate was escalated. BG was determined every 1-2 hours while receiving the insulin infusion. BG control was evaluated on the day prior to RHI infusion and for a maximum of 7 days while receiving RHI. Target BG during the RHI infusion was 70 to 149 mg/dL (3.9 to 8.3 mmol/L). Glycemic control and incidence of hypoglycemia for those with renal failure were compared to a historical cohort of critically ill, hyperglycemic trauma patients without renal failure given our conventional RHI algorithm. Results: Twenty-one patients with renal failure who received the modified RHI algorithm were evaluated and compared to forty patients without renal failure given our conventional RHI algorithm. Average BG was significantly greater for those with renal failure (133 + 14 mg/dL or 7.3 + 0.7 mmol/L) compared to those without renal failure (122 + 15 mg/dL or 6.8 + 0.8 mmol/L), respectively (p \u3c 0.01). Patients with renal failure experienced worsened glycemic variability with 16.1 + 3.3 hours/day within the target BG range, 6.9 + 3.2 hours/day above the target BG range, and 1.4 + 1.1 hours below the target BG range compared to 19.6 + 4.7 hours/day (p \u3c 0.001), 3.4 + 3.0 hours/day (p \u3c 0.001), and 0.7 + 0.8 hours/day (p \u3c 0.01) for those without renal failure, respectively. Moderate hypoglycemia (\u3c 60 mg/dL or \u3c 3.3 mmol/L) occurred in 76% of patients with renal failure compared to 35% without renal failure (p \u3c 0.005). Severe hypoglycemia (BG \u3c 40 mg/dL or \u3c 2.2 mmol/L) occurred in 29% of patients with renal failure compared to none of those without renal failure (p \u3c 0.001). Conclusion: Despite receiving a modified RHI infusion, critically ill trauma patients with renal failure are at higher risk for developing hypoglycemia and experience more glycemic variability than patients without renal failure

Stimulate the Adoption of Solar PV on Nantucket

Two undersea cables provide Nantucket with electricity, but a third cable may be needed in the future to accommodate peak summer demands. To avoid this eventuality Nantucket is exploring a variety of options, including the adoption of renewable energies in conjunction with energy storage systems to enhance energy independence. The goal of our project was to assist the Nantucket Energy Office in promoting the adoption of photovoltaics on Nantucket. We conducted research, interviewed stakeholders, and distributed a survey to local residents to identify the current barriers to solar PV on Nantucket. We developed web-based promotional materials, including an interactive map, solar PV owner profiles, and a comprehensive list of FAQs, and recommended improvements to the permitting process