An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis

Caesarean section delivery and childhood obesity in a British longitudinal cohort study

Background: Several studies reported an association between Caesarean section (CS) birth and childhood obesity. However, there are several limitations in the current literature. These include an inability to distinguish between planned and emergency CS, small study sample sizes and not adjusting for pre-pregnancy body-mass-index (BMI). We examined the association between CS delivery and childhood obesity using the United Kingdom Millennium Cohort Study (MCS). Methods: Mother-infant pairs were recruited into the MCS. Use of sampling weights ensured the sample was representative of the population. The exposure was categorised as normal vaginal delivery (VD) [reference], assisted VD, planned CS and emergency CS. Childhood obesity prevalence, at age three, five, seven, eleven and fourteen years was calculated using the International Obesity Taskforce criteria. Mixed-effects linear regression models were fitted with associations adjusted for several potential confounders like maternal age, pre-pregnancy BMI, education and infant macrosomia. Linear regression models were fitted evaluating body fat percentage (BF%), at age seven and fourteen years. Results: Of the 18,116 infants, 3872 (21.4%) were delivered by CS; 9.2% by planned CS. Obesity prevalence was 5.4%, 5.7%, 6.5%, 7.1% and 7.6% at age three, five, seven, eleven and fourteen years respectively. The mixed-effects linear regression model showed no association between planned (adjusted mean difference = 0.00; [95% confidence interval (CI) -0.10; 0.10], p-value = 0.97) or emergency CS (adjusted mean difference = 0.08; [95% CI -0.01; 0.17], p-value = 0.09) and child BMI. At age seven years, there was no association between planned CS and BF% (adjusted mean difference = 0.13; [95% CI -0.23; 0.49]); there was no association at age fourteen years. Conclusions: Infants born by planned CS did not have a significantly higher BMI or BF% compared to those born by normal VD. This may suggest that the association, described in the literature, could be due to the indications/reasons for CS birth or residual confounding

A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Therapeutic Surgical Management of Palpable Melanoma Groin Metastases: Superficial or Combined Superficial and Deep Groin Lymph Node Dissection

Item does not contain fulltextBACKGROUND: Management of patients with clinically detectable lymph node metastasis to the groin is by ilioinguinal or combined superficial and deep groin dissection (CGD) according to most literature, but in practice superficial groin dissection (SGD) only is still performed in some centers. The aim of this study is to evaluate the experience in CGD versus SGD patients in our center. METHODS: Between 1991 and 2009, 121 therapeutic CGD and 48 SGD were performed in 169 melanoma patients with palpable groin metastases at our institute. Median follow-up was 20 and, for survivors, 45 months. RESULTS: In this heterogeneous group of patients, overall (OS) and disease-free survival, local control rates, and morbidity rates were not significantly different between CGD and SGD patients. However, CGD patients had a trend towards more chronic lymphedema. Superficial lymph node ratio, the number of positive superficial lymph nodes, and the presence of deep nodes were prognostic factors for survival. CGD patients with involved deep lymph nodes (24.8%) had estimated 5-year OS of 12% compared with 40% with no involved deep lymph nodes (p = 0.001). Preoperative computed tomography (CT) scan had high negative predictive value of 91% for detection of pelvic nodal involvement. CONCLUSIONS: This study demonstrated that survival and local control do not differ for patients with palpable groin metastases treated by CGD or SGD. Patients without pathological iliac nodes on CT might safely undergo SGD, while CGD might be reserved for patients with multiple positive nodes on SGD and/or positive deep nodes on CT scan

Display of probability densities for data from a continuous distribution

Based on cumulative distribution functions, Fourier series expansion and Kolmogorov tests, we present a simple method to display probability densities for data drawn from a continuous distribution. It is often more efficient than using histograms.Comment: 5 pages, 4 figures, presented at Computer Simulation Studies XXIV, Athens, GA, 201

Risk factors for oral mucositis in paediatric oncology patients receiving alkylant chemotherapy

BACKGROUND: We describe the risk indicators for oral mucositis (OM) in paediatric oncology patients hospitalised in the Institut Gustave Roussy (Villejuif-Paris) and treated with alkylant chemotherapy with autologous peripheral blood progenitor cells. METHODS: The sample was selected using PIGAS software. Three groups of subjects received different chemotherapy regimens: A. Melphalan, B. Busulfan and C. other alkylant protocols. The degree of mucositis was recorded by CTC version 2.0 (Common Toxicity Criteria). Descriptive statistics were performed. The association between mucositis and risk indicator variables was tested using a χ(2 )test. The association between case status and covariates was tested using unconditional logistic regression analysis. RESULTS: Of the 337 children enrolled, 241 showed mucositis (group 1) and 96 did not show mucositis (group 2) during alkylant chemotherapy. There was a higher prevalence of male patients in both groups. The three different chemotherapy regimen groups are correlated with the appearance of oral mucositis (χ(2 )= 22.42, p < 0.01). Weight loss was higher in group 1 (χ(2 )= 6.31, p = 0.01). The duration of aplasia was lower in the Busulfan protocol (7.5 days) than in the Melphalan group (9.3 days) or the other regimens (8.6 days). The use of Bufulfan(® )was directly associated with case status (presence of oral mucositis): odds ratio [OR] = 2.1 and confidence interval [95%CI] = 1.3–3.0. Also, occurrences of germinal tumours and secondary bacterial infections were directly linked with case status: [OR] = 1.4 and 1.8, confidence interval [95%CI] = 1.2 – 1.7 and 1.1 – 2.5, respectively. CONCLUSION: The presence of OM was associated with the three different chemotherapy regimens considered; in particularly patients treated with Busulfan had the highest prevalence