Rotational dynamics of optically trapped polymeric nanofibers

The optical trapping of polymeric nanofibers and the characterization of the rotational dynamics are reported. A strategy to apply a torque to a polymer nanofiber, by tilting the trapped fibers using a symmetrical linear polarized Gaussian beam is demonstrated. Rotation frequencies up to 10 Hz are measured, depending on the trapping power, the fiber length and the tilt angle. A comparison of the experimental rotation frequencies in the different trapping configurations with calculations based on optical trapping and rotation of linear nanostructures through a T-Matrix formalism, accurately reproduce the measured data, providing a comprehensive description of the trapping and rotation dynamics.Comment: (21 pages, 5 figures

Epigenetic Landscape in Leukemia and Its Impact on Antileukemia Therapeutics

Epigenomic landscape mapping in leukemia cells supports germ line mutation studies to understand pathogenicity and treatment plans. The differential regulation of gene expression and heterogeneity between cell types during hematopoiesis and leukemia development is important in understanding oncogenesis. Oncogenesis in leukemia occurs at both genomic and epigenomic levels in order for hematological cells to evade lineage commitment. To ensure that therapies target the entire malignancy, it is important to consider the regulatory network that drives malignancy caused by mutations. Therapies tailored to respond to a patient-specific epigenetic landscape have the potential to minimize risk in administering chemotherapies that may not work. In this chapter, a focused study on childhood acute lymphoblastic leukemia (ALL) will be used as an example of the current research in the field of epigenetics in leukemia and the impact it carries on our understanding of the disease and treatment plans

Optogenetic acidification of synaptic vesicles and lysosomes

Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes

Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality – a systematic review and dose-response meta-analysis of prospective studies

Background: Questions remain about the strength and shape of the dose-response relationship between fruit and vegetable intake and risk of cardiovascular disease, cancer and mortality, and the effects of specific types of fruit and vegetables. We conducted a systematic review and meta-analysis to clarify these associations. Methods: PubMed and Embase were searched up to 29 September 2016. Prospective studies of fruit and vegetable intake and cardiovascular disease, total cancer and all-cause mortality were included. Summary relative risks (RRs) were calculated using a random effects model, and the mortality burden globally was estimated; 95 studies (142 publications) were included. Results: For fruits and vegetables combined, the summary RR per 200 g/day was 0.92 [95% confidence interval (CI): 0.90–0.94, I2 = 0%, n = 15] for coronary heart disease, 0.84 (95% CI: 0.76–0.92, I2 = 73%, n = 10) for stroke, 0.92 (95% CI: 0.90–0.95, I2 = 31%, n = 13) for cardiovascular disease, 0.97 (95% CI: 0.95–0.99, I2 = 49%, n = 12) for total cancer and 0.90 (95% CI: 0.87–0.93, I2 = 83%, n = 15) for all-cause mortality. Similar associations were observed for fruits and vegetables separately. Reductions in risk were observed up to 800 g/day for all outcomes except cancer (600 g/day). Inverse associations were observed between the intake of apples and pears, citrus fruits, green leafy vegetables, cruciferous vegetables, and salads and cardiovascular disease and all-cause mortality, and between the intake of green-yellow vegetables and cruciferous vegetables and total cancer risk. An estimated 5.6 and 7.8 million premature deaths worldwide in 2013 may be attributable to a fruit and vegetable intake below 500 and 800 g/day, respectively, if the observed associations are causal. Conclusions: Fruit and vegetable intakes were associated with reduced risk of cardiovascular disease, cancer and all-cause mortality. These results support public health recommendations to increase fruit and vegetable intake for the prevention of cardiovascular disease, cancer, and premature mortality

A competitive integration model of exogenous and endogenous eye movements

We present a model of the eye movement system in which the programming of an eye movement is the result of the competitive integration of information in the superior colliculi (SC). This brain area receives input from occipital cortex, the frontal eye fields, and the dorsolateral prefrontal cortex, on the basis of which it computes the location of the next saccadic target. Two critical assumptions in the model are that cortical inputs are not only excitatory, but can also inhibit saccades to specific locations, and that the SC continue to influence the trajectory of a saccade while it is being executed. With these assumptions, we account for many neurophysiological and behavioral findings from eye movement research. Interactions within the saccade map are shown to account for effects of distractors on saccadic reaction time (SRT) and saccade trajectory, including the global effect and oculomotor capture. In addition, the model accounts for express saccades, the gap effect, saccadic reaction times for antisaccades, and recorded responses from neurons in the SC and frontal eye fields in these tasks. © The Author(s) 2010

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Disparities in the frequency of fruit and vegetable consumption by socio-demographic and lifestyle characteristics in Canada

<p>Abstract</p> <p>Background</p> <p>The health benefits of adequate fruit and vegetable (F&V) consumption are significant and widely documented. However, many individuals self-report low F&V consumption frequency per day. This paper examines the disparities in the frequency of F&V consumption by socio-demographic and lifestyle characteristics.</p> <p>Method</p> <p>This study uses a representative sample of 93,719 individuals from the Canadian Community Health Survey (2007). A quantile regression model is estimated in order to capture the differential effects of F&V determinants across the conditional distribution of F&V consumption.</p> <p>Results</p> <p>The conditional and unconditional analyses reveal the existence of a socioeconomic gradient in F&V consumption frequency, in which the low income-education groups consume F&V less frequently than the high income-education groups. We also find significant disparities in F&V consumption frequency by demographic and lifestyle characteristics. The frequency of F&V consumption is relatively lower among: males, those in middle age, singles, smokers, individuals with weak social interaction and households with no children. The quantile regression results show that the association between F&V consumption frequency, and socio-demographic and lifestyle factors varies significantly along the conditional F&V consumption distribution. In particular, individual educational attainment is positively and significantly associated with F&V consumption frequency across different parts of the F&V distribution, while the income level matters only over the lower half of the distribution. F&V consumption follows a U-shaped pattern across the age categories. Those aged 30-39, 40-49 and 50-59 years consume F&V less frequently than those aged 18-29 years. The smallest F&V consumption is among the middle aged adults (40-49).</p> <p>Conclusions</p> <p>Understanding the socio-demographic and lifestyle characteristics of individuals with low F&V consumption frequency could increase the effectiveness of policies aimed at promoting F&V consumption. The differential effects of individual characteristics along the F&V consumption distribution suggest the need for a multifaceted approach to address the variation in F&V consumption frequency.</p

Inflammatory Manifestations of Experimental Lymphatic Insufficiency

BACKGROUND: Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. METHODS AND FINDINGS: We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response. CONCLUSIONS: We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency