Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation.
The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an important chromatin modifying complex that can both acetylate and deubiquitinate histones. Sgf29 is a novel component of the SAGA complex. Here, we report the crystal structures of the tandem Tudor domains of Saccharomyces cerevisiae and human Sgf29 and their complexes with H3K4me2 and H3K4me3 peptides, respectively, and show that Sgf29 selectively binds H3K4me2/3 marks. Our crystal structures reveal that Sgf29 harbours unique tandem Tudor domains in its C-terminus. The tandem Tudor domains in Sgf29 tightly pack against each other face-to-face with each Tudor domain harbouring a negatively charged pocket accommodating the first residue alanine and methylated K4 residue of histone H3, respectively. The H3A1 and K4me3 binding pockets and the limited binding cleft length between these two binding pockets are the structural determinants in conferring the ability of Sgf29 to selectively recognize H3K4me2/3. Our in vitro and in vivo functional assays show that Sgf29 recognizes methylated H3K4 to recruit the SAGA complex to its targets sites and mediates histone H3 acetylation, underscoring the importance of Sgf29 in gene regulation.


Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants.
Several indicators suggest that food allergy in infants is common and possibly increasing. Few studies have used oral food challenge to measure this phenomenon at the population level. To measure the prevalence of common IgE-mediated childhood food allergies in a population-based sample of 12-month-old infants by using predetermined food challenge criteria to measure outcomes. A sampling frame was used to select recruitment areas to attain a representative population base. Recruitment occurred at childhood immunization sessions in Melbourne, Australia. Infants underwent skin prick testing, and those with any sensitization (wheal size ≥ 1 mm) to 1 or more foods (raw egg, peanut, sesame, shellfish, or cow's milk) were invited to attend an allergy research clinic. Those who registered a wheal size ≥ 1 mm to raw egg, peanut, or sesame underwent oral food challenge. Amongst 2848 infants (73% participation rate), the prevalence of any sensitization to peanut was 8.9% (95% CI, 7.9-10.0); raw egg white, 16.5% (95% CI, 15.1-17.9); sesame, 2.5% (95% CI, 2.0-3.1); cow's milk, 5.6% (95% CI, 3.2-8.0); and shellfish, 0.9% (95% CI, 0.6-1.5). The prevalence of challenge-proven peanut allergy was 3.0% (95% CI, 2.4-3.8); raw egg allergy, 8.9% (95% CI, 7.8-10.0); and sesame allergy, 0.8% (95% CI, 0.5-1.1). Oral food challenges to cow's milk and shellfish were not performed. Of those with raw egg allergy, 80.3% could tolerate baked egg. More than 10% of 1-year-old infants had challenge-proven IgE-mediated food allergy to one of the common allergenic foods of infancy. The high prevalence of allergic disease in Australia requires further investigation and may be related to modifiable environmental factors.


Duration, combination and timing: the signal integration model of dendritic cell activation.
The activation of resting dendritic cells (DCs) is a crucial step in the initiation of adaptive immunity because it links peripheral events initiated by the encounter with pathogens to the activation and expansion of antigen-specific T lymphocytes in secondary lymphoid organs. It is well recognized that a wide variety of microbial products and endogenous signals can trigger DC activation, and that different DC subsets are specialized in inducing different classes of immune responses. In this review, we will focus on how different aspects of DC maturation are regulated not only by the nature of the DC maturation stimuli, but also by their duration, combination and timing, and provide an overview of how different modes of DC activation can affect T cell responses.


Kaposi's sarcoma-associated herpesvirus ORF57 protein protects viral transcripts from specific nuclear RNA decay pathways by preventing hMTR4 recruitment.
Nuclear RNAs are subject to a number of RNA decay pathways that serve quality control and regulatory functions. As a result, any virus that expresses its genes in the nucleus must have evolved mechanisms that avoid these pathways, but the how viruses evade nuclear RNA decay remains largely unknown. The multifunctional Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 (Mta) protein is required for the nuclear stability of viral transcripts. In the absence of ORF57, we show that viral transcripts are subject to degradation by two specific nuclear RNA decay pathways, PABPN1 and PAPα/γ-mediated RNA decay (PPD) in which decay factors are recruited through poly(A) tails, and an ARS2-mediated RNA decay pathway dependent on the 5' RNA cap. In transcription pulse chase assays, ORF57 appears to act primarily by inhibiting the ARS2-mediated RNA decay pathway. In the context of viral infection in cultured cells, inactivation of both decay pathways by RNAi is necessary for the restoration of ORF57-dependent viral genes produced from an ORF57-null bacmid. Mechanistically, we demonstrate that ORF57 protects viral transcripts by preventing the recruitment of the exosome co-factor hMTR4. In addition, our data suggest that ORF57 recruitment of ALYREF inhibits hMTR4 association with some viral RNAs, whereas other KSHV transcripts are stabilized by ORF57 in an ALYREF-independent fashion. In conclusion, our studies show that KSHV RNAs are subject to nuclear degradation by two specific host pathways, PPD and ARS2-mediated decay, and ORF57 protects viral transcripts from decay by inhibiting hMTR4 recruitment.


STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates.
STAT3 can be transcriptionally activated by phosphorylation of its tyrosine 705 or serine 727 residue. In mouse embryonic stem cells (mESCs), leukemia inhibitory factor (LIF) signaling maintains pluripotency by inducing JAK-mediated phosphorylation of STAT3 Y705 (pY705). However, the function of phosphorylated S727 (pS727) in mESCs remains unclear. In this study, we examined the roles of STAT3 pY705 and pS727 in regulating mESC identities, using a small molecule-based system to post-translationally modulate the quantity of transgenic STAT3 in STAT3(-/-) mESCs. We demonstrated that pY705 is absolutely required for STAT3-mediated mESC self-renewal, while pS727 is dispensable, serving only to promote proliferation and optimal pluripotency. S727 phosphorylation is regulated directly by fibroblast growth factor/Erk signaling and crucial in the transition of mESCs from pluripotency to neuronal commitment. Loss of S727 phosphorylation resulted in significantly reduced neuronal differentiation potential, which could be recovered by a S727 phosphorylation mimic. Moreover, loss of pS727 sufficed LIF to reprogram epiblast stem cells to naïve pluripotency, suggesting a dynamic equilibrium of STAT3 pY705 and pS727 in the control of mESC fate.


Genetic mapping of rust resistance genes in confection sunflower line HA-R6 and oilseed line RHA 397.
Few widely effective resistance sources to sunflower rust, incited by Puccinia helianthi Schwein., have been identified in confection sunflower (Helianthus annuus L.). The USDA inbred line HA-R6 is one of the few confection sunflower lines resistant to rust. A previous allelism test indicated that rust resistance genes in HA-R6 and RHA 397, an oilseed-type restorer line, are either allelic or closely linked; however, neither have been characterized nor molecularly mapped. The objectives of this study are (1) to locate the rust resistance genes in HA-R6 and RHA 397 on a molecular map, (2) to develop closely linked molecular markers for rust resistance diagnostics, and (3) to determine the resistance spectrum of two lines when compared with other rust-resistant lines. Two populations of 140 F2:3 families each from the crosses of HA 89, as susceptible parent, with HA-R6 and RHA 397 were inoculated with race 336 of P. helianthi in the greenhouse. The resistance genes (R-genes) in HA-R6 and RHA 397 were molecularly mapped to the lower end of linkage group 13, which encompasses a large R-gene cluster, and were designated as R 13a and R 13b, respectively. In the initial maps, SSR (simple sequence repeat) and InDel (insertion and deletion) markers revealed 2.8 and 8.2 cM flanking regions for R 13a and R 13b, respectively, linked with a common marker set of four co-segregating markers, ORS191, ORS316, ORS581, and ZVG61, in the distal side and one marker ORS464 in the proximal side. To identify new markers closer to the genes, sunflower RGC (resistance gene candidate) markers linked to the downy mildew R-gene Pl 8 and located at the same region as R 13a and R 13b were selected to screen the two F2 populations. The RGC markers RGC15/16 and a newly developed marker SUN14 designed from a BAC contig anchored by RGC251 further narrowed down the region flanking R 13a and R 13b to 1.1 and 0.1 cM, respectively. Both R 13a and R 13b are highly effective against all rust races tested so far. Our newly developed molecular markers will facilitate breeding efforts to pyramid the R 13 genes with other rust R-genes and accelerate the development of rust-resistant sunflower hybrids in both confection and oilseed sunflowers.


Hypo-interventions: Intimate activism in toxic environments.
Chemical toxicity is part of everyday life in Puchuncaví. The most polluted industrial compound in Chile, Puchuncaví is home of fourteen industrial complexes, including the largest copper smelting plant in the country and four thermoelectric plants. Stories of biological mutation, corrosion and death among plants, humans, fishes and cattle are proliferate in Puchuncaví. Engaging with the growing interest in care and affective modes of attention within STS, this paper examines how ill, intoxicated or otherwise affected people in Puchuncaví act upon and know about their chronic sufferings. Drawing on ethnographic fieldwork, I focus on what I call 'hypo-interventions', or the minimal and unspectacular yet life-enabling practices of caring, cleaning and healing the ailments of their significant others, human and otherwise. By minutely engaging with somatic and affective alterations in the domestic spaces of the body, the home and the garden, Puchuncavinos render industrial harm visible and knowable, and hence a type of political action is invoked. While outside technical validation and alien to conventional politics, these actions have proved crucial for people in Puchuncaví striving to persevere in the face of industrial violence and institutional abandonment. I coin the term 'intimate activism' to describe the ethical and political affordances of the subdued doings and engagements deployed in Puchuncaví. Intimate activism, I claim, draws its political power on its capacity to create minimal conditions for ethical and material endurance.


Multiple cycles of dose-intensive chemotherapy with repeated stem cell support as induction treatment in metastatic breast cancer: a feasibility study.
The purpose of this trial was to study feasibility and tolerance of a dose-intensive multicyclic alternating induction chemotherapy with repeated stem cell support in a series of 43 metastatic breast cancer patients. Anthracycline-naive patients (n = 21) received cyclophosphamide 2.5 g/m(2) plus doxorubicin 80 mg/m(2) alternating every 14 days with paclitaxel 200-350 mg/m(2) plus cisplatin 120 mg/m(2). Patients who had previously received anthracyclines (n = 22) received cisplatin 120 mg/m(2) plus etoposide 600 mg/m(2) alternating with paclitaxel 200-350 mg/m(2) plus ifosfamide 8 g/m(2). Peripheral blood stem cells were infused after every course except the first, with a median CD34(+) dose of 2.1 x 10(6)/kg per cycle. Positive selection of CD34(+) cells was performed in good mobilizers. The median number of cycles administered was six (4-8), and the time interval between them was 17 days. Median summation dose intensities (SDI) actually administered for the CA-TP and PE-TI protocol were 4.95 and 4.69, respectively (87% of scheduled SDI). There were 15 complete (35%) and 21 partial responses (49%), for an overall response rate of 84% (95% CI, 73%-95%). Infection or neutropenic fever occurred in 50% of the cycles. There was one treatment-related death. After a median follow-up of 26 months, the median event-free-survival was 12 months (95% CI: 10-14) and overall survival was 31 months. These high dose-intensity induction treatments seem to be feasible with sequential stem cell support.


Role of CYP2E1 in ketone-stimulated insulin release in pancreatic B-cells.
The role of CYP2E1 in ketone-stimulated insulin release was investigated using isolated pancreatic islets of Langerhans and two mammalian insulin secreting pancreatic beta-cell lines engineered to stably express human CYP2E1 (designated BRIN BD11h2E1 and INS-1h2E1). Isolated rat pancreatic islets were shown to express the CYP2E1 isoform which was inducible by pretreatment of animals with acetone. The cDNA encoded CYP2E1 was expressed and inducible in the engineered cells as shown by Western blotting. The transfected protein was enzymatically active in the heterologous cells as determined by p-nitrophenol hydroxylation rates (0.176 +/- 0.08 vs. 0.341 +/- 0.08 nmol/min/mg microsomal protein in BRIN BD11 control cells and BRIN BD11h2E1 cells respectively, P < 0.001; 0.204 +/- 0.03 vs. 0.633 +/- 0.102 nmol/min/mg microsomal protein in INS-1 and INS-1h2E1, respectively, P < 0.001). Cultivation of CYP2E1 expressing BRIN BD11h2E1 and INS-1h2E1 cells in 40 mM ethanol increased the rate of p-nitrophenol hydroxylation (0.968 +/- 0.09 nmol/min/mg microsomal protein, P < 0.001 and 0.846 +/- 0.103 nmol/min/mg microsomal protein, P < 0.001, respectively) providing further evidence that the heterologous protein is inducible. Cultivation of control cells with ethanol had no observable effect (0.186 +/- 0.05 and 0.195 +/- 0.03 in BRIN BD11 and INS-1, respectively). These cell lines also express NADPH-cytochrome P450 reductase protein which was enzymatically active (0.632 +/- 0.023 in parental BRIN BD11 vs. 0.657 +/- 0.066 without ethanol and 0.824 +/- 0.014 nmol/min/mg microsomal protein with ethanol in BRIN BD11h2E1, P < 0.05; and 1.568 +/- 0.118 in parental INS-1 vs. 1.607 +/- 0.093 without ethanol and 1.805 +/- 0.066 nmol/min/mg microsomal protein with ethanol in INS-1h2E1, P < 0.05) thereby providing a functional cytochrome P450 system. The insulin secretory response of control cell lines and islets was similar to cell lines and islets which had been chemically pretreated, to induce CYP2E1 expression, in response to known nutrient secretagogues. However, insulin output was significantly higher in pretreated islets (1.3-fold, P < 0.05) and CYP2E1 expressing cell lines (BRIN BD11h2E1 2.3-fold, P < 0.001; INS1-1h2E1 1.6-fold, P < 0.001) when stimulated with the ketone 3-hydroxybutyrate than control islets and parental cell lines respectively. Similar acute exposure to acetoacetate enhanced insulin secretion by 1.3-fold (P < 0.05) in pretreated islets, 2.6-fold (P < 0.001) in ethanol pretreated BRIN BD11h2E1 and 1.4-fold (P < 0.001) in ethanol pretreated INS-1h2E1 cells compared to the respective control islets or ethanol pretreated control parental cells. Therefore, these studies highlight a possible role for CYP2E1 in pancreatic cell dysfunction.


Prevention of Infection in Adults Receiving Intravenous Antibiotic Treatment via Indwelling Central Venous Access Devices.
The use of indwelling Central Venous Access Devices (CVADs) is associated with the development of bloodstream infections. When CVADs are used to administer systemic antibiotics, particularly second- or higher-generation cephalosporins, there is a particular risk of developing Clostridium difficile infection. The overall bloodstream infection rate is estimated to be around 1.74 per 1000 Central Venous Catheter (CVC)-days. We hypothesised that daily oral administration of the anion-binding resin colestyramine (cholestyramine) would help prevent infections in those receiving intravenous antibiotic treatment via CVADs. A small case series is described of adult patients who received regular intravenous antibiotic treatment (ceftriaxone, daptomycin or vancomycin) for up to 40 weeks via indwelling CVADs; this represented a total of 357 CVC-days. In addition to following well-established strategies to prevent C. difficile infection, during the course of the intravenous antibiotic treatment the patients also received daily oral supplementation with 4 g colestyramine. There were no untoward infectious events. In particular, none of the patients developed any symptoms or signs of C. difficile infection, whereas approximately one case of a bloodstream infection would have been expected. It is suggested that oral colestyramine supplementation may help prevent such infection through its ability to bind C. difficile toxin A (TcdA) and C. difficile toxin B (TcdB); these toxins are able to gain entry into host cells through receptor-mediated endocytosis, while anti-toxin antibody responses to TcdA and TcdB have been shown to induce protection against C. difficile infection sequelae.


Counter-Discourse Activism on Social Media: The Case of Challenging "Poverty Porn" Television.
In this paper we investigate how online counter-discourse is designed, deployed and orchestrated by activists to challenge dominant narratives around socio-political issues. We focus on activism related to the UK broadcast media's negative portrayal of welfare benefit claimants; portrayals characterised as "poverty porn" by critics. Using critical discourse analysis, we explore two activist campaigns countering the TV programme Benefits Street. Through content analysis of social media, associated traditional media texts, and interviews with activists, our analysis highlights the way activists leverage the specific technological affordances of different social media and other online platforms in order to manage and configure counter-discourse activities. We reveal how activists use different platforms to carefully control and contest discursive spaces, and the ways in which they utilise both online and offline activities in combination with new and broadcast media to build an audience for their work. We discuss the challenges associated with measuring the success of counter-discourse, and how activists rely on combinations of social media analytics and anecdotal feedback in order to ascertain that their campaigns are successful. We also discuss the often hidden power-relationships in such campaigns, especially where there is ambiguity regarding the grassroots legitimacy of activism, and where effort is placed into controlling and owning the propagation of counter-discourse. We conclude by highlighting a number of areas for further work around the blurred distinctions between corporate advocacy, digilantism and grassroots activism.


A qualitative analysis of cannabis vaporization among medical users.
Cannabis vaporization is a prevailing mode of administration among medical users for symptom relief. Limited research to date has considered factors that contribute to vaporization in medical users, although initial evidence suggests that vaporization may provide unique therapeutic advantages relative to other modes. This study aimed to provide an in-depth qualitative examination of vaping behavior and use preferences among medical cannabis users. Qualitative interviews were conducted with Rhode Island medical cannabis registration card holders (n = 25). Interviews followed a semistructured agenda and were audio-recorded and transcribed for applied thematic analysis. Key vaporization themes were summarized. Several themes emerged related to (a) medication dosing and administration (flexible timing of medication delivery; ease when traveling; type of device/cannabis formulation), (b) physical health advantages of vaping (general health benefits; better for medical condition; promoting tobacco cessation), (c) general advantages of vaping (portability, concealability, efficiency), and (d) disadvantages (weaker medication delivery; device cost; technology-use barriers). Various factors contribute to cannabis vaporization among medical users that are both general and medical-specific. Certain aspects of vaping may also interfere with effective delivery of cannabis, including technology aspects and device cost. These findings highlight the heterogeneity in vaporization behavior. Future work is needed to further identify factors that contribute to the therapeutic efficacy of cannabis and its modalities of use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Neurons in the cochlear nuclei controlling the tensor tympani muscle in the rat: a study using pseudorabies virus.
The middle ear muscle reflex has been implicated in modulation of auditory input and protection of the inner ear from acoustic trauma. However, the identification of neurons in the cochlear nuclei participating in this reflex has not been fully elucidated. In the present study, we injected the retrograde transynaptic tracer pseudorabies virus into single tensor tympani (TT) muscles, and identified transynaptically labeled cochlear nucleus neurons at multiple survival times. Motoneurons controlling TT were located ventral to the ipsilateral motor trigeminal nucleus and extended rostrally towards the medial aspect of the lateral lemniscus. Transynaptically labeled neurons were observed bilaterally in the dorsal and dorso-medial parts of ventral cochlear nuclei as early as 48 h after virus injection, and had morphological features of radiate multipolar cells. After >or=69 h, labeled cells of different types were observed in all cochlear nuclei. At those times, labeling was also detected bilaterally in the medial nucleus of the trapezoid body and periolivary cell groups in the superior olivary complex. Based on the temporal course of viral replication, our data strongly suggest the presence of a direct projection of neurons from the ventral cochlear nuclei bilaterally to the TT motoneuron pool in rats. The influence of neurons in the cochlear nuclei upon TT activity through direct and indirect pathways may account for multifunctional roles of this muscle in auditory functions.


Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms.
The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious.


Human antibodies neutralizing diphtheria toxin in vitro and in vivo.
Diphtheria is an infectious disease caused by Corynebacterium diphtheriae. The bacterium primarily infects the throat and upper airways and the produced diphtheria toxin (DT), which binds to the elongation factor 2 and blocks protein synthesis, can spread through the bloodstream and affect organs, such as the heart and kidneys. For more than 125 years, the therapy against diphtheria has been based on polyclonal horse sera directed against DT (diphtheria antitoxin; DAT). Animal sera have many disadvantages including serum sickness, batch-to-batch variation in quality and the use of animals for production. In this work, 400 human recombinant antibodies were generated against DT from two different phage display panning strategies using a human immune library. A panning in microtiter plates resulted in 22 unique in vitro neutralizing antibodies and a panning in solution combined with a functional neutralization screening resulted in 268 in vitro neutralizing antibodies. 61 unique antibodies were further characterized as scFv-Fc with 35 produced as fully human IgG1. The best in vitro neutralizing antibody showed an estimated relative potency of 454 IU/mg and minimal effective dose 50% (MED50%) of 3.0 pM at a constant amount of DT (4x minimal cytopathic dose) in the IgG format. The targeted domains of the 35 antibodies were analyzed by immunoblot and by epitope mapping using phage display. All three DT domains (enzymatic domain, translocation domain and receptor binding domain) are targets for neutralizing antibodies. When toxin neutralization assays were performed at higher toxin dose levels, the neutralizing capacity of individual antibodies was markedly reduced but this was largely compensated for by using two or more antibodies in combination, resulting in a potency of 79.4 IU/mg in the in vivo intradermal challenge assay. These recombinant antibody combinations are candidates for further clinical and regulatory development to replace equine DAT.


Investigating the fairness of the National Resident Matching Program.
The National Resident Matching Program (NRMP) was established in the early 1950s to bring order and fairness to a previously chaotic application process for internship and residency positions. Over the years many reservations were raised about the fairness of the process, specifically, that hospital programs are doing better than students are (i.e., programs obtain preferred residents more often than students receive preferred programs). This paper presents an analysis of the results of the 1986 Match. The findings do not support the claim that the results of the Match are biased in a way that favors programs. Overall, the students' success was greater (i.e., receiving on average higher-ranked choices) than was the hospital programs' success. In fact, in 20 of 22 specialty programs, the students' degree of success was greater than or equal to the success of the programs. This finding raises the question of fairness toward programs rather than students. The authors analyze factors that affected both the hospitals' and the students' degrees of success in the 1986 Match and suggest strategies for improving the Match results.


Two-Stage Cultivation of Dunaliella tertiolecta with Glycerol and Triethylamine for Lipid Accumulation: a Viable Way To Alleviate the Inhibitory Effect of Triethylamine on Biomass.
Microalgae are promising alternatives for sustainable biodiesel production. Previously, it was found that 100 ppm triethylamine greatly enhanced lipid production and lipid content per cell of Dunaliella tertiolecta by 20% and 80%, respectively. However, triethylamine notably reduced biomass production and pigment contents. In this study, a two-stage cultivation with glycerol and triethylamine was attempted to improve cell biomass and lipid accumulation. At the first stage with 1.0 g/liter glycerol addition, D. tertiolecta cells reached the late log phase in a shorter time due to rapid cell growth, leading to the highest cell biomass (1.296 g/liter) for 16 days. However, the increased glycerol concentrations with glycerol addition decreased the lipid content. At the second-stage cultivation with 100 ppm triethylamine, the highest lipid concentration and lipid weight content were 383.60 mg/liter and 37.7% of dry cell weight (DCW), respectively, in the presence of 1.0 g/liter glycerol, which were 27.36% and 72.51% higher than those of the control group, respectively. Besides, the addition of glycerol alleviated the inhibitory effect of triethylamine on cell morphology, algal growth, and pigment accumulation in D. tertiolecta The results indicated that two-stage cultivation is a viable way to improve lipid yield in microalgae.IMPORTANCE Microalgae are promising alternatives for sustainable biodiesel production. Two-stage cultivation with glycerol and triethylamine enhanced the lipid productivity of Dunaliella tertiolecta, indicating that two-stage cultivation is an efficient strategy for biodiesel production from microalgae. It was found that glycerol significantly enhanced cell biomass of D. tertiolecta, and the presence of glycerol alleviated the inhibitory effect of triethylamine on algal growth. Glycerol, the major byproduct from biodiesel production, was used for the biomass accumulation of D. tertiolecta at the first stage of cultivation. Triethylamine, as a lipid inducer, was used for lipid accumulation at the second stage of cultivation. Two-stage cultivation with glycerol and triethylamine enhanced lipid productivity and alleviated the inhibitory effect of triethylamine on the algal growth of D. tertiolecta, which is an efficient strategy for lipid production from D. tertiolecta.


Self-Care Monitoring of Heart Failure Symptoms and Lung Impedance at Home Following Hospital Discharge: Longitudinal Study.
Self-care is key to the daily management of chronic heart failure (HF). After discharge from hospital, patients may struggle to recognize and respond to worsening HF symptoms. Failure to monitor and respond to HF symptoms may lead to unnecessary hospitalizations. This study aimed to (1) determine the feasibility of lung impedance measurements and a symptom diary to monitor HF symptoms daily at home for 30 days following hospital discharge and (2) determine daily changes in HF symptoms of pulmonary edema, lung impedance measurements, and if self-care behavior improves over time when patients use these self-care monitoring tools. This study used a prospective longitudinal design including patients from cardiology wards in 2 university hospitals-one in Norway and one in Lithuania. Data on HF symptoms and pulmonary edema were collected from 10 participants (mean age 64.5 years; 90% (9/10) male) with severe HF (New York Heart Association classes III and IV) who were discharged home after being hospitalized for an HF condition. HF symptoms were self-reported using the Memorial Symptom Assessment Scale for Heart Failure. Pulmonary edema was measured by participants using a noninvasive lung impedance monitor, the CardioSet Edema Guard Monitor. Informal caregivers aided the participants with the noninvasive measurements. The prevalence and burden of shortness of breath varied from participants experiencing them daily to never, whereas lung impedance measurements varied for individual participants and the group participants, as a whole. Self-care behavior score improved significantly (P=.007) from a median of 56 (IQR range 22-75) at discharge to a median of 81 (IQR range 72-98) 30 days later. Noninvasive measurement of lung impedance daily and the use of a symptom diary were feasible at home for 30 days in HF patients. Self-care behavior significantly improved after 30 days of using a symptom diary and measuring lung impedance at home. Further research is needed to determine if daily self-care monitoring of HF signs and symptoms, combined with daily lung impedance measurements, may reduce hospital readmissions.


The association of mitochondrial content with prevalent and incident type 2 diabetes.
It has been shown that mitochondrial DNA (mtDNA) content is associated with type 2 diabetes (T2D) and related traits. However, empirical data, often based on small samples, did not confirm this observation in all studies. Therefore, the role of mtDNA content in T2D remains elusive. In this study, we assessed the heritability of mtDNA content in buccal cells and analyzed the association of mtDNA content in blood with prevalent and incident T2D. mtDNA content from cells from buccal and blood samples was assessed using a real-time PCR-based assay. Heritability of mtDNA content was estimated in 391 twins from the Netherlands Twin Register. The association with prevalent T2D was tested in a case control study from The Netherlands (n = 329). Incident T2D was analyzed using prospective samples from Finland (n = 444) and The Netherlands (n = 238). We measured the heritability of mtDNA content and the association of mtDNA content in blood with prevalent and incident T2D. A heritability of mtDNA content of 35% (19-48%) was estimated in the twin families. We did not observe evidence of an association between mtDNA content and prevalent or incident T2D and related traits. Furthermore, we observed a decline in mtDNA content with increasing age that was male specific (P = 0.001). In this study, we show that mtDNA content has a heritability of 35% in Dutch twins. There is no association between mtDNA content in blood and prevalent or incident T2D and related traits in our study samples.


The influence of bicuspid aortic valves on the dynamic pressure distribution in the ascending aorta: a porcine ex vivo model.
The aim of the study was to simulate the effect of different bicuspid aortic valve configurations on the dynamic pressure distribution in the ascending aorta. Aortic specimens were harvested from adult domestic pigs. In Group 1, bicuspidalization was created by a running suture between the left and the right coronary leaflets (n = 6) and in Group 2 by a running suture between the left and the non-coronary leaflets (n = 6). Eleven tricuspid specimens served as controls. Two intraluminal pressure catheters were positioned at the concavity and the convexity of the ascending aorta. The specimens were connected to a mock circulation (heart rate: 60 bpm, target pressure: 95 mmHg). A comparison of the different conditions was also done in a numerical simulation. At a distal mean aortic pressure of 94 ± 10 mmHg, a mean flow rate of 5.2 ± 0.3 l/min was achieved. The difference of maximal dynamic pressure values (which occurred in systole) between locations at the convexity and the concavity was 7.8 ± 2.9 mmHg for the bicuspid and 1.0 ± 0.9 mmHg for the tricuspid specimens (P < 0.001). The numerical simulation revealed an even higher pressure difference between convexity and concavity for bicuspid formation. In this hydrodynamic mock circulation model, we were able to demonstrate that bicuspid aortic valves are associated with significant pressure differences in different locations within the ascending aorta compared with tricuspid aortic valves. These altered pressure distributions and flow patterns may further add to the understanding of aneurismal development in patients with bicuspid aortic valves and might serve to anticipate adverse aortic events due to a better knowledge of the underlying mechanisms.


Venous thromboembolism prophylaxis in hospitalized elderly patients: Time to consider a 'MUST' strategy.
Venous thromboembolism (VTE) is the commonest cause of preventable death in hospitalized patients. Elderly patients have higher risk of VTE because of the high prevalence of predisposing co-morbidities and acute illnesses. Clinical diagnosis of VTE in the elderly patient is particularly difficult and, as such, adequate VTE prophylaxis is of pivotal importance in reducing the mortality and morbidities of VTE. Omission of VTE prophylaxis is, however, very common despite continuous education. A simple way to overcome this problem is to implement universal VTE prophylaxis for all hospitalized elderly patients instead of selective prophylaxis for some patients only according to individual's risk of VTE. Although pharmacological VTE prophylaxis is effective for most patients, a high prevalence of renal impairment and drug interactions in the hospitalized elderly patients suggests that a multimodality approach may be more appropriate. Mechanical VTE prophylaxis, including calf and thigh compression devices and/or an inferior vena cava filter, are often underutilized in hospitalized elderly patients who are at high-risk of bleeding and VTE. Because pneumatic compression devices and thigh length stockings are virtually risk free, mechanical VTE prophylaxis may allow early or immediate implementation of VTE prophylaxis for all hospitalized elderly patients, regardless of their bleeding and VTE risk. Although the cost-effectiveness of this Multimodality Universal STat ('MUST') VTE prophylaxis approach for hospitalized elderly patients remains uncertain, this strategy appears to offer some advantages over the traditional 'selective and single-modal' VTE prophylaxis approach, which often becomes 'hit or miss' or not implemented promptly in many hospitalized elderly patients. A large clustered randomized controlled trial is, however, needed to assess whether early, multimodality, universal VTE prophylaxis can improve important clinical outcomes of hospitalized elderly patients.


Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden.
To investigate the changes in prevalence and incidence of pharmacologically and non-pharmacologically treated diabetes in Sweden during 2005 to 2013. We obtained data on gender, date of birth and pharmacologically and non-pharmacologically treated diabetes from national registers for all Swedish residents. During the study period a total of 240 871 new cases of pharmacologically treated diabetes was found. The age-standardized incidence during the follow-up was 4.34 and 3.16 per 1000 individuals in men and women, respectively. A decreasing time trend in incidence for men of 0.6% per year (0.994, 95% CI 0.989-0.999) and for women of 0.7% per year (0.993, 95% CI 0.986-0.999) was observed. The age-standardized prevalence increased from 41.9 and 29.9 per 1000 in 2005/2006 to 50.8 and 34.6 in 2012/2013 in men and women, respectively. This corresponds to an annually increasing time trend for both men (1.024, 95% CI 1.022-1.027) and women (1.019, 95% CI 1.016-1.021). The total age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes (2012) was 46.9 per 1000 (55.6 for men and 38.8 for women). This corresponds to an annually increasing time trend (2010-2012) for both men (1.017, 95% CI 1.013-1.021) and women (1.012, 95% CI 1.008-1.016). The prevalence of pharmacologically treated diabetes increased moderately during 8 years of follow-up, while the incidence decreased modestly. This is in contrast to the results reported by most other studies. The total prevalence of diabetes (both pharmacologically and non-pharmacologically treated) in Sweden is relatively low, from a global viewpoint.


Sequencing wild and cultivated cassava and related species reveals extensive interspecific hybridization and genetic diversity.
Cassava (Manihot esculenta) provides calories and nutrition for more than half a billion people. It was domesticated by native Amazonian peoples through cultivation of the wild progenitor M. esculenta ssp. flabellifolia and is now grown in tropical regions worldwide. Here we provide a high-quality genome assembly for cassava with improved contiguity, linkage, and completeness; almost 97% of genes are anchored to chromosomes. We find that paleotetraploidy in cassava is shared with the related rubber tree Hevea, providing a resource for comparative studies. We also sequence a global collection of 58 Manihot accessions, including cultivated and wild cassava accessions and related species such as Ceará or India rubber (M. glaziovii), and genotype 268 African cassava varieties. We find widespread interspecific admixture, and detect the genetic signature of past cassava breeding programs. As a clonally propagated crop, cassava is especially vulnerable to pathogens and abiotic stresses. This genomic resource will inform future genome-enabled breeding efforts to improve this staple crop.


The influence of pinealectomy and melatonin administration on the dynamic pattern of biochemical markers of bone metabolism in experimental osteoporosis in the rat.
There have been suggestions in literature that characteristic changes of bone mass in osteoporosis may be related to the melatonin (Mel): The aim of this study was to demonstrate whether pinealectomy and Mel administration can affect postmenopausal osteoporosis processes induced in female rats by way of ovariectomy. The study included 198 animals; 6 remained intact (0), 96 were ovariectomized (Ox), and the remaining ones underwent a sham operation (SOx). Two weeks after surgery, the rats were divided into eight groups: 1) SOx + SPx, 2) SOx + SPx + Mel, 3) Ox + SPx, 4) Ox + SPx + Mel, 5) SOx + Px, 6) SOx + Px + Mel, 7) Ox + Px, 8) Ox + Px + Mel. Animals from the 5th, 6th, 7th and 8th groups were pinealectomized (Px) while the remaining ones underwent a sham operation (SPx). Two weeks after surgery Mel (50microg/100g of bm) were administered intraperitoneally in rats in the 2nd, 4th, 6th and 8th groups while the remaining animals were administered with solvent only (5% solution of ethyl alcohol in physiological saline). Rats were administered the Mel solution or the solvent daily between 5 and 6 pm during a 4-week period. At the appropriate time, i.e. prior to surgery (group 0) and after 6, 12, 18 and 24 weeks from Px or SPx (time subgroups a, b, c and d) the animals were placed separately in metabolic cages (from 6.30 until 9.30 am) in order to collect urine aliquots for HYP and Ca determinations. The blood for the assay of ALP, PICP and ICTP was collected within the next 24 hours at 8 am (rats killed by decapitation). The study has shown that pinealectomy had inducing, while exogenous Mel suppressing effect upon the level of investigated markers of bone metabolism; these changes were more pronounced in ovariectomized rats. Administration of Mel only partially levelled changes of bone metabolism caused by pinealectomy. In rats with preserved pineal gland effect of Mel on bone turnover markers was less pronounced. After discontinuing administration of Mel distinct tendency to increase studied biochemical markers of bone metabolism was shown. Our findings suggest that Mel is an important modulator of experimental osteoporosis processes induced in female rats by way of ovariectomy.


Clinical commissioning and use of the Novalis Tx linear accelerator for SRS and SBRT.
The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2) MLC commissioning: Winston Lutz test, light/radiation field congruence, and Picket Fence tests were performed and were within criteria established by the relevant task group reports. The measured mean MLC transmission and dynamic leaf gap of 6 MV SRS beam were 1.17% and 0.36 mm, respectively. (3) Baseline characteristics of OBI and ETX: The isocenter localization errors in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 ± 0.2 mm, -0.8 ± 0.2 mm, and -0.8 ± 0.4 mm for ETX, and 0.5 ± 0.7 mm, 0.6 ± 0.5 mm, and 0.0 ± 0.5 mm for OBI cone-beam computed tomography. The registration angular discrepancy was 0.1 ± 0.2°, and the maximum robotic couch error was 0.2°. (4) End-to-end tests: The measured isocenter dose differences from the planned values were 0.8% and 0.4%, measured respectively by an ion chamber and film. The gamma pass rate, measured by EBT2 film, was 95% (3% DD and 1 mm DTA). Through a systematic series of quantitative commissioning experiments and end-to-end tests and our initial clinical experience, described in this report, we demonstrate that the NTX is a robust system, with the image guidance and MLC requirements to treat a wide variety of sites - in particular for highly accurate delivery of SRS and SBRT-based treatments.


Obfuscation of Embedded Codes in Additive Manufactured Components for Product Authentication.
Enhancement in the capabilities of additive manufacturing (AM) methods has led to development of many high-value components for aerospace, automotive and medical fields. Security concerns, such as (a) a predominantly cloud based process chain of AM may be breached and stolen files can be used for unauthorized reproduction of parts and (b) legitimately acquired parts can be reverse engineered, need to be addressed for this field to protect intellectual property and deter counterfeiting or unauthorized production. In the present work, a method of embedding an identification code inside the parts manufactured by AM methods is presented, which takes advantage of the layer-by-layer manufacturing process. The code is obfuscated by segmenting it into a specific number of parts, which are distributed throughout a large number of printed layers. In this case, viewing the code only from a specific direction is provides the correct visualization. A further obfuscation scheme is demonstrated that embeds multiple identification codes in the interpenetrating format. Only a specific set of processing conditions can lead to printing of the authentic code inside the part correctly. Numerous other conditions lead to printing of wrong code inside the part, which will lead to positive identification of counterfeit or unauthorized parts. Securing the AM process chain can help in accelerating the industrial applications of this versatile method.


Clinicopathologic study of six cases of meningitis and meningoencephalitis in chimpanzees (Pan troglodytes).
Three fatal cases of purulent meningitis and one fatal case of thromboembolic necrotizing meningoencephalitis occurred in chimpanzees from the Primate Center TNO, The Netherlands. In addition, two apes had clinical signs of meningitis and were successfully treated. The severity of the residual hemiparesis and dysphagia in one of these two apes was such that it was killed for humane reasons. The histopathological diagnosis was chronic active meningoencephalitis. Streptococcus pneumoniae was isolated from five apes and Klebsiella pneumoniae from one. In the majority of cases, the primary site of infection was the upper respiratory tract. After reducing the population density, initiating a vaccination program using a commercially available human polyvalent pneumococcal vaccine, and changing the cleaning procedure of the animal facilities, no other cases of meningitis or meningoencephalitis have occurred in the chimpanzee colony in the ensuing 3.5 years.


Guggulsterone inhibits osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand and by tumor cells by suppressing nuclear factor-kappaB activation.
Bone resorption is commonly associated with aging and with certain types of cancer, including multiple myeloma and breast cancer. What induces bone resorption is not fully understood, but the role of osteoclasts is well established. Recently, receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL), a member of the tumor necrosis factor superfamily, was implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. Guggulsterone [4,17(20)-pregnadiene-3,16-dione], isolated from the guggul tree Commiphora mukul and used to treat osteoarthritis and bone fractures, was recently shown to antagonize the farnesoid X receptor, decrease the expression of bile acid-activated genes, and suppress the NF-kappaB activation induced by various carcinogens. We investigated whether guggulsterone could modulate RANKL signaling and osteoclastogenesis induced by RANKL or tumor cells. We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-kappaB activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of IkappaBalpha kinase and phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. Suppression of osteoclastogenesis by the NF-kappaB-specific inhibitory peptide implies a link between NF-kappaB and osteoclastogenesis. Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone. Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell-induced osteoclastogenesis by suppressing the activation of NF-kappaB.


The direction of transport through the nuclear pore can be inverted.
Transport of macromolecules across the nuclear envelope is an active process that depends on soluble factors including the GTPase Ran. Ran-GTP is predominantly located in the nucleus and has been shown to regulate cargo binding and release of import and export receptors in their respective target compartments. Recently, it was shown that transport of receptor-cargo complexes across the nuclear pore complex (NPC) does not depend on GTP-hydrolysis by Ran; however, the mechanism of translocation is still poorly understood. Here, we show that the direction of transport through the NPC can be inverted in the presence of high concentrations of cytoplasmic Ran-GTP. Under these conditions, two different classes of export cargoes are transported into the nucleus in the absence of GTP hydrolysis. The inverted transport is very rapid and can be blocked by known inhibitors of nuclear protein export. These results suggest that the NPC functions as a facilitated transport channel, allowing the selective translocation of receptor-cargo complexes. We conclude that the directionality of nucleocytoplasmic transport is determined mainly by the compartmentalized distribution of Ran-GTP.


Hydrogen-bonded perylene bisimide J-aggregate aqua material.
A new twelvefold methoxy-triethyleneglycol-jacketed tetraphenoxy-perylene bisimide (MEG-PBI) amphiphile was synthesized that self-assembles into two types of supramolecular aggregates in water: red-coloured aggregates of low order and with weak exciton coupling among the PBIs and blue-coloured strongly coupled J-aggregates consisting of a highly ordered hydrogen-bonded triple helix of PBIs. At room temperature this PBI is miscible with water at any proportions which enables the development of robust dye aggregates in solution, in hydrogel states and in lyotropic liquid crystalline states. In the presence of 60-95 wt% water, self-standing coloured hydrogels exhibit colour changes from red to blue accompanied by a fluorescence light-up in the far-red region upon heating in the range of 30-50 °C. This phenomenon is triggered by an entropically driven temperature-induced hydrogen-bond-directed slipped stacking arrangement of the MEG-PBI chromophores within structurally well-defined J-aggregates. This versatile aqua material is the first example of a stable PBI J-aggregate in water. We anticipate that this study will open a new avenue for the development of biocompatible functional materials based on self-assembled dyes and inspire the construction of other hydrogen-bonded supramolecular materials in the highly competitive solvent water.


Structured and Sparse Canonical Correlation Analysis as a Brain-Wide Multi-Modal Data Fusion Approach.
Multi-modal data fusion has recently emerged as a comprehensive neuroimaging analysis approach, which usually uses canonical correlation analysis (CCA). However, the current CCA-based fusion approaches face problems like high-dimensionality, multi-collinearity, unimodal feature selection, asymmetry, and loss of spatial information in reshaping the imaging data into vectors. This paper proposes a structured and sparse CCA (ssCCA) technique as a novel CCA method to overcome the above problems. To investigate the performance of the proposed algorithm, we have compared three data fusion techniques: standard CCA, regularized CCA, and ssCCA, and evaluated their ability to detect multi-modal data associations. We have used simulations to compare the performance of these approaches and probe the effects of non-negativity constraint, the dimensionality of features, sample size, and noise power. The results demonstrate that ssCCA outperforms the existing standard and regularized CCA-based fusion approaches. We have also applied the methods to real functional magnetic resonance imaging (fMRI) and structural MRI data of Alzheimer's disease (AD) patients (n = 34) and healthy control (HC) subjects (n = 42) from the ADNI database. The results illustrate that the proposed unsupervised technique differentiates the transition pattern between the subject-course of AD patients and HC subjects with a p-value of less than 1×10-6 . Furthermore, we have depicted the brain mapping of functional areas that are most correlated with the anatomical changes in AD patients relative to HC subjects.


High crustacean toxicity of microcystin congeners does not correlate with high protein phosphatase inhibitory activity.
Microcystins are strong toxins and efficient inhibitors of eukaryotic protein phosphatases. To determine structure related properties of six different microcystin congeners, we applied standardized inhibition assays for the protein phosphatases 1 and 2A, and an acute toxicity assay with Thamnocephalus platyurus. Protein phosphatase inhibition and acute toxicity did not correlate with each other. While the inhibition of the protein phosphatases 1 and 2A was much weaker for [D-Asp3,(E)-Dhb7]microcystin-RR than for the other congeners, the toxicity was one of the highest. [D-Asp3]microcystin-LR exhibited only small differences to microcystin-LR. The data show that mechanisms other than the inhibition of protein phosphatases, such as uptake, transport, detoxification or other target sites may have a strong modulating effect on the toxicity of a microcystin congener for a particular animal. Structural changes can offset or even reverse the specific toxicity of microcystin congeners.


Comparison of muscle activation levels during arm abduction in the plane of the scapula vs. proprioceptive neuromuscular facilitation upper extremity patterns.
This study quantified activation of 8 muscles of the shoulder, trunk, and back during standing performance of (a) arm abduction in the plane of the scapula (scaption), (b) proprioceptive neuromuscular facilitation (PNF) diagonal 1 flexion (D1F), and (c) PNF diagonal 2 flexion (D2F) while lifting a dumbbell with the dominant hand. Twelve men (26.1 ± 4.4 years) and 13 women (24.5 ± 1.9 years) volunteered to participate. Electromyographic signals were collected with DE-3.1 double-differential surface electrodes at a sampling frequency of 1,000 Hz. Electromyographic signals were normalized to peak activity in the maximum voluntary isometric contraction (MVIC) trial and expressed as a percentage. One-way repeated-measures analysis of variance with Bonferroni corrections (α = 0.05) examined muscle activation patterns across the 3 conditions. For the middle trapezius, average activation was greater (p < 0.001) for D2F (70.5 ± 23.4% MVIC) than D1F (46.4 ± 19.6% MVIC). Lower trapezius average activation was greater (p < 0.001) for D2F (55.3 ± 23.8% MVIC) than D1F (40.1 ± 16% MVIC). The anterior deltoid showed greater activation (p = 0.009) for scaption (92.4 ± 26% MVIC) than D1F (74.4 ± 21.4% MVIC). The erector spinae showed greater activation for D2F (34.2 ± 12% MVIC; p < 0.001) and D1F (41.7 ± 21.4% MVIC; p < 0.001) than scaption (14.5 ± 12.3% MVIC). During D2F and scaption, all 6 muscles of the shoulder complex demonstrated very high activation levels (>60% MVIC) with the exception of the lower trapezius (55% MVIC). In contrast, erector spinae and external oblique muscles exhibited moderate activation (21-40% MVIC) during arm elevation. The 6 muscles of the shoulder complex displayed high to very high muscle activation at a level appropriate for strength training during all 3 exercise conditions.


Impact of adjuvant chemotherapy in patients with upper tract urothelial carcinoma and lymphovascular invasion after radical nephroureterectomy.
To evaluate the impact of adjuvant chemotherapy (AC) in patients with upper tract urothelial carcinoma and lymphovascular invasion (LVI) after radical nephroureterectomy (RNU). We retrospectively analyzed the clinical records and clinicopatholgic outcomes of patients (n=552) treated with RNU between 1986 and 2013. Patients treated with neoadjuvant chemotherapy and those for whom LVI status was not recorded were excluded. Patients were divided into two groups according to LVI (n=86) or no LVI (n=256). The study included 344 patients (240 men and 104 women) with a median of 53.9 months of follow-up (range, 1-297 months) after RNU. Tumors were organ confined (T2/N0) in 211 (61.3%) and tumor grade high in 291 (84.6%). AC was administered in 64 patients (18.6%). A total of 280 patients (81.4%) were treated with surgery alone. Patients with LVI tended to be older (p=0.049), have a higher pT stage (pT3/T4, p<0.001), be pN+ (p<0.001), have a high tumor grade (p<0.001), and experience recurrence (p<0.001). In the multivariate analysis, LVI was an independent prognostic factor for cancer-specific survival and overall survival (p=0.002 and p<0.001, respectively). The multivariate analysis demonstrated that in the subgroup of patients with LVI, AC was a significant prognostic factor for cancer-specific survival and overall survival (hazard ratio, 0.51; p=0.027 and hazard ratio, 0.50; p=0.025, respectively). AC does not seem to reduce mortality in patients with advanced upper tract urothelial carcinoma after RNU. In the subgroup of patients with LVI, AC had a positive impact on cancer-specific survival and overall survival. LVI would be helpful for selecting patients who are appropriate for AC.


Transglutaminase 2 Depletion Attenuates α-Synuclein Mediated Toxicity in Mice.
α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking through transglutaminase 2 (TG2). We previously demonstrated that overexpression of TG2 exacerbates α-Syn toxicity in mice and yeast by increasing the higher-order species of α-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of α-Syn in vivo. Compared with α-Syn transgenic (SynTg) mice, TG2 null /α-Syn transgenic mice (TG2KO/SynTg) exhibited a reduced amount of phosphorylated α-Syn aggregates and fewer proteinase K-resistant α-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in SynTg mice compared to wild-type mice were preserved in double TG2KO/SynTg mice. Additionally, the neuroinflammatory reaction to α-Syn was attenuated in TG2KO/SynTg animals. These neuropathological markers of diminished α-Syn toxicity in the absence of TG2 were associated with better motor performance on the rotarod and balance beam. These results suggest that deleting TG2 reduces the toxicity of α-Syn in vivo and improves the behavioral performance of SynTg mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for α-synucleinopathies.


How uncommon is tickertaping? Prevalence and characteristics of seeing the words you hear.
Tickertape experience is the subjective phenomenon of routinely visualizing the orthographic appearance of words that one hears, speaks, or thinks, like mental subtitles in the mind's eye. It has been observed in grapheme-color synesthetes, whose letter visualizations are colored, but has been very little studied. We report a survey, among 425 Norwegian adults from varied sub-samples, of the prevalence, character, and associated skills of tickertaping. Our questionnaire was designed to reflect different degrees of automaticity of the experience. While strongly automatic tickertaping appeared rare (n = 6; CI95 = 0.6% to 3.2% of sample), lesser degrees of text visualization were reported by more than half of respondents, indicating a continuity between extreme tickertaping and normal cognition. Tickertaping was not strongly associated with greater awareness of an inner voice while reading silently. We also found no strong evidence that tickertapers are unusually likely to self-report skill in rapidly enumerating heard words, or in backward spelling and backward speaking, despite the fact that these skills have been observed in single-case studies of tickertapers. The qualitative character of tickertaping varied among respondents, and included negative experiences. However visualization of letters was predominantly uncolored, indicating that tickertaping is a phenomenon in its own right and not just a subset of grapheme-color synesthesia. We suggest tickertaping is an explicit expression of the close interconnection between phonemic and graphemic representations of words which, for reasons we do not yet understand, manifests as visual imagery with a varying degree of automaticity.


The invasion paradox: reconciling pattern and process in species invasions.
The invasion paradox describes the co-occurrence of independent lines of support for both a negative and a positive relationship between native biodiversity and the invasions of exotic species. The paradox leaves the implications of native-exotic species richness relationships open to debate: Are rich native communities more or less susceptible to invasion by exotic species? We reviewed the considerable observational, experimental, and theoretical evidence describing the paradox and sought generalizations concerning where and why the paradox occurs, its implications for community ecology and assembly processes, and its relevance for restoration, management, and policy associated with species invasions. The crux of the paradox concerns positive associations between native and exotic species richness at broad spatial scales, and negative associations at fine scales, especially in experiments in which diversity was directly manipulated. We identified eight processes that can generate either negative or positive native-exotic richness relationships, but none can generate both. As all eight processes have been shown to be important in some systems, a simple general theory of the paradox, and thus of the relationship between diversity and invasibility, is probably unrealistic. Nonetheless, we outline several key issues that help resolve the paradox, discuss the difficult juxtaposition of experimental and observational data (which often ask subtly different questions), and identify important themes for additional study. We conclude that natively rich ecosystems are likely to be hotspots for exotic species, but that reduction of local species richness can further accelerate the invasion of these and other vulnerable habitats.


Human cytomegalovirus epidemiology and relationship to tuberculosis and cardiovascular disease risk factors in a rural Ugandan cohort.
Human cytomegalovirus (HCMV) infection has been associated with increased mortality, specifically cardiovascular disease (CVD), in high-income countries (HICs). There is a paucity of data in low- and middle-income countries (LMICs) where HCMV seropositivity is higher. Serum samples from 2,174 Ugandan individuals were investigated for HCMV antibodies and data linked to demographic information, co-infections and a variety of CVD measurements. HCMV seropositivity was 83% by one year of age, increasing to 95% by five years. Female sex, HIV positivity and active pulmonary tuberculosis (TB) were associated with an increase in HCMV IgG levels in adjusted analyses. There was no evidence of any associations with risk factors for CVD after adjusting for age and sex. HCMV infection is ubiquitous in this rural Ugandan cohort from a young age. The association between TB disease and high HCMV IgG levels merits further research. Known CVD risk factors do not appear to be associated with higher HCMV antibody levels in this Ugandan cohort.


Pharmacokinetics, pharmacodynamics and local tolerance at injection site of marbofloxacin administered by regional intravenous limb perfusion in standing horses.
To evaluate pharmacokinetic-pharmacodynamic variables and local tolerance at injection-site of marbofloxacin administered via regional intravenous limb perfusion (RIVLP) in standing horses. Adult horses (n = 6). RIVLP were performed with rubber tourniquets applied to the forelimbs of standing sedated horses. Marbofloxacin (0.67 mg/kg) was randomly injected in 1 forelimb, with the contralateral limb serving as a control (0.9% NaCl solution). Samples of jugular blood and synovial fluid from the radiocarpal joint of the marbofloxacin-perfused limb were collected before and at intervals after RIVLP for determination of drug concentrations. All injection sites were evaluated before, 24 and 48 hours after RIVLP by means of ultrasonographic examination, circumferential measurements and subjective visible inflammation scores by veterinarians unaware of treatment received. No adverse effects associated with the technique or antibiotic were observed. High marbofloxacin concentrations were obtained in the synovial fluid, AUCINF was significantly higher in synovial fluid than in plasma (78.64 ± 49.41 and 2.85 ± 0.60 µg h/mL respectively, P = .028). The efficacy indices, AUC0-24 /MIC90 and Cmaxobs/MIC90 , predicted a favorable outcome in the treatment of synovial fluid infections caused by enterobacteriaceae and Staphylococcus aureus. After RIVLP, there was no statistically significant difference between marbofloxacin-injected and control limbs for lameness, visual inflammation score, limb circumference, and ultrasonographic appearance of the veins. Marbofloxacin injected limbs had a significantly greater subcutaneous thickness, compared with control limbs. These data suggest that RIVLP of marbofloxacin (0.67 mg/kg) could be a safe and effective method for treatment of infections of the distal portion of the limb for susceptible organisms.


Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion.
The first-dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate post-operative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FK506, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.


Crossing barriers: the new dimension of 2D cell migration assays.
In our body cells move in three dimensions, embedded in an extracellular matrix that varies in composition, density and stiffness, and this movement is fundamental to life. Next to 3D cell migration assays, representing these physiological circumstances, still we need 2D migrations assays to perform detailed studies on the contribution of matrix-components and (extra)cellular proteins to cell movements. Next to the debate on differences between 3D and 2D migration, there also are many new perspectives on the use and development of novel or modified 2D cell migration assays. Of special significance is the introduction of so-called barrier migration assays, methods that avoid cell and matrix damage, as complementation or replacement of scratch/wound healing assays. Here, we discuss the possibilities and limitations of different 2D barrier migration assays.


Prevention of breast cancer in postmenopausal women: approaches to estimating and reducing risk.
It is uncertain whether evidence supports routinely estimating a postmenopausal woman's risk of breast cancer and intervening to reduce risk. We systematically reviewed prospective studies about models and sex hormone levels to assess breast cancer risk and used meta-analysis with random effects models to summarize the predictive accuracy of breast density. We also reviewed prospective studies of the effects of exercise, weight management, healthy diet, moderate alcohol consumption, and fruit and vegetable intake on breast cancer risk, and used random effects models for a meta-analyses of tamoxifen and raloxifene for primary prevention of breast cancer. All studies reviewed were published before June 2008, and all statistical tests were two-sided. Risk models that are based on demographic characteristics and medical history had modest discriminatory accuracy for estimating breast cancer risk (c-statistics range = 0.58-0.63). Breast density was strongly associated with breast cancer (relative risk [RR] = 4.03, 95% confidence interval [CI] = 3.10 to 5.26, for Breast Imaging Reporting and Data System category IV vs category I; RR = 4.20, 95% CI = 3.61 to 4.89, for >75% vs <5% of dense area), and adding breast density to models improved discriminatory accuracy (c-statistics range = 0.63-0.66). Estradiol was also associated with breast cancer (RR range = 2.0-2.9, comparing the highest vs lowest quintile of estradiol, P < .01). Most studies found that exercise, weight reduction, low-fat diet, and reduced alcohol intake were associated with a decreased risk of breast cancer. Tamoxifen and raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer and invasive breast cancer overall. Evidence from this study supports screening for breast cancer risk in all postmenopausal women by use of risk factors and breast density and considering chemoprevention for those found to be at high risk. Several lifestyle changes with the potential to prevent breast cancer should be recommended regardless of risk.


Conditional protein splicing: a new tool to control protein structure and function in vitro and in vivo.
Protein splicing is a naturally occurring process in which an intervening intein domain excises itself out of a precursor polypeptide in an autocatalytic fashion with concomitant linkage of the two flanking extein sequences by a native peptide bond. We have recently reported an engineered split VMA intein whose splicing activity in trans between two polypeptides can be triggered by the small molecule rapamycin. In this report, we show that this conditional protein splicing (CPS) system can be used in mammalian cells. Two model constructs harboring maltose-binding protein (MBP) and a His-tag as exteins were expressed from a constitutive promoter after transient transfection. The splicing product MBP-His was detected by Western blotting and immunoprecipitation in cells treated with rapamycin or a nontoxic analogue thereof. No background splicing in the absence of the small-molecule inducer was observed over a 24-h time course. Product formation could be detected within 10 min of addition of rapamycin, indicating the advantage of the posttranslational nature of CPS for quick responses. The level of protein splicing was dose dependent and could be competitively attenuated with the small molecule ascomycin. In related studies, the geometric flexibility of the CPS components was investigated with a series of purified proteins. The FKBP and FRB domains, which are dimerized by rapamycin and thereby induce the reconstitution of the split intein, were fused to the extein sequences of the split intein halves. CPS was still triggered by rapamycin when FKBP and FRB occupied one or both of the extein positions. This finding suggests yet further applications of CPS in the area of proteomics. In summary, CPS holds great promise to become a powerful new tool to control protein structure and function in vitro and in living cells.


Advances in tailoring resorcinol-formaldehyde organic and carbon gels.
An overview on the preparation and properties of resorcinol-formaldehyde (RF) organic and carbon gels reveals the fascinating and remarkably flexible properties of RF carbon and organic gels and how these properties are related to the synthesis and processing conditions. The structural properties can be easily tailored by rigidly controlling such conditions. However, slight variations in some conditions may cause drastic variations in the structural characteristics, and hence properties. Therefore, the effects of different conditions must be well-understood before attempting to tailor organic or carbon gels to specific applications. The most important factors that affect the properties of an organic gel are the precursor concentrations, the catalyst type and concentration, the time and temperature of curing, and the drying method. In addition to these factors, characteristics of activated carbon gels also depend on the pyrolysis temperature and the activation method. These conditions impact the structural and performance characteristics significantly.


On neuromechanical approaches for the study of biological and robotic grasp and manipulation.
Biological and robotic grasp and manipulation are undeniably similar at the level of mechanical task performance. However, their underlying fundamental biological vs. engineering mechanisms are, by definition, dramatically different and can even be antithetical. Even our approach to each is diametrically opposite: inductive science for the study of biological systems vs. engineering synthesis for the design and construction of robotic systems. The past 20 years have seen several conceptual advances in both fields and the quest to unify them. Chief among them is the reluctant recognition that their underlying fundamental mechanisms may actually share limited common ground, while exhibiting many fundamental differences. This recognition is particularly liberating because it allows us to resolve and move beyond multiple paradoxes and contradictions that arose from the initial reasonable assumption of a large common ground. Here, we begin by introducing the perspective of neuromechanics, which emphasizes that real-world behavior emerges from the intimate interactions among the physical structure of the system, the mechanical requirements of a task, the feasible neural control actions to produce it, and the ability of the neuromuscular system to adapt through interactions with the environment. This allows us to articulate a succinct overview of a few salient conceptual paradoxes and contradictions regarding under-determined vs. over-determined mechanics, under- vs. over-actuated control, prescribed vs. emergent function, learning vs. implementation vs. adaptation, prescriptive vs. descriptive synergies, and optimal vs. habitual performance. We conclude by presenting open questions and suggesting directions for future research. We hope this frank and open-minded assessment of the state-of-the-art will encourage and guide these communities to continue to interact and make progress in these important areas at the interface of neuromechanics, neuroscience, rehabilitation and robotics.


WIN55,212-2 induces caspase-independent apoptosis on human glioblastoma cells by regulating HSP70, p53 and Cathepsin D.
Despite the standard approaches to treat the highly aggressive and invasive glioblastoma (GBM), it remains incurable. In this sense, cannabinoids highlight as a promising tool, because this tumor overexpresses CB1 and/or CB2 receptors and being, therefore, can be susceptible to cannabinoids treatment. Thus, this work investigated the action of the cannabinoid agonist WIN55-212-2 on GBM cell lines and non-malignant cell lines, in vitro and in vivo. WIN was selectively cytotoxic to GBM cells. These presented blebbing and nuclear alterations in addition to cell shrinkage and chromatin condensation. WIN also significantly inhibited the migration of GAMG and U251 cells. Finally, the data also showed that the antitumor effects of WIN are exerted, at least to some extent, by the expression of p53 and increased cathepsin D in addition to the decreased expression of HSP70.This data can indicate caspase-independent cell death mechanism. In addition, WIN decreased tumoral perimeter as well as caused a reduction the blood vessels in this area, without causing lysis, hemorrhage or blood clotting. So, the findings herein presented reinforce the usefulness of cannabinoids as a candidate for further evaluation in treatment in glioblastoma treatment.


Unsupervised Discovery of Demixed, Low-Dimensional Neural Dynamics across Multiple Timescales through Tensor Component Analysis.
Perceptions, thoughts, and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor component analysis (TCA) can meet this challenge by extracting three interconnected, low-dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.


An algorithm for the detection of faces on the basis of Gabor features and information maximization.
We propose an algorithm for the detection of facial regions within input images. The characteristics of this algorithm are (1) a vast number of Gabor-type features (196,800) in various orientations, and with various frequencies and central positions, which are used as feature candidates in representing the patterns of an image, and (2) an information maximization principle, which is used to select several hundred features that are suitable for the detection of faces from among these candidates. Using only the selected features in face detection leads to reduced computational cost and is also expected to reduce generalization error. We applied the system, after training, to 42 input images with complex backgrounds (Test Set A from the Carnegie Mellon University face data set). The result was a high detection rate of 87.0%, with only six false detections. We compared the result with other published face detection algorithms.


The diagnosis of schizophrenia and its impact on the primary caregiver.
This qualitative study investigates how the diagnosis of schizophrenia in a young adult impacts on the primary caregiver in the family. In this study all participants were mothers who had sons recently diagnosed with schizophrenia. An extensive literature review revealed a lack of research in this area. The research methodology is described. Data analysis determined themes or patterns of experience amongst participants in this study. From this small study it was seen that the impact on the participants was intensely traumatic and far reaching. Six themes emerged: trauma/distress, fear, uncertainty, relief, disruption and powerlessness. The results have major implications for nurses and other health professionals working in the Mental Health field.


Noise characterization of a subsea tidal kite.
This paper presents the first noise measurements of a quarter-scale subsea tidal kite (anchored to the sea floor by a tether and flying in a figure-eight configuration in the water column) operating in field conditions. Challenges in the measurement and post-processing of the data are detailed. Results are presented for three operating conditions of the kite: (1) varying turbine rotations per minute (RPM), (2) varying kite speed, and (3) a twisted tether. Turbine RPM was identified as the main parameter influencing noise emissions.


Ethnic differences regarding arterial stiffness of 6-8-year-old black and white boys.
Vascular deterioration is suggested to occur earlier in black than white populations, thereby increasing their risk for developing hypertension. To establish whether this is the case, we compared different estimates of arterial stiffness in black and white children and investigated the links with body composition and advanced glycation end products (AGEs) as potential contributors. We included 40 black and 41 white boys (aged 6-8 years) from similar schools and measured arterial stiffness [pulse wave velocity (PWV) in different arterial sections, systemic arterial compliance and carotid stiffness estimates], anthropometry as well as urinary pentosidine as a marker of AGEs. Black boys displayed increased PWV [carotid-to-radial (P = 0.002), carotid-to-femoral (P < 0.0001) and carotid-to-dorsalis pedis (P = 0.008)], DBP (P = 0.001) and carotid intima-media thickness (P = 0.007) than white boys. Despite higher pentosidine in black boys (P = 0.039), arterial stiffness indices did not correlate with pentosidine in any group. However, only in black boys, pentosidine correlated negatively with BMI (P = 0.015), BSA (P = 0.017), weight (P = 0.018), waist (P = 0.022) and hip circumference (P = 0.010). Arterial stiffness indices related inversely to body composition in white boys, but femoral PWV correlated inversely with BMI (r = -0.32; P = 0.049) in black boys. Already at very young ages (6-8 years), with a high proportion of prehypertension, black boys in our study have increased arterial stiffness in all sections of the arterial tree, along with higher DBP, carotid intima-media thickness and AGEs. This phenotype underlines the increasing trend of early-onset vascular aging among black populations.


Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients.
Ascorbic acid (vitamin C, ascorbate) is a key water soluble antioxidant that, when administered in doses well above its recommended dietary allowance, may have preventative and therapeutic value against a number of pathologies. The intravenous administration of high dose ascorbate (IVC) has increased in popularity among complementary and alternative medicine practitioners: thousands of patients received IVC, at an average dose of 0.5 g/kg, without significant side effects. While IVC may have a variety of possible applications, it has generated the most interest for its potential use in treating cancer. Medical records of patients with cancer treated with IVC at the Riordan Clinic were retrospectively reviewed. Cancer patients, for whom plasma ascorbate concentration data before and after treatment were available, along with C-reactive protein (CRP) measurements, were chosen for analysis. The results of the analysis can be summarized as follows. IVC produces peak plasma ascorbate concentrations on the order of ten millimolars with lower peak plasma concentrations obtained in cancer patients as compared to healthy subjects. Cancer patients who are deficient in vitamin C prior to therapy tend to achieve lower plasma levels post infusion. High inflammation or tumor burdens, as measured by CRP or tumor antigen levels, tend to lower peak plasma ascorbate levels after IVC. When compared to patients with localized tumors, patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate concentrations. The data indicate that, while potentially therapeutic plasma ascorbate concentrations can be achieved with IVC, levels attained will vary based on tumor burden and degree of inflammation (among other factors). Evidence suggests that IVC may be able to modulate inflammation, which in turn might improve outcomes for cancer patients. IVC may serve as a safe, adjunctive therapy in clinical cancer care.


Substantial increase of malaria in inland areas of eastern French Guiana.
This study includes malaria cases diagnosed by the Parasitology Unit of the Cayenne Hospital (French Guiana) using the same procedure from 1996 to 2003. We provide data for two main rural communities in slightly inland areas of eastern French Guiana (Cacao, Regina) and for Cayenne, the capital of this French department. The frequency of bouts of malaria has been increasing rapidly since mid-2001, in these regions that were virtually considered to be malaria-free. This substantial increase of malaria appears mainly to involve Plasmodium vivax and recent Brazilian immigrants. Other plausible explanations which could account for the observed trend are discussed.


PDK2: a complex tail in one Akt.
The kinase Akt contains two phosphatidylinositol-3 kinase (PI3K)-dependent phosphorylation sites, one in the activation loop (Thr(308)) and one in the carboxyl-terminal tail (Ser(473)), both of which are conserved among the members of the AGC kinase family. Under physiological conditions, the phosphorylation of Thr(308) appears to be coordinately regulated with the phosphorylation of Ser(473). Under experimental conditions, however, the two sites can be uncoupled, suggesting that their phosphorylation is controlled by different kinases and phosphatases. Phosphoinositide-dependent kinase 1 (PDK1), the kinase that phosphorylates the activation loop site, has been unambiguously identified. However, PDK2, a kinase that is hypothesized to phosphorylate the hydrophobic carboxyl-terminal site, remains elusive. This Perspective examines the regulation and biological significance of Akt phosphorylation at Ser(473). The authors propose that Ser(473) undergoes both autophosphorylation and phosphorylation by other kinases. Both events may be promoted by interactions between PDK1 and phosphorylated or phosphomimetically altered hydrophobic phosphorylation motifs in kinases associated with Akt. These interactions may induce conformational changes in Akt that make Ser(473) accessible to phosphorylation.


Acquisition of Conditioning between Methamphetamine and Cues in Healthy Humans.
Environmental stimuli repeatedly paired with drugs of abuse can elicit conditioned responses that are thought to promote future drug seeking. We recently showed that healthy volunteers acquired conditioned responses to auditory and visual stimuli after just two pairings with methamphetamine (MA, 20 mg, oral). This study extended these findings by systematically varying the number of drug-stimuli pairings. We expected that more pairings would result in stronger conditioning. Three groups of healthy adults were randomly assigned to receive 1, 2 or 4 pairings (Groups P1, P2 and P4, Ns = 13, 16, 16, respectively) of an auditory-visual stimulus with MA, and another stimulus with placebo (PBO). Drug-cue pairings were administered in an alternating, counterbalanced order, under double-blind conditions, during 4 hr sessions. MA produced prototypic subjective effects (mood, ratings of drug effects) and alterations in physiology (heart rate, blood pressure). Although subjects did not exhibit increased behavioral preference for, or emotional reactivity to, the MA-paired cue after conditioning, they did exhibit an increase in attentional bias (initial gaze) toward the drug-paired stimulus. Further, subjects who had four pairings reported "liking" the MA-paired cue more than the PBO cue after conditioning. Thus, the number of drug-stimulus pairings, varying from one to four, had only modest effects on the strength of conditioned responses. Further studies investigating the parameters under which drug conditioning occurs will help to identify risk factors for developing drug abuse, and provide new treatment strategies.


On the Effect of Substrate Viscoelasticity on the Evaporation Kinetics and Deposition Patterns of Nanosuspension Drops.
This study investigates the evaporation of sessile pure water and nanosuspension drops on viscoelastic polydimethylsiloxane (PDMS) films. We varied the viscoelasticity of the PDMS films by controlling the curing ratio and categorized them into three types: stiff (10:1, 20:1, 40:1), soft (60:1, 80:1), and very soft (100:1, 120:1, 140:1, 160:1). On stiff surfaces, pure water drops initially evaporate in a constant contact radius (CCR) mode, followed by a constant contact angle mode, and finally in a mixed mode of evaporation. Nanosuspension drops follow the same trend as water drops but with a difference toward the end of their lifetimes, when a short second CCR mode is observed. Complete evaporation of nanosuspension drops on stiff substrates leads to particle deposition patterns similar to a coffee ring with cracks and deposition tails. On soft surfaces, the initial spreading is followed by a pseudo-CCR mode. Complete evaporation of nanosuspension drops on soft substrates leads to deposits in the form of a uniform ring with a sharp ox-horn profile. Unexpectedly, the initial spreading is followed by a mixed mode on very soft substrates, on which wetting ridges (WRs) pulled up by the vertical component of surface tension are clearly observed in the vicinity of the contact line (CL). As the evaporation proceeds, the decreasing contact angle breaks the force balance in the horizontal direction at the CL and gives rise to a net horizontal force, which causes the CL to recede, transferring the horizontal force to the WR. Because of the viscoelastic nature of the very soft substrate, this horizontal force acting on the WR cannot be completely countered by the bulk of the substrate underneath. As a result, the WR moves horizontally in a viscous-flow way, which also enables the CL to be continuously anchored to the ridge and to recede relative to the bulk of the substrate. Consequently, a mixed mode of evaporation occurs. Complete evaporation of nanosuspension drops on very soft substrates leads to finger-like deposits.


Reaching high-risk underserved individuals for cancer genetic counseling by video-teleconferencing.
Breast and colorectal cancers are common cancers for which genetic risk assessment and counseling are available. However, these services are often limited to metropolitan areas and are not readily accessible to underserved populations. Moreover, ethnic and racial disparities present additional obstacles to identifying and screening high-risk individuals and have a bearing on treatment outcomes. To provide cancer genetic risk assessment and counseling through telemedicine to the remote, underserved primarily Hispanic population of the Texas-Mexico border region. Program participants were mailed a questionnaire to assess their satisfaction with the program so that we could determine the acceptability of video-teleconferencing for cancer risk assessment. The overall level of satisfaction with the program was very high, demonstrating the acceptability of a cancer genetic risk assessment program that relied on telemedicine to reach and underserved minority community. Delivery model requires the availability of and access to communication technologies; trained staff are needed at remote sites for sample collection and patient handling. Video-teleconferencing is an acceptable method of providing cancer risk assessment in a remote, underserved population.


In vitro assessment of flow patterns and turbulence intensity in prosthetic heart valves using generalized phase-contrast MRI.
To assess in vitro the three-dimensional mean velocity field and the extent and degree of turbulence intensity (TI) in different prosthetic heart valves using a generalization of phase-contrast MRI (PC-MRI). Four 27-mm aortic valves (Björk-Shiley Monostrut tilting-disc, St. Jude Medical Standard bileaflet, Medtronic Mosaic stented and Freestyle stentless porcine valve) were tested under steady inflow conditions in a Plexiglas phantom. Three-dimensional PC-MRI data were acquired to measure the mean velocity field and the turbulent kinetic energy (TKE), a direction-independent measure of TI. Velocity and TI estimates could be obtained up- and downstream of the valves, except where metallic structure in the valves caused signal void. Distinct differences in the location, extent, and peak values of velocity and TI were observed between the valves tested. The maximum values of TKE varied between the different valves: tilting disc, 100 J/m(3); bileaflet, 115 J/m(3); stented, 200 J/m(3); stentless, 145 J/m(3). The TI downstream from a prosthetic heart valve is dependent on the specific valve design. Generalized PC-MRI can be used to quantify velocity and TI downstream from prosthetic heart valves, which may allow assessment of these aspects of prosthetic valvular function in postoperative patients.


Enhancing Adoption of a Home-Based Exercise Program for Mild Balance Dysfunction: A Qualitative Study.
The aim was to identify barriers and opportunities facing community health physiotherapists in delivering a home-based balance exercise program to address mild balance dysfunction and, secondly, to understand the perspectives of older people in adopting this program. Focus groups, written surveys, and data recording sheets were used with nine older people and five physiotherapists. Focus groups were audio taped, transcribed, and coded independently by two researchers. Thematic content analysis was undertaken. Emerging themes were: engaging in preventive health (various benefits, enhancing independence); adoption of strategies (acceptable design and implementation feasibility); exercising in context (convenience, practicality, and safety); and broader implementation issues (program design, proactive health messages, and a solid evidence base). The views of older people and physiotherapists were sought to understand the adoption of a previously successful home-based program for mild balance dysfunction. Understanding the unique context and circumstances for individuals and organizations will enhance adoption.