Structural characterisation of two forms of procyclic acidic repetitive protein expressed by procyclic forms of Trypanosoma brucei.
A procyclic acidic repetitive protein (PARP) fraction was purified from long-term cultures of Trypanosoma brucei procyclic forms by a solvent-extraction and reverse phase chromatography procedure. The PARP fraction yielded small quantities of a single N-linked oligosaccharide with the structure Man alpha1-6(Man alpha1-3)Man alpha1-6(Man alpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc (Man5GlcNAc2). Fractionation of PARP on Con A-Sepharose revealed that the majority (80 to 90%) of the PARP fraction did not bind to Con A and was composed of the parpA alpha gene product that contains repeats of -Glu-Pro-Pro-Thr- (GPEET-PARP) and that lacks an N-glycosylation site. This form of PARP has not been previously identified at the protein-level. The minor Con-A-binding fraction was shown to be rich in the previously described form of PARP, encoded by the parpAbeta and/or parpB alpha genes, that contains a -Glu-Pro- repeat domain (EP-PARP) and an N-glycosylation site. Analysis of longer and shorter-term cultures suggested that procyclic cells initially express predominantly EP-PARP that is gradually replaced by GPEET-PARP. Both forms of PARP were shown to contain indistinguishable glycosylphosphatidylinositol (GPI) membrane anchors, where the conserved GPI core structure is substituted by heterogeneous sialylated branched polylactosamine-like structures that are predicted to form a dense surface glycocalyx above which the polyanionic -Glu-Pro-Pro-Thr- and -Glu-Pro- repeat domains are displayed. The phosphatidylinositol (PI) component of the GPI anchor was shown to be a mixture of 2-O-acyl-myo-inositol-1-HPO4-(sn-1-stearoyl-2-lyso-glycerol) and 2-O-acyl-myo-inositol-1-HPO4-(sn-1-octadecyl-2-lyso-glycerol), where the acyl chain substituting the inositol ring showed considerable heterogeneity. Mass spectrometric and light scattering experiments both suggested an average mass of approximately 15 kDa for GPEET-PARP, with individual glycoforms ranging from about 12 kDa to 20 kDa, that is consistent with its amino acid and carbohydrate composition. A measured translational diffusion coefficient of 3.9 x 10(7) cm2 s(-1) indicates that this molecule has a highly elongated shape. The possible functions of these unusual glycoproteins are discussed.


Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis.
Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10(-6) M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors.


Understanding solid/solid organic reactions.
The concept of an organic reaction between two macroscopic solid particles is investigated. Thus, we study several reactions that have been recently reported to proceed "in the solid phase" and clearly show that, in most cases, grinding the two solid reactants together results in the formation of a liquid phase. This is true both for catalytic transformations (e.g., aldol condensations and oligomerization of benzylic compounds) and for noncatalytic reactions (Baeyer-Villiger oxidations, oxidative coupling of naphthols using iron chloride, condensation of amines and aldehydes to form azomethines, homo-etherification of benzylic alcohols using p-toluenesulfonic acid, and nuclear aromatic bromination with NBS). This liquefaction implies the existence of a eutectic mixture with T(fusion) below ambient temperature (although both reagents have higher than ambient melting points). In cases where heating is required, it is again clear that a phase change (from solid to liquid) occurs, explaining the observed reaction kinetics. On the basis of 19 experimental examples, we discuss the possibility of solid-phase organic reactions and the implications of these findings to the reaction between two solid reagents. A general description of such reactive systems is proposed, based on a consideration of the potential for eutectic (or peritectic) formation between the constituents of the liquid phases that arise during the process of mechanical mixing of the solid reagents and products.


Unaltered Fungal Burden and Lethality in Human CEACAM1-Transgenic Mice During Candida albicans Dissemination and Systemic Infection.
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is a receptor for Candida albicans. It is crucial for the immune response of intestinal epithelial cells to this opportunistic pathogen. Moreover, CEACAM1 is of importance for the mucosal colonization by different bacterial pathogens. We therefore studied the influence of the human CEACAM1 receptor in human CEACAM1-transgenic mice on the C. albicans colonization and infection utilizing a colonization/dissemination and a systemic infection mouse model. Our results showed no alterations in the host response between the transgenic mice and the wild-type littermates to the C. albicans infections. Both mouse strains showed comparable C. albicans colonization and mycobiota, similar fungal burdens in various organs, and a similar survival in the systemic infection model. Interestingly, some of the mice treated with anti-bacterial antibiotics (to prepare them for C. albicans colonization via oral infection) also showed a strong reduction in endogenous fungi instead of the normally observed increase in fungal numbers. This was independent of the expression of human CEACAM1. In the systemic infection model, the human CEACAM1 expression was differentially regulated in the kidneys and livers of Candida-infected transgenic mice. Notably, in the kidneys, a total loss of the largest human CEACAM1 isoform was observed. However, the overwhelming immune response induced in the systemic infection model likely covered any CEACAM1-specific effects in the transgenic animals. In vitro studies using bone marrow-derived neutrophils from both mouse strains also revealed no differences in their reaction to C. albicans. In conclusion, in contrast to bacterial pathogens interacting with CEACAM1 on different mucosal surfaces, the human CEACAM1-transgenic mice did not reveal a role of human CEACAM1 in the in vivo candidiasis models used here. Further studies and different approaches will be needed to reveal a putative role of CEACAM1 in the host response to C. albicans.


Gene Regulatory Networks for the Haploid-to-Diploid Transition of Chlamydomonas reinhardtii.
The sexual cycle of the unicellular Chlamydomonas reinhardtii culminates in the formation of diploid zygotes that differentiate into dormant spores that eventually undergo meiosis. Mating between gametes induces rapid cell wall shedding via the enzyme g-lysin; cell fusion is followed by heterodimerization of sex-specific homeobox transcription factors, GSM1 and GSP1, and initiation of zygote-specific gene expression. To investigate the genetic underpinnings of the zygote developmental pathway, we performed comparative transcriptome analysis of both pre- and post-fertilization samples. We identified 253 transcripts specifically enriched in early zygotes, 82% of which were not up-regulated in gsp1 null zygotes. We also found that the GSM1/GSP1 heterodimer negatively regulates the vegetative wall program at the posttranscriptional level, enabling prompt transition from vegetative wall to zygotic wall assembly. Annotation of the g-lysin-induced and early zygote genes reveals distinct vegetative and zygotic wall programs, supported by concerted up-regulation of genes encoding cell wall-modifying enzymes and proteins involved in nucleotide-sugar metabolism. The haploid-to-diploid transition in Chlamydomonas is masterfully controlled by the GSM1/GSP1 heterodimer, translating fertilization and gamete coalescence into a bona fide differentiation program. The fertilization-triggered integration of genes required to make related, but structurally and functionally distinct organelles-the vegetative versus zygote cell wall-presents a likely scenario for the evolution of complex developmental gene regulatory networks.


Parallel optical readout of cantilever arrays in dynamic mode.
Parallel frequency readout of an array of cantilevers is demonstrated using optical beam deflection with a single laser-diode pair. Multi-frequency addressing makes the individual nanomechanical response of each cantilever distinguishable within the received signal. Addressing is accomplished by exciting the array with the sum of all cantilever resonant frequencies. This technique requires considerably less hardware compared to other parallel optical readout techniques. Readout is demonstrated in beam deflection mode and interference mode. Many cantilevers can be readout in parallel, limited by the oscillators' quality factor and available bandwidth. The proposed technique facilitates parallelism in applications at the nano-scale, including probe-based data storage and biological sensing.


Proximal ulnar reconstruction with strut allograft in revision total elbow arthroplasty.
The growing frequency of joint arthroplasty has led to increasing numbers of patients requiring revision surgery. In the treatment of a failed total elbow arthroplasty not associated with infection, one of the main issues is poor or absent proximal ulnar bone stock due to osteolysis. We report our experience with the use of strut allograft reconstruction of the proximal part of the ulna as an adjunct to revision total elbow arthroplasty with a noncustom implant. Our aim was to better define the indications, outcomes, and complications of this technique in a population of patients with a failed total elbow arthroplasty. We reviewed the cases of patients with aseptic failure of a total elbow replacement and proximal ulnar bone deficiency who were treated with allograft bone struts. The patients had had an average of 2.5 (range, one to four) prior open osseous operations addressing the elbow joint. In addition to revision of the prosthetic components, the deficient bone stock was treated with allograft strut grafts in one of four ways: (1) discrete cortical defects were contained, (2) periprosthetic fractures were splinted, (3) deficient triceps attachments were reconstructed, and (4) expanded segments were augmented with struts and filled with impaction graft. Twenty-one patients (twenty-two elbows) were followed for an average of four years (range, two to eleven years). The mean Mayo Elbow Performance Score improved from 34 points preoperatively to 79 points at the time of the latest follow-up. The scores for pain, stability, and activities of daily living improved most; there was little change in motion. Complications, consisting of four soft-tissue and four osseous problems, occurred in eight patients. Three patients had incorporation of 26% to 50% of the graft; five, 51% to 75%; and fourteen, 76% to 100%. Most deficiencies of proximal ulnar bone stock and fractures complicating revision total elbow surgery can be treated with allograft strut grafting. Although the complication rate is high, this technique is suitable for discrete cortical lesions, periprosthetic fractures, and an expanded proximal part of the ulna, which also requires augmentation with impaction grafting. The technique has been unreliable, however, in restoring deficient olecranon bone stock.


Anammox moving bed biofilm reactor pilot at the 26th Ward wastewater treatment plants in Brooklyn, New York: start-up, biofilm population diversity and performance optimization.
New York City Environmental Protection in conjunction with City College of New York assessed the application of the anammox process in the reject water treatment using a moving bed biofilm reactor (MBBR) located at the 26th Ward wastewater treatment plant, in Brooklyn, NY. The single-stage nitritation/anammox MBBR was seeded with activated sludge and consequently was enriched with its own 'homegrown' anammox bacteria (AMX). Objectives of this study included collection of additional process kinetic and operating data and assessment of the effect of nitrogen loading rates on process performance. The initial target total inorganic nitrogen removal of 70% was limited by the low alkalinity concentration available in the influent reject water. Higher removals were achieved after supplementing the alkalinity by adding sodium hydroxide. Throughout startup and process optimization, quantitative real-time polymerase chain reaction (qPCR) analyses were used for monitoring the relevant species enriched in the biofilm and in the suspension. Maximum nitrogen removal rate was achieved by stimulating the growth of a thick biofilm on the carriers, and controlling the concentration of dissolved oxygen in the bulk flow and the nitrogen loading rates per surface area; all three appear to have contributed in suppressing nitrite-oxidizing bacteria activity while enriching AMX density within the biofilm.


Cloning, sequencing, and disruption of the Bacillus subtilis psd gene coding for phosphatidylserine decarboxylase.
The psd gene of Bacillus subtilis Marburg, encoding phosphatidylserine decarboxylase, has been cloned and sequenced. It encodes a polypeptide of 263 amino acid residues (deduced molecular weight of 29,689) and is located just downstream of pss, the structural gene for phosphatidylserine synthase that catalyzes the preceding reaction in phosphatidylethanolamine synthesis (M. Okada, H. Matsuzaki, I. Shibuya, and K. Matsumoto, J. Bacteriol. 176:7456-7461, 1994). Introduction of a plasmid containing the psd gene into temperature-sensitive Escherichia coli psd-2 mutant cells allowed growth at otherwise restrictive temperature. Phosphatidylserine was not detected in the psd-2 mutant cells harboring the plasmid; it accumulated in the mutant up to 29% of the total phospholipids without the plasmid. An enzyme activity that catalyzes decarboxylation of 14C-labeled phosphatidylserine to form phosphatidylethanolamine was detected in E. coli psd-2 cells harboring a Bacillus psd plasmid. E. coli cells harboring the psd plasmid, the expression of which was under the control of the T7phi10 promoter, produced proteins of 32 and 29 kDa upon induction. A pulse-labeling experiment suggested that the 32-kDa protein is the primary translation product and is processed into the 29-kDa protein. The psd gene, together with pss, was located by Southern hybridization to the 238- to 306-kb SfiI-NotI fragment of the chromosome. A B. subtilis strain harboring an interrupted psd allele, psd1::neo, was constructed. The null psd mutant contained no phosphatidylethanolamine and accumulated phosphatidylserine. It grew well without supplementation of divalent cations which are essential for the E. coli pssA null mutant lacking phosphatidylethanolamine. In both the B. subtilis null pss and psd mutants, glucosyldiacylglycerol content increased two- to fourfold. The results suggest that the lack of phosphatidylethanolamine in the B. subtilis membrane may be compensated for by the increases in the contents of glucosyldiacylglycerols by an unknown mechanism.


A novel smartphone ophthalmic imaging adapter: User feasibility studies in Hyderabad, India.
To evaluate the ability of ancillary health staff to use a novel smartphone imaging adapter system (EyeGo, now known as Paxos Scope) to capture images of sufficient quality to exclude emergent eye findings. Secondary aims were to assess user and patient experiences during image acquisition, interuser reproducibility, and subjective image quality. The system captures images using a macro lens and an indirect ophthalmoscopy lens coupled with an iPhone 5S. We conducted a prospective cohort study of 229 consecutive patients presenting to L. V. Prasad Eye Institute, Hyderabad, India. Primary outcome measure was mean photographic quality (FOTO-ED study 1-5 scale, 5 best). 210 patients and eight users completed surveys assessing comfort and ease of use. For 46 patients, two users imaged the same patient's eyes sequentially. For 182 patients, photos taken with the EyeGo system were compared to images taken by existing clinic cameras: a BX 900 slit-lamp with a Canon EOS 40D Digital Camera and an FF 450 plus Fundus Camera with VISUPAC™ Digital Imaging System. Images were graded post hoc by a reviewer blinded to diagnosis. Nine users acquired 719 useable images and 253 videos of 229 patients. Mean image quality was ≥ 4.0/5.0 (able to exclude subtle findings) for all users. 8/8 users and 189/210 patients surveyed were comfortable with the EyeGo device on a 5-point Likert scale. For 21 patients imaged with the anterior adapter by two users, a weighted κ of 0.597 (95% confidence interval: 0.389-0.806) indicated moderate reproducibility. High level of agreement between EyeGo and existing clinic cameras (92.6% anterior, 84.4% posterior) was found. The novel, ophthalmic imaging system is easily learned by ancillary eye care providers, well tolerated by patients, and captures high-quality images of eye findings.


Tiotropium bromide step-up therapy for adults with uncontrolled asthma.
Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).


Subjective headache before and after endoscopic sinus surgery.
The aim of this study was to show the effect of endoscopic sinus surgery on subjective headache scores in patients diagnosed with chronic rhinosinusitis (CRS) with or without nasal polyps. We performed a retrospective analysis of prospectively collected data from 201 patients over a 2-year period. Headache and Sino-Nasal Outcomes Test (SNOT-20) mean scores were compared preoperatively and 2 years postoperatively on patients diagnosed with CRS with or without nasal polyps. Two hundred one patients underwent surgical management of CRS with or without nasal polyps over a 3-year period. One hundred four patients were men and 97 were women, with a mean age of 49 (range, 18-80 years) years. Polyps were present in 78 patients with CRS. The mean subjective headache score based on a 0-10 visual analog scale improved from 4.7 preoperatively to 0.8 2 years postoperatively (p < 0.0001). The mean headache score of 123 patients without polyps was larger compared with 78 patients with polyps (5.1 versus 4.1, respectively; p < 0.05). As previously reported, the mean overall preoperative and postoperative SNOT-20 scores were 28.7 and 6.7, respectively (p < 0.0001). Headache is a common symptom with CRS, present in 73.6% of our patients undergoing functional endoscopic sinus surgery for CRS with or without nasal polyps. An overall decrease in mean headache scores was noted at 2-year follow-up.


Controlling Neglected Tropical Diseases (NTDs) in Haiti: Implementation Strategies and Evidence of Their Success.
Lymphatic filariasis (LF) and soil-transmitted helminths (STH) have been targeted since 2000 in Haiti, with a strong mass drug administration (MDA) program led by the Ministry of Public Health and Population and its collaborating international partners. By 2012, Haiti's neglected tropical disease (NTD) program had reached full national scale, and with such consistently good epidemiological coverage that it is now able to stop treatment for LF throughout almost all of the country. Essential to this success have been in the detail of how MDAs were implemented. These key programmatic elements included ensuring strong community awareness through an evidence-based, multi-channel communication and education campaign facilitated by voluntary drug distributors; strengthening community trust of the drug distributors by ensuring that respected community members were recruited and received appropriate training, supervision, identification, and motivation; enforcing a "directly observed treatment" strategy; providing easy access to treatment though numerous distribution posts and a strong drug supply chain; and ensuring quality data collection that was used to guide and inform MDA strategies. The evidence that these strategies were effective lies in both the high treatment coverage obtained- 100% geographical coverage reached in 2012, with almost all districts consistently achieving well above the epidemiological coverage targets of 65% for LF and 75% for STH-and the significant reduction in burden of infection- 45 communes having reached the target threshold for stopping treatment for LF. By taking advantage of sustained international financial and technical support, especially during the past eight years, Haiti's very successful MDA campaign resulted in steady progress toward LF elimination and development of a strong foundation for ongoing STH control. These efforts, as described, have not only helped establish the global portfolio of "best practices" for NTD control but also are poised to help solve two of the most important future NTD challenges-how to maintain control of STH infections after the community-based LF "treatment platform" ceases and how to ensure appropriate morbidity management for patients currently suffering from lymphatic filarial disease.


Terahertz notch and low-pass filters based on band gaps properties by using metal slits in tapered parallel-plate waveguides.
We present a tunable notch filter having a wide terahertz (THz) frequency range and a low-pass filter (LPF) having a 0.78 THz cutoff frequency. Single slit and multiple slits are positioned at the center of air gaps in tapered parallel-plate waveguides (TPPWG) to obtain the notch filter and LPF, respectively. The notch filter has a dispersion-free and low-loss transverse magnetic (TM) mode. The Q factor was proved to be 138, and the resonant frequency is easily tunable by adjusting the air gaps between TPPWG. On the other hand, the cut off frequency of the LPF was determined using a Bragg stop band, which depends on slit period. The LPF has a transition width of 68 GHz at the cutoff frequency and a dynamic range of 35 dB at stop bands. In addition, the characteristics of such filters were analyzed using finite-difference time-domain (FDTD) simulations.


Enhanced faint companion photometry and astrometry using wavelength diversity.
In this paper we examine approaches to faint companion detection and estimation in multi-spectral images. We will employ the Hotelling observer, which is the optimal linear algorithm for signal detection. We have shown how to use this observer to estimate faint object position and brightness in the presence of residual speckle, which usually limits astrometric and photometric techniques. These speckles can be reduced by differential imaging techniques such as Angular Differential Imaging and Spectral Differential Imaging. Here we present results based on simulations of adaptive-optics-corrected images from an Extremely Large Telescope (ELT) that contain quasi-static speckle noise. The simulation includes Angular Differential Imaging and Spectral Differential Imaging to reduce the residual speckle and subsequent multi-wavelength processing. We examine the feasibility of this approach on simulated ELT observations of faint companions.


Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis.
To rescue visual loss and optic neuropathy in experimental autoimmune encephalomyelitis (EAE). Encephalomyelitis was induced in mice that received intravitreal injections of AAV2-mtHSP70Flag or AAV2-Cox8-mCherry. Additional mice were injected with AAV2-Cox8-mCherry, but not sensitized for EAE. Visual function was assessed by pattern electroretinograms (PERG) at 1, 3, and 6 months post injection (MPI). Optical coherence tomography (OCT) evaluated the thickness of the inner plexiform layer + nerve fiber layers at 1, 3, and 6 MPI. Retinas and optic nerves (ONs) of mice euthanized 6 MPI were processed for light and electron microscopy. Expression of mtHSP70Flag in the retina and ONs was evaluated by RT-PCR, immunofluorescence, and Western blotting. The activities of respiratory complexes I and III, as well as mitochondrial protein import were quantitated. Expression: immunofluorescence revealed punctate and perinuclear expression of mtHSP70Flag that colocalized with mitochondrial porin in thy1.2 labeled retinal ganglion cells (RGCs). Immunoblotting and RT-PCR confirmed mtHSP70Flag expression in the retina and ON. Rescue: treatment with mtHSP70Flag resulted in a 44% increase in PERG amplitude and less delays in latency relative to the EAE-mCherry group that also showed progressive inner retinal thinning. At 6 MPI, the almost 50% loss of RGCs and optic nerve axons in EAE mice was suppressed by mtHSP70Flag. In addition, retinas of EAE-mtHSP70Flag mice showed nearly complete rescue of complex I and III activities that was reduced by one-third in the EAE-mCherry retinas. Lastly, reductions in import of COX8-mCherry into mitochondria of mice sensitized for EAE improved by 30% with mtHSP70Flag gene therapy. Mitochondrial HSP70 ameliorates mitochondrial dysfunction that culminates in irreversible visual loss and atrophy of the optic nerve in EAE suggesting that it may be useful to prevent irreversible disability in patients with optic neuritis and multiple sclerosis (MS).


Mealybug transmission of Grapevine leafroll viruses: an analysis of virus-vector specificity.
To understand ecological factors mediating the spread of insect-borne plant pathogens, vector species for these pathogens need to be identified. Grapevine leafroll disease is caused by a complex of phylogenetically related closteroviruses, some of which are transmitted by insect vectors; however, the specificities of these complex virus-vector interactions are poorly understood thus far. Through biological assays and phylogenetic analyses, we studied the role of vector-pathogen specificity in the transmission of several grapevine leafroll-associated viruses (GLRaVs) by their mealybug vectors. Using plants with multiple virus infections, several virus species were screened for vector transmission by the mealybug species Planococcus ficus and Pseudococcus longispinus. We report that two GLRaVs (-4 and -9), for which no vector transmission evidence was available, are mealybug-borne. The analyses performed indicated no evidence of mealybug-GLRaV specificity; for example, different vector species transmitted GLRaV-3 and one vector species, Planococcus ficus, transmitted five GLRaVs. Based on available data, there is no compelling evidence of vector-virus specificity in the mealybug transmission of GLRaVs. However, more studies aimed at increasing the number of mealybug species tested as vectors of different GLRaVs are necessary. This is especially important given the increasing importance of grapevine leafroll disease spread by mealybugs in vineyards worldwide.


Therapeutic Promises of Chlorogenic Acid with Special Emphasis on its Anti-Obesity Property.
Chlorogenic acid (CGA) is a quinic acid conjugate of caffeic acid. It is an ester formed between caffeic acid and the 3-hydroxyl of L-quinic acid. This polyphenol is naturally present in substantial amount in the green coffee beans. Minor quantities of CGA are also reported in apples, eggplant, blueberries, tomatoes, strawberries and potatoes. CGA is reported to be beneficial in hypertension, hyperglycemia, antimicrobial, antitumor, memory enhancer, weight management etc. Further, it is also reported to have anticancer, antioxidant and anti-inflammatory activities. Since the last decade, CGA drew public attention for its widely recommended use as a medicine or natural food additive supplement for the management of obesity. The current review explores the medicinal promises of CGA and emphasizes on its antiobese property as reported by various scientific reports and publication. CGA shows promises as an antioxidant, glycemic control agent, anti-hypertensive, antiinflammatory, antimicrobial, neuro-protective and anti-obesity agent. It primarily activates the AMPactivated protein kinase, inhibits 3-hydroxy 3-methylglutaryl coenzyme-A reductase and strengthens the activity of carnitine palmitoyltransferase to control the obesity.


Prevalence of dating violence among sexual minority youth: variation across gender, sexual minority identity and gender of sexual partners.
Dating violence during adolescence negatively influences concurrent psychosocial functioning, and has been linked with an increased likelihood of later intimate partner violence. Identifying who is most vulnerable for this negative outcome can inform the development of intervention practices addressing this problem. The two goals of this study were to assess variations in the prevalence of dating violence across different measures of sexual minority status (e.g., sexual minority identity or same-sex sexual behavior), and to assess whether this association was mediated by bullying, the number of sexual partners, binge drinking or aggressive behaviors. These goals were assessed by employing the Massachusetts Youth Risk Behavior Survey (N = 12,984), a regionally representative sample of youth ages 14-18. In this sample, a total of 540 girls and 323 boys reported a non-heterosexual identity, and 429 girls and 230 boys reported having had one or more same-sex sexual partners. The results generally supported a higher prevalence of dating violence among sexual minority youth. This vulnerability varied considerably across gender, sexual minority identity and the gender of sexual partners, but generally persisted when accounting for the mediating variables. The findings support investigating dating violence as a mechanism in the disparities between sexual minority and heterosexual youth, and the importance of addressing sexual minority youth specifically in interventions targeting dating violence.


Autophagic Degradation of Collagen 1A1 by Cortisol in Human Amnion Fibroblasts.
Rupture of fetal membranes can initiate parturition at both term and preterm. Collagen is the crucial factor determining the tensile strength of the membranes. Toward the end of gestation, a feed-forward regeneration of cortisol via 11β-hydroxysteroid dehydrogenase 1 exists in fetal membranes. It remains undetermined whether cortisol contributes to collagen reduction in fetal membranes. In this study, we have examined whether cortisol accumulation is a causative factor for collagen reduction in human amnion fibroblasts, the major source of collagens in the membranes. Cortisol had no effect on collagen 1A1 (COL1A1) and 1A2 (COL1A2) messenger RNA (mRNA) abundance but decreased their protein abundance. The latter effect was affected by neither mRNA transcription inhibitor nor protein translation inhibitor. Mechanistic studies revealed that the reduction in COL1A1 but not COL1A2 protein by cortisol was blocked by lysosome inhibitor chloroquine or small interfering RNA (siRNA)-mediated knockdown of autophagy-related protein 7, an essential protein for autophagy, whereas the proteasome inhibitors MG132 and bortezomib were ineffective. Further analysis showed that cortisol dose dependently increased the ratio of LC3II/LC3I, a marker of lysosome activation, an effect blocked by the glucocorticoid receptor (GR) antagonist RU486 and siRNA-mediated knockdown of GR. Consistently, cortisol decreased COL1A1 and COL1A2 protein abundance in amnion tissue explants, and decreased COL1A1 and COL1A2 protein abundance was observed at parturition in the amnion tissue. Conclusively, cortisol regeneration in fetal membranes may contribute to rupture of fetal membranes at parturition by reducing collagen protein abundance. Lysosome-mediated autophagy accounts for the reduction in COL1A1 by cortisol, but the mechanism underlying the reduction in COL1A2 awaits further investigation.


Spatial navigation by congenitally blind individuals.
Spatial navigation in the absence of vision has been investigated from a variety of perspectives and disciplines. These different approaches have progressed our understanding of spatial knowledge acquisition by blind individuals, including their abilities, strategies, and corresponding mental representations. In this review, we propose a framework for investigating differences in spatial knowledge acquisition by blind and sighted people consisting of three longitudinal models (i.e., convergent, cumulative, and persistent). Recent advances in neuroscience and technological devices have provided novel insights into the different neural mechanisms underlying spatial navigation by blind and sighted people and the potential for functional reorganization. Despite these advances, there is still a lack of consensus regarding the extent to which locomotion and wayfinding depend on amodal spatial representations. This challenge largely stems from methodological limitations such as heterogeneity in the blind population and terminological ambiguity related to the concept of cognitive maps. Coupled with an over-reliance on potential technological solutions, the field has diffused into theoretical and applied branches that do not always communicate. Here, we review research on navigation by congenitally blind individuals with an emphasis on behavioral and neuroscientific evidence, as well as the potential of technological assistance. Throughout the article, we emphasize the need to disentangle strategy choice and performance when discussing the navigation abilities of the blind population. For further resources related to this article, please visit the WIREs website.


Change in diet, physical activity, and body weight among young-adults during the transition from high school to college.
The freshmen year of college is likely a critical period for risk of weight gain among young-adults. A longitudinal observational study was conducted to examine changes in weight, dietary intake, and other health-related behaviors among first-year college students (n = 186) attending a public University in the western United States. Weight was measured at the beginning and end of fall semester (August - December 2005). Participants completed surveys about dietary intake, physical activity and other health-related behaviors during the last six months of high school (January - June 2005) in August 2005 and during their first semester of college (August - December 2005) in December 2005. 159 students (n = 102 women, 57 men) completed both assessments. The average BMI at the baseline assessment was 23.0 (standard deviation (SD) 3.8). Although the average amount of weight gained during the 15-week study was modest (1.5 kg), 23% of participants gained > or = 5% of their baseline body weight. Average weight gain among those who gained > or = 5% of baseline body weight was 4.5 kg. Those who gained > or = 5% of body weight reported less physical activity during college than high school, were more likely to eat breakfast, and slept more than were those who did not gain > or = 5% of body weight. Almost one quarter of students gained a significant amount of weight during their first semester of college. This research provides further support for the implementation of education or other strategies aimed at helping young-adults entering college to achieve or maintain a healthy body weight.


Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma.
TP53 mutations are extremely rare in malignant pleural mesothelioma (MPM). In TP53 wild-type tumors, the functional p53 protein can be inactivated by MDM2. A total of 61 patient samples were tested for their Mdm2 and p53 protein expression levels via immunohistochemistry. This study demonstrates nuclear Mdm2 expression in three out of four mesothelioma cell lines and 21.3% of the MPM specimens investigated. After silencing of the MDM2 gene by siRNA in MPM cell lines, Mdm2 immunoexpression is lost and cells show changes indicative of severe damage. Mdm2 protein expression in MPM is detected in epithelioid and biphasic subtypes only and is significantly associated with poor survival compared with Mdm2-negative tumors. This may be explained by increased Mdm2 levels possibly leading to an increased ubiquitilation and proteasomal degradation of functional p53 protein. Expression of Mdm2 is a strong prognostic factor associated with shortened overall survival in MPM.


Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition.
Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.


Myosin repertoire expansion coincides with eukaryotic diversification in the Mesoproterozoic era.
The last eukaryotic common ancestor already had an amazingly complex cell possessing genomic and cellular features such as spliceosomal introns, mitochondria, cilia-dependent motility, and a cytoskeleton together with several intracellular transport systems. In contrast to the microtubule-based dyneins and kinesins, the actin-filament associated myosins are considerably divergent in extant eukaryotes and a unifying picture of their evolution has not yet emerged. Here, we manually assembled and annotated 7852 myosins from 929 eukaryotes providing an unprecedented dense sequence and taxonomic sampling. For classification we complemented phylogenetic analyses with gene structure comparisons resulting in 79 distinct myosin classes. The intron pattern analysis and the taxonomic distribution of the classes suggest two myosins in the last eukaryotic common ancestor, a class-1 prototype and another myosin, which is most likely the ancestor of all other myosin classes. The sparse distribution of class-2 and class-4 myosins outside their major lineages contradicts their presence in the last eukaryotic common ancestor but instead strongly suggests early eukaryote-eukaryote horizontal gene transfer. By correlating the evolution of myosin diversity with the history of Earth we found that myosin innovation occurred in independent major "burst" events in the major eukaryotic lineages. Most myosin inventions happened in the Mesoproterozoic era. In the late Neoproterozoic era, a process of extensive independent myosin loss began simultaneously with further eukaryotic diversification. Since the Cambrian explosion, myosin repertoire expansion is driven by lineage- and species-specific gene and genome duplications leading to subfunctionalization and fine-tuning of myosin functions.


Universities scale like cities.
Recent studies of urban scaling show that important socioeconomic city characteristics such as wealth and innovation capacity exhibit a nonlinear, particularly a power law scaling with population size. These nonlinear effects are common to all cities, with similar power law exponents. These findings mean that the larger the city, the more disproportionally they are places of wealth and innovation. Local properties of cities cause a deviation from the expected behavior as predicted by the power law scaling. In this paper we demonstrate that universities show a similar behavior as cities in the distribution of the 'gross university income' in terms of total number of citations over 'size' in terms of total number of publications. Moreover, the power law exponents for university scaling are comparable to those for urban scaling. We find that deviations from the expected behavior can indeed be explained by specific local properties of universities, particularly the field-specific composition of a university, and its quality in terms of field-normalized citation impact. By studying both the set of the 500 largest universities worldwide and a specific subset of these 500 universities--the top-100 European universities--we are also able to distinguish between properties of universities with as well as without selection of one specific local property, the quality of a university in terms of its average field-normalized citation impact. It also reveals an interesting observation concerning the working of a crucial property in networked systems, preferential attachment.


Femtosecond temporal encoding in barium titanate.
We describe two-beam coupling and temporal encoding experiments in barium titanate. Volume gratings are created in the photorefractive material by 50-fs optical pulses. Information in the writing pulses may be encoded as spatially distributed volume gratings in the crystal. Femtosecond temporal waveform reconstruction is demonstrated.


Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome.
In mammals, several classes of monoallelic genes have been identified, including those subject to X-chromosome inactivation (XCI), genomic imprinting, and random monoallelic expression (RMAE). However, the extent to which these epigenetic phenomena are influenced by underlying genetic variation is unknown. Here we perform a systematic classification of allelic imbalance in mouse hybrids derived from reciprocal crosses of divergent strains. We observe that deviation from balanced biallelic expression is common, occurring in ∼20% of the mouse transcriptome in a given tissue. Allelic imbalance attributed to genotypic variation is by far the most prevalent class and typically is tissue-specific. However, some genotype-based imbalance is maintained across tissues and is associated with greater genetic variation, especially in 5' and 3' termini of transcripts. We further identify novel random monoallelic and imprinted genes and find that genotype can modify penetrance of parental origin even in the setting of large imprinted regions. Examination of nascent transcripts in single cells from inbred parental strains reveals that genes showing genotype-based imbalance in hybrids can also exhibit monoallelic expression in isogenic backgrounds. This surprising observation may suggest a competition between alleles and/or reflect the combined impact of cis- and trans-acting variation on expression of a given gene. Our findings provide novel insights into gene regulation and may be relevant to human genetic variation and disease.


Timeliness of follow-up after abnormal screening mammography.
Little information has been published concerning the timeliness of follow-up after abnormal mammography. This article presents data on follow-up after abnormal mammography, including differences in follow-up by age, race, mammographic interpretation, and type of tracking system. From unpublished data, the rate of timely follow-up 8 to 12 weeks after index abnormal mammography ranges from 69% to 99%. Women aged 65 and older, those of lower socioeconomic status, and those who are instructed to have repeat evaluations in four to six months have the highest proportion of untimely follow-up. With use of computer-based tracking systems, timely follow-up ranges from 89% to 99%. Computer-based tracking systems should be encouraged to promote timely follow-up of abnormal mammography. Further research is needed to better delineate those at risk for untimely follow-up after abnormal mammography, causes of untimely follow-up, the impact of untimely follow-up on breast cancer stage and mortality, and interventions that maximize timely follow-up.


Frequency of Translocation t(11;22)(q24;q12) Using Fluorescence In Situ Hybridization (FISH) in Histologically and Immunohistochemically Diagnosed Cases of Ewing's Sarcoma.
Introduction Ewing sarcoma (ES) family of tumors is one of the most common groups of malignancies arising in children, adolescents, and young adults. Although characteristic histology with immunohistochemical expression of CD99 and FLI1 after exclusion of other small round blue cell tumors is considered diagnostic of ES, frequency of typical ES translocation, i.e., t(11;22)(q24;q12) is not known in our population. Therefore, in this study, we aimed to evaluate the frequency of this translocation in histologically and immunohistochemically diagnosed cases of ES along with its association with other pathological parameters. Methods A total of 43 morphologically and immunohistochemically diagnosed cases of ES were included in the study. Fluorescence in situ hybridization (FISH) was performed on representative paraffin blocks to identify t(11;22)(q24;q12) translocation. Association with various clinicopathological characteristics was determined. Results Mean age of the patients was 18.23±9.57 years. Bone was the most commonly involved site (22; 51.2%) followed by soft tissue (17; 39.5%) and parenchymal organs (4; 9.3%). A total of 88.4% of cases were found to be FISH-positive for t(11;22)(q24;q12). No significant association of translocation positive cases was noted with tumor size or disease-free survival. Similarly, no significant association of tumor size with disease-free survival was found. Conclusions A significant proportion of cases of histologically diagnosed cases of ES exhibited characteristic t(11;22)(q24;q12). This signifies that histology along with immunohistochemistry is reliable for the diagnosis of this tumor; however, in difficult cases, FISH can be performed to detect characteristic translocation. Moreover, we did not find tumor size to be a significant prognostic indicator of survival in ES.


Beyond Adaptive Mental Functioning With Pain as the Absence of Psychopathology: Prevalence and Correlates of Flourishing in Two Chronic Pain Samples.
Chronic pain outcomes are traditionally defined in terms of disability and illness. A definition of adaptive functioning in the context of chronic pain beyond the mere absence of negative outcomes, is the ability to flourish (i.e., experience emotional, psychological and social well-being; Keyes, 2002). We explored in two chronic pain samples the prevalence and sociodemographic, physical and psychological correlates of flourishing, and complemented this exploration with a similar examination of (being at risk for) psychopathology to help contextualize findings. Sample 1 (n = 1498) was a nationally representative sample. Subgroups included people with regular joint pain (1), regular joint pain and rheumatoid arthritis (2) and without chronic pain (3). Using chi-square tests we calculated the prevalence of both mental health outcomes and examined if people with or without chronic pain were more/less likely to flourish/at risk for psychopathology. Sample 2 (n = 238) concerned baseline data of a Randomized Controlled Trial on the effectiveness of Acceptance and Commitment Therapy for chronic pain (Trompetter et al., 2015b). We performed logistic regression analysis to identify flourishers/those at risk for depression. The Mental Health Continuum-Short Form was used to measure flourishing. The prevalence of flourishing was 34% (recurrent joint pain) and 38% (recurrent joint pain and arthritis) in sample 1, and 23% in sample 2. Compared to those without chronic pain, people with chronic pain were as likely to flourish, but more likely to be at risk for psychopathology. In sample 2, both flourishing and being at risk for depression were related foremost to psychological correlates. While engaged living was the most important correlate of flourishing, pain catastrophizing and psychological inflexibility were most important correlates of being at risk for depression. In conclusion, people with chronic pain are able to flourish. Findings suggest that positive and negative chronic pain outcomes function on two different continua, with potentially unique protective and risk factors. The Psychological Flexibility model provides pathways to explain both poor and optimal functioning in the presence of chronic pain. A better understanding of people with chronic pain who are able to flourish can be a fruitful endeavor to improve chronic pain models and interventions.


Comment on "Non-linear photoelectron effect contributes to the formation of negative matrix ions in UV-MALDI".
Alonso and Zenobi (AZ) recently claimed "a comprehensive theoretical description of negative ion formation in UV-MALDI" (Phys. Chem. Chem. Phys., 2016, 18, 19574). Emphasizing photoelectrons, it is found to be unphysical in several respects, including violation of charge and mass conservation, and in the treatment of ablation, expansion and electron capture. It is not internally consistent, and ions created by the photoelectron mechanism are given artificial preference. Although AZ claimed the "first proposal for a comprehensive theoretical description of negative ion formation in UV-MALDI", the Coupled Physical and Chemical Dynamics model has successfully reproduced a number of phenomena relevant to negative ion production over many years.


Using data to attribute episodes of warming and cooling in instrumental records.
The observed global-warming rate has been nonuniform, and the cause of each episode of slowing in the expected warming rate is the subject of intense debate. To explain this, nonrecurrent events have commonly been invoked for each episode separately. After reviewing evidence in both the latest global data (HadCRUT4) and the longest instrumental record, Central England Temperature, a revised picture is emerging that gives a consistent attribution for each multidecadal episode of warming and cooling in recent history, and suggests that the anthropogenic global warming trends might have been overestimated by a factor of two in the second half of the 20th century. A recurrent multidecadal oscillation is found to extend to the preindustrial era in the 353-y Central England Temperature and is likely an internal variability related to the Atlantic Multidecadal Oscillation (AMO), possibly caused by the thermohaline circulation variability. The perspective of a long record helps in quantifying the contribution from internal variability, especially one with a period so long that it is often confused with secular trends in shorter records. Solar contribution is found to be minimal for the second half of the 20th century and less than 10% for the first half. The underlying net anthropogenic warming rate in the industrial era is found to have been steady since 1910 at 0.07-0.08 °C/decade, with superimposed AMO-related ups and downs that included the early 20th century warming, the cooling of the 1960s and 1970s, the accelerated warming of the 1980s and 1990s, and the recent slowing of the warming rates. Quantitatively, the recurrent multidecadal internal variability, often underestimated in attribution studies, accounts for 40% of the observed recent 50-y warming trend.


Late outcome after repair of aortico-left ventricular tunnel: 10-year follow-up.
Despite successful surgical repair, patients with congenital aortico-left ventricular tunnel (ALVT) are at risk of developing aortic incompetence in the late postoperative period. Two cases of ALVT were followed for 10 years with special reference to aortic incompetence and geometry of the aortic root. The patients underwent repair of ALVT, one at 4 years of age and the other at 4 months of age. The first patient had a slit-like tunnel (type I) and the aortic orifice was closed with a pericardial patch. The second patient had a large tunnel with an extracardiac aneurysm (type II) and was closed with a pericardial patch at the aortic orifice and a Dacron patch at the left ventricular orifice, thereby completely obliterating the tunnel. The last echocardiographic evaluation showed no residual flow in the tunnel and no aortic incompetence in case 1, but there was mild aortic valvular regurgitation with deformity of the right sinus in case 2. Careful long-term follow-up is necessary because patients with ALVT have some inherent structural abnormalities from the left ventricular outflow tract to the aortic root.


A large-scale deforestation experiment: effects of patch area and isolation on Amazon birds.
As compared with extensive contiguous areas, small isolated habitat patches lack many species. Some species disappear after isolation; others are rarely found in any small patch, regardless of isolation. We used a 13-year data set of bird captures from a large landscape-manipulation experiment in a Brazilian Amazon forest to model the extinction-colonization dynamics of 55 species and tested basic predictions of island biogeography and metapopulation theory. From our models, we derived two metrics of species vulnerability to changes in isolation and patch area. We found a strong effect of area and a variable effect of isolation on the predicted patch occupancy by birds.


Compositions of phenolic compounds, amino acids and reducing sugars in commercial potato varieties and their effects on acrylamide formation.
Potato is consumed as an important source of carbohydrate and other nutrients as well as a good source of phenolics. Acrylamide is a potential carcinogen formed during frying of potato products. This study investigated the compositions of phenolic compounds, amino acids and reducing sugars in 16 commercial potato varieties from eight countries and analysed the relationships between these compositions and the levels of acrylamide generated by heating (185 °C, 25 min) potato powders. Major phenolic compounds in the tested potato varieties were identified as hydroxycinnamoylquinic/hydroxycinnamoyl derivatives by liquid chromatography/mass spectrometry. Great variations in the contents of phenolic compounds, free reducing sugars and amino acids as well as wide variations in acrylamide concentration were found among the different potato varieties. Correlation analysis revealed that fructose (r = 0.956***), glucose (r = 0.826***) and asparagine (r = 0.842***) were positively correlated with acrylamide formation. Interestingly, it was observed that higher levels of phenolic compounds were related to lower levels of acrylamide (r = - 0.692*). Careful selection of potato varieties with lower levels of fructose, glucose and asparagine and higher levels of phenolic compounds may mitigate acrylamide formation during thermal processing of potato products.


Motor unit synchronization during fatigue: a novel quantification method.
Motor unit (MU) synchronization is the result of commonality in the pre-synaptic input to MUs. Previously proposed techniques to estimate MU synchronization based on invasive and surface electromyography (sEMG) recordings have been, respectively, limited by the analyzed MU population size and influence of changes in muscle fibre conduction velocities (MFCVs). The aim of this paper was to evaluate a novel descriptor of MU synchronization on a large MU population, and to minimize its dependency on MFCV. The method is based on the asymmetry of MU action potentials, causing synchronized MU action potentials to skew the monopolar sEMG signal distribution. The descriptor was the skewness statistic used on sub-band filtered monopolar sEMG signals (sub-band skewness). The method was evaluated using simulated signals and its performance was evaluated in terms of bias and sensitivity of the sub-band skewness quantifying the MU synchronization level. The best sensitivity was obtained using sub-band filtering at scale 5 (Mexican hat wavelet). The sensitivity was in general about 0.1units per 5% MU synchronization level. Changes in MFCV had a minimal influence, and caused at most a 5% deviant MU synchronization quantification level. A halved recruitment level had higher bias and a 20% lower sensitivity. Increased firing rate (14-34Hz) reduced the sensitivity about 50%. The sensitivity of the descriptor was robust to noise, and different volume conduction properties. It should be noted that the sub-band skewness comprises a subject-dependent component implying that only changes in MU synchronization level can be quantified.


Ivermectin: a potent new antiparasitic agent.
Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis. It is active at extremely low dosage against a wide variety of nematode and arthropod parasites, apparently by virtue of its action on the mediation of neurotransmission by gamma-aminobutyric acid. It is now in commercial use in various countries for the treatment and control of parasites in cattle, horses, and sheep, and is expected to become available for use in swine and dogs. Since studies with the drug in man are in a preliminary stage, it is not yet known whether ivermectin will be useful in human medicine.


A guide for using NIH Image J for single slice cross-sectional area and composition analysis of the thigh from computed tomography.
Reports using computed tomography (CT) to estimate thigh skeletal muscle cross-sectional area and mean muscle attenuation are often difficult to evaluate due to inconsistent methods of quantification and/or poorly described analysis methods. This CT tutorial provides step-by-step instructions in using free, NIH Image J software to quantify both muscle size and composition in the mid-thigh, which was validated against a robust commercially available software, SliceOmatic. CT scans of the mid-thigh were analyzed from 101 healthy individuals aged 65 and older. Mean cross-sectional area and mean attenuation values are presented across seven defined Hounsfield unit (HU) ranges along with the percent contribution of each region to the total mid-thigh area. Inter-software correlation coefficients ranged from R2 = 0.92-0.99 for all specific area comparisons measured using the Image J method compared to SliceOmatic. We recommend reporting individual HU ranges for all areas measured. Although HU range 0-100 includes the majority of skeletal muscle area, HU range -29 to 150 appears to be the most inclusive for quantifying total thigh muscle. Reporting all HU ranges is necessary to determine the relative contribution of each, as they may be differentially affected by age, obesity, disease, and exercise. This standardized operating procedure will facilitate consistency among investigators reporting computed tomography characteristics of the thigh on single slice images. Trial Registration: ClinicalTrials.gov NCT02308228.


Analysis of older adults' domestic kitchen storage practices in the United Kingdom: identification of risk factors associated with listeriosis.
Increased listeriosis incidence among older adults (≥ 60 years) has been reported internationally, with many cases reported to be sporadic and associated with ready-to-eat (RTE) food products with extended refrigerated shelf life. Given that the home kitchen is recognized as a significant location where foodborne illnesses are acquired, it is important that consumers implement safe food practices to minimize risks. This is crucial for vulnerable consumers, such as older adults. Consumer food safety recommendations in the United Kingdom to reduce the risk of listeriosis at home include (i) following "use-by" dates on unopened prepacked RTE food products, (ii) consuming RTE food products within 2 days of opening, and (iii) ensuring the safe operating temperatures of domestic refrigerators (≤ 5 °C). This study utilized observation, self-reporting, and microbiological analysis to determine actual food storage practices to identify behavioral risk factors. A domestic kitchen survey was conducted in older adult (≥ 60 years) consumers' domestic kitchens (n = 100) in South Wales, United Kingdom. Forty-one percent of foods in home refrigerators were beyond the use-by date, of which 11% were unopened RTE food products commonly associated with listeriosis. Sixty-six percent of opened RTE foods had been or were intended to be stored beyond the recommended 2 days after opening. Older adults failed to ensure safe refrigeration temperatures, with 50% of central storage and 85% of door storage areas operating at temperatures >5 °C. Older refrigerators operated at significantly (P < 0.05) higher temperatures. Given that Listeria monocytogenes was isolated in 2% of kitchens, these findings suggest that storage malpractices may have a greater effect on the potential risk of listeriosis than its presence alone. The study has determined that many older adults fail to adhere to recommendations and subject RTE foods associated with L. monocytogenes to prolonged storage at unsafe temperatures which may render food unsafe for consumption.


Association of note quality and quality of care: a cross-sectional study.
While physician notes are known to vary in organisation, content and quality, the relationship between note quality and clinical quality is uncertain. We performed a cross-sectional study of outpatient visit physician notes by adult patients with coronary artery disease or diabetes mellitus seen in 2010. We assessed physician note quality using the 9-item Physician Documentation Quality Instrument (PDQI-9) and compared this to disease-specific clinical quality scores constructed from data extracted from the electronic health record (EHR). We also assessed the presence of typical note subsections, and indicators of quality care in physician notes. We evaluated 239 notes, written by 111 physicians; 110 notes were written by primary care physicians, 52 by cardiologists and 77 by endocrinologists. Reason for visit was absent in 10% of notes, medication list was not present in the note in 19.7% and timing for follow-up was absent in 18.0% of notes. Significant copy/pasted material was present in 10.5% of notes. Laboratory quality indicators were more often found in other EHR sections than in the physician note. Clinical quality scores for diabetes and coronary artery disease (CAD) showed no significant association with subjective note quality (diabetes: r -0.119, p=0.065, CAD: r -0.124, p=0.06). Notes varied in documentation method and length, and important note subsections were frequently missing. Key clinical data to support quality patient care were often not present in physician notes, but were often found elsewhere in the EHR. Subjective assessment of note quality did not correlate with clinical quality scores, suggesting that writing high-quality notes and meeting quality measures are not mutually reinforcing activities.


Consensus statement: Palliative and supportive care in advanced heart failure.
A consensus conference was convened to define the current state and important gaps in knowledge and needed research on "Palliative and Supportive Care in Advanced Heart Failure." Evidence was drawn from expert opinion and from extensive review of the medical literature, evidence-based guidelines, and reviews. The conference identified gaps in current knowledge, practice, and research relating to prognostication, symptom management, and supportive care for advanced heart failure (HF). Specific conclusions include: (1) although supportive care should be integrated throughout treatment of patients with advanced HF, data are needed to understand how to best decrease physical and psychosocial burdens of advanced HF and to meet patient and family needs; (2) prognostication in advanced HF is difficult and data are needed to understand which patients will benefit from which interventions and how best to counsel patients with advanced HF; (3) research is needed to identify which interventions improve quality of life and best achieve the outcomes desired by patients and family members; (4) care should be coordinated between sites of care, and barriers to evidence-based practice must be addressed programmatically; and (5) more research is needed to identify the content and technique of communicating prognosis and treatment options with patients with advanced HF; physicians caring for patients with advanced HF must develop skills to better integrate the patient's preferences into the goals of care.


Gravity complexes as a focus of seafloor fluid seepage: the Rio Grande Cone, SE Brazil.
Seafloor methane emissions can affect Earth's climate and ocean chemistry. Vast quantities of methane formed by microbial decomposition of organic matter are locked within gas hydrate and free gas on continental slopes, particularly in large areas with high sediment accumulations such as deep-sea fans. The release of methane in slope environments has frequently been associated with dissociation of gas hydrates near the edge of the gas hydrate stability zone on the upper slope, with discharges in greater water depths less understood. Here we show, using data from the Rio Grande Cone (western South Atlantic), that the intrinsic, gravity-induced downslope collapse of thick slope sediment accumulations creates structures that serve as pathways for gas migration, unlocking methane and causing seafloor emissions via giant gas flares in the water column. The observed emissions in the study region (up to 310 Mg year-1) are three times greater than estimates for the entire US North Atlantic margin and reveal the importance of collapsing sediment accumulations for ocean carbon cycling. Similar outgassing systems on the Amazon and Niger fans suggest that gravity tectonics on passive margins is a common yet overlooked mechanism driving massive seafloor methane emissions in sediment-laden continental slopes.


A review of glucosamine for knee osteoarthritis: why patented crystalline glucosamine sulfate should be differentiated from other glucosamines to maximize clinical outcomes.
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for knee osteoarthritis (OA) recommends symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) first line for the medium to long term management of OA, due to their ability to control pain, improve function, and delay joint structural changes. Among SYSADOAs, glucosamine is probably the most widely used intervention. In the present review of glucosamine for knee OA, we have investigated whether the evidence is greater for the patented crystalline glucosamine sulfate (pCGS) preparation (Rottapharm/Meda) than for other glucosamine formulations. Glucosamine is actually widely available in many forms, as the prescription-grade pCGS preparation, generic and over-the-counter formulations of glucosamine sulfate (GS) and food supplements containing glucosamine hydrochloride (GH), which vary substantially in molecular form, pharmaceutical formulation and dose regimens. Only pCGS is given as a highly bioavailable once daily dose (1500 mg) with a proven pharmacological effect. pCGS consistently reaches the plasma levels of around 10 μM required to inhibit interleukin-1 induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction, compared with sub-therapeutic levels achieved with GH. It is evident, from careful consideration of the evidence base, that only the pCGS formulation of glucosamine reliably provides an effect size on pain that is higher than that of paracetamol and equivalent to that provided by non-steroidal anti-inflammatory drugs. In comparison, the effect size on pain of non-crystalline GS preparations and GH from randomized controlled trials is repeatedly demonstrated to be zero. In addition, there is evidence that chronic administration of pCGS has disease-modifying effects, with a reduction in the need for total joint replacement surgery lasting for at least 5 years after treatment cessation. Consequently, the pCGS preparation (Rottapharm/Meda) is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression.


High risk of malignant melanoma in melanoma-prone families with dysplastic nevi.
The risk of hereditary cutaneous malignant melanoma was evaluated in 401 members of 14 families with an autosomal dominant form of melanoma. We documented 127 primary melanomas in 69 family members, including 39 new melanomas diagnosed in 22 study participants from the time of first examination through a maximum of 8 years of follow-up. The 39 newly diagnosed melanomas occurred only in family members with dysplastic nevi, a known precursor of familial melanoma. Of 77 patients with dysplastic nevus syndrome without prior melanomas, 4 developed their first melanoma during prospective follow-up, as compared with 0.03 cases expected. The prospective age-adjusted incidence for melanoma was 14.3/1000 patients with dysplastic nevus per year, with a cumulative melanoma risk (+/- SE) of 7.2% (+/- 3.6) at 8 years. The actuarial probability of melanoma developing in family members with dysplastic nevi was 56.0% (+/- 10.1) from age 20 to age 59. This study confirms that dysplastic nevi are clinical markers of high risk for, and precursors of, hereditary melanoma.


Comparative proteomic analysis reveals different responses in porcine lymph nodes to virulent and attenuated homologous African swine fever virus strains.
African swine fever (ASF) is a pathology of pigs against which there is no treatment or vaccine. Understanding the equilibrium between innate and adaptive protective responses and immune pathology might contribute to the development of strategies against ASFV. Here we compare, using a proteomic approach, the course of the in vivo infection caused by two homologous strains: the virulent E75 and the attenuated E75CV1. Our results show a progressive loss of proteins by day 7 post-infection (pi) with E75, reflecting tissue destruction. Many signal pathways were affected by both infections but in different ways and extensions. Cytoskeletal remodelling and clathrin-endocytosis were affected by both isolates, while a greater number of proteins involved on inflammatory and immunological pathways were altered by E75CV1. 14-3-3 mediated signalling, related to immunity and apoptosis, was inhibited by both isolates. The implication of the Rho GTPases by E75CV1 throughout infection is also evident. Early events reflected the lack of E75 recognition by the immune system, an evasion strategy acquired by the virulent strains, and significant changes at 7 days post-infection (dpi), coinciding with the peak of infection and the time of death. The protein signature at day 31 pi with E75CV1 seems to reflect events observed at 1 dpi, including the upregulation of proteosomal subunits and molecules described as autoantigens (vimentin, HSPB1, enolase and lymphocyte cytosolic protein 1), which allow the speculation that auto-antibodies could contribute to chronic ASFV infections. Therefore, the use of proteomics could help understand ASFV pathogenesis and immune protection, opening new avenues for future research.


Size matters--nanotechnology and therapeutics in rheumatology and immunology.
Nanotechnology, or the use of technology at the submicron scale, and its application to medicine (nanomedicine) draws from many ideas and technological advancements across myriad fields of materials technology and has improved biomedical understanding. Nanotechnology puts current materials science on the same physical scale as classic immune mediating substances, including viruses, moieties found on prokaryotic bacteria, and antigen presenting cells. Functionalized nanoparticles, fullerenes, liposomes, nanogels, and virus-like particles, are several examples of nanotechnology that are currently being applied to the treatment of oncologic and infectious diseases. However, the majority of the current commercial utilization of nanomedicine has been directed towards creating improved vaccines in order to prevent infectious diseases. These processes may have direct applications toward the creation of vaccines used to treat autoimmune disease as well. Current therapeutics utilizing nanotechnology, are gaining traction in treatments for gout and rheumatoid arthritis, and experimental animal models have demonstrated success in using the above technologies to improve the effectiveness and safety of current standard treatment of rheumatologic illnesses. Here we review many of the common forms of nanoparticles used in medical applications as well as where they have found a role in rheumatology. Continued technical feasibility, ongoing safety studies, and lingering questions on cost are all issues that have not yet been resolved in regards to widespread application in rheumatology and immunology.


Stable graphene oxide-gold nanoparticle platforms for biosensing applications.
Graphene oxide-gold nanoparticle (AuNPs@GO) hybrids were fabricated in water dispersions of graphene oxide (GO) and Au precursor completely free of stabilizing agents by UV-light irradiation. Gold nanoparticle (AuNP) nucleation, growth, and stabilization mechanisms at the surface of GO are discussed on the basis of UV-Vis, Raman, IR, and X-Ray photo-spectroscopy studies. The analyses of AuNPs@GO hybrids by transmission electron microscopy (TEM), thermogravimetric (TGA) and electrochemical tests show that they exhibit outstanding chemical, thermal and electrochemical stabilities. Thus, AuNPs@GO biosensing platforms were fabricated for surface enhanced Raman spectroscopy (SERS) detection of crystal violet (CV), a SERS standard molecule, and in a different set of experiments, for flavin adenine dinucleotide (FAD), a flavoprotein coenzyme that plays an important role in many oxidoreductase and reversible redox conversions in biochemical reactions. AuNPs@GO hybrids synthesized by using UV light irradiation show exceptional stability and high intensification of the Raman signals showing that they have high potential for use as biomedical probes for the detection, monitoring, and diagnosis of medical diseases.


Amplitude-integrated EEG and range-EEG modulation associated with pneumatic orocutaneous stimulation in preterm infants.
Controlled somatosensory stimulation strategies have demonstrated merit in developing oral feeding skills in premature infants who lack a functional suck, however, the effects of orosensory entrainment stimulation on electrocortical dynamics is unknown. The objective of the study was to determine the effects of servo-controlled pneumatic orocutaneous stimulation presented during gavage feedings on the modulation of amplitude-integrated electroencephalogram (aEEG) and range electroencephalogram (rEEG) activity. Two-channel EEG recordings were collected during 180 sessions that included orocutaneous stimulation and non-stimulation epochs among 22 preterm infants (mean gestational age=28.56 weeks) who were randomized to treatment and control 'sham' conditions. The study was initiated at around 32 weeks post-menstrual age. The raw EEG was transformed into aEEG margins, and rEEG amplitude bands measured at 1-min intervals and subjected to a mixed models statistical analysis. Multiple significant effects were observed in the processed EEG during and immediately following 3-min periods of orocutaneous stimulation, including modulation of the upper and lower margins of the aEEG, and a reorganization of rEEG with an apparent shift from amplitude bands D and E to band C throughout the 23-min recording period that followed the first stimulus block when compared with the sham condition. Cortical asymmetry also was apparent in both EEG measures. Orocutaneous stimulation represents a salient trigeminal input, which has both short- and long-term effects in modulating electrocortical activity, and thus is hypothesized to represent a form of neural adaptation or plasticity that may benefit the preterm infant during this critical period of brain maturation.


[The effects of the taping therapy on range of motion, pain and depression in stroke patient].
The purpose of this study was to test the effect of Taping therapy on Range of Motion, pain, and depression in stroke patients in the home without complete recovery as a means of nursing intervention. Twenty seven subjects out of fifty four people who were attending in the stroke self-help group in one community health center in S city were asked to participate in this Quai-experimental study. The Taping therapy was a method that stick to the illness area and the point of pressure pain, the elastic and cross tape without medicine treatment with domestic products. Nursing intervention was independently completed by researcher once a week over two period of 12 weeks from September 2001 to March 2002 year. Data were analyzed using the SPSS win. The homogeneity between the experimental group and control group was test by chi2 and t-test. The difference of experimental before and after were tested by the unpaired t-test. The shoulder joint flexion and abduction, the elbow joint flexion and extension, the hip joint flexion, and the flexion of knee joint in the ROM of the experimental group were significantly improved over those of the control group. In difference of pain, rest and painful movement, the experimental group were significantly decreased over those of the control group. The difference of depression in experimental before and after was significantly decreased in the experimental group over those of the control group. The Taping therapy intervention proved effect pain relief and depression decrease as well as promote of range of motion.


V gamma 2V delta 2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer.
The predominant subpopulation of gamma delta T cells in human peripheral blood expresses TCR V region genes V gamma 2 paired with V delta 2. Previous studies have shown that these V gamma 2V delta 2+ T cells proliferate in response to Daudi Burkitt lymphoma cells, synthetic alkyl phosphate molecules including monoethylphosphate (MEP), and an Ag chemically similar to MEP purified from mycobacterial extracts of several species including Mycobacterium tuberculosis. This proliferation is polyclonal and determined by the TCR V gene. However, because these alkyl phosphate molecules are so distinct from conventional peptides and superantigens, we questioned whether these substances induce gamma delta T cell proliferation via TCR-dependent recognition. Here we report that transfection of TCR- Jurkat T cells with cDNA constructs encoding a V gamma 2V delta 2 TCR enabled the transfectants to produce IL-2 in response to Daudi cells, mycobacterial extract, and MEP. The responses were dose dependent and Ag specific. These results demonstrate an essential role for the gamma delta TCR in V gamma 2V delta 2 T cell-mediated recognition of non-peptide Ags by human T cells and suggest a structural similarity or cross-reactivity between cellular and microbial Ags recognized by these gamma delta T cells.


Further evaluation of saline infusion for the diagnosis of primary aldosteronism.
Normal subjects, normal-renin hypertensive patients, and low-renin hypertensive patients were evaluated by intravenous saline infusion and with a fludrocortisone acetate (Florinef) protocol to clarify diagnostic criteria for primary aldosteronism that are recommended for the saline infusion protocol. The patients consumed a 200 mEq sodium, 70 mEq potassium diet for 6 days, and on the last 3 days received Florinef 0.5 mg orally twice daily. On Days 3 and 6, urinary aldosterone and tetrahydroaldosterone excretions were determined, and on Days 4 and 7 plasma aldosterone (PA) was determined at 0600 after overnight recumbency and at 0800 after 2 hours of walking. Although the level of normal PA suppression by saline infusion has been commonly defined as 10 ng/dl, a value of 5 ng/dl was originally recommended. In 20 normal subjects and 45 normal-renin hypertensive patients, we found that the PA was almost always suppressed below 5 ng/dl. In 18 of 75 low-renin patients including five with aldosterone-producing adenoma (APA), the PA was never suppressed below 10 ng/dl; thus, these 18 patients had classical primary aldosteronism by generally accepted criteria. The Florinef protocol was performed in eight of these 18 patients and was abnormal in all. An abnormal Florinef protocol was also found in seven of 15 patients studied with PA suppression after saline infusion to between 5 and 10 ng/dl, but in only one of 24 patients studied with PA suppression below 5 ng/dl. Additional studies in the subgroup with abnormal results from the Florinef protocol indicated that none of these patients had evidence of APA, so they had nontumorous primary aldosteronism (NTPA).(ABSTRACT TRUNCATED AT 250 WORDS)


Seven- to 11-Year-Olds' Developing Ability to Recognize Natural Facial Expressions of Basic Emotions.
Being able to recognize facial expressions of basic emotions is of great importance to social development. However, we still know surprisingly little about children's developing ability to interpret emotions that are expressed dynamically, naturally, and subtly, despite real-life expressions having such appearance in the vast majority of cases. The current research employs a new technique of capturing dynamic, subtly expressed natural emotional displays (happy, sad, angry, shocked, and disgusted). Children aged 7, 9, and 11 years (and adults) were systematically able to discriminate each emotional display from alternatives in a five-way choice. Children were most accurate in identifying the expression of happiness and were also relatively accurate in identifying the expression of sadness; they were far less accurate than adults in identifying shocked and disgusted. Children who performed well academically also tended to be the most accurate in recognizing expressions, and this relationship maintained independently of chronological age. Generally, the findings testify to a well-developed ability to recognize very subtle naturally occurring expressions of emotions.


The genetics of murine Hox loci: TAMERE, STRING, and PANTHERE to engineer chromosome variants.
Following their duplications at the base of the vertebrate clade, Hox gene clusters underwent remarkable sub- and neo-functionalization events. Many of these evolutionary innovations can be associated with changes in the transcriptional regulation of their genes, where an intricate relationship between the structure of the gene cluster and the architecture of the surrounding genomic landscape is at play. Here, we report on a portfolio of in vivo genome engineering strategies in mice, which have been used to probe and decipher the genetic and molecular underpinnings of the complex regulatory mechanisms implemented at these loci.


Acute appendicitis during pregnancy: a clinical assessment.
Acute appendicitis is the most common non-obstetric reason for laparotomy during pregnancy. The purpose of this study was to analyze the characteristics of the clinical presentations and postoperative outcomes of these patients and their fetuses. Patients who underwent appendectomies during pregnancy from July 1991 to June 1997 were retrospectively identified. Their ages, clinical presentations, the severity of the inflammatory change in the appendices, and the postoperative complications of these patients and fetuses were recorded and analyzed. Long-term outcomes were confirmed by telephone contact, when possible. Forty-five pregnant women who underwent appendectomies for suspected acute appendicitis were retrospectively reviewed. The histopathological inflammatory change in the appendix was proven in 35 patients (78%). Sixty-three percent of the patients were multiparous, and 86% were in the first 2 trimesters. In the clinical settings, pain and tenderness in the right lower abdominal quadrant were the most common symptoms and signs in presentation. Perioperative administration of ritodrine had no obvious advantage in the prevention of fetal loss. Appendectomy was performed beyond 36 hours of onset of symptoms in 28% of the patients, among whom one-half had gangrenous or perforated appendices. Only one fetus was spontaneously lost in 32 patients with diseased appendices (3%), excluding 3 patients choosing artificial abortion. There was no maternal death in our series. The rate of fetal loss due to surgery for acute appendicitis during pregnancy was low. Delay of operation was pertinent to the more-inflammatory changes of the appendix and to the higher maternal complication rate. Early surgical intervention is essential.


Clinical holistic medicine: mental disorders in a holistic perspective.
From a holistic perspective, psychiatric diseases are caused by the patient's unwillingness to assume responsibility for his life, existence, and personal relations. The loss of responsibility arises from the repression of the fundamental existential dimensions of the patients. Repression of love and purpose causes depersonalization (i.e., a lack of responsibility for being yourself and for the contact with others, loss of direction and purpose in life). Repression of strength in mind and emotions leads to derealization (the breakdown of the reality testing, often with mental delusions and hallucinations). The repression of joy and gender leads to devitalization (emotional emptiness, loss of joy, personal energy, sexuality, and pleasure in life). The losses of existential dimensions are invariably connected to traumas with life-denying decisions. Healing the wounds of the soul by holding and processing will lead to the recovery of the person's character, purpose of life, and existential responsibility. It can be very difficult to help a psychotic patient. The physician must first love his patient unconditionally and then fully understand the patient in order to meet and support the patient to initiate the holistic process of healing. It takes motivation and willingness to suffer on behalf of the patients in order to heal, as the existential and emotional pain of the traumas resulting in insanity is often overwhelming. We believe that most psychiatric diseases can be alleviated or cured by the loving and caring physician who masters the holistic toolbox. Further research is needed to document the effect of holistic medicine in psychiatry.


Combating HIV and/or AIDS: A challenge to Millennium Development Goals for disaster managers in the Southern African Development Community.
Disaster management is a process of planning and implementation of measures involving multiple disciplines and sectors; hence Millennium Development Goals (MDGs) cannot go unnoticed. Approximately 189 member states agreed to endeavour to achieve MDGs which should be accomplished by 2015. The purpose of this research was to establish the primary involvement of the disaster management fraternity within the Southern African Development Community (SADC) region in this agreement. SADC countries are the countries with a high prevalence of HIV and AIDS and they feature on the disaster manager's priority list of hazards, hence the focus on MDG 6 for this study. Various data gathering tools were employed and included making use of indicators developed by the United Nations to review disaster management statutes or civil protection statutes and scholarly documents on the progress of MDG 6. Structured interviews were carried out with heads of disaster management centres of SADC countries through the guidance of MDG 6 indicators. The main findings were that most statutes do acknowledge the fight against epidemics and most disaster managers are aware of MDG 6 and are involved in its achievement. It was recommended that disaster managers should be part of the Post 2015 MDG delegation.


Regulatory networks controlling nitrogen sensing and uptake in Candida albicans.
Nitrogen is one of the key nutrients for microbial growth. During infection, pathogenic fungi like C. albicans need to acquire nitrogen from a broad range of different and changing sources inside the host. Detecting the available nitrogen sources and adjusting the expression of genes for their uptake and degradation is therefore crucial for survival and growth as well as for establishing an infection. Here, we analyzed the transcriptional response of C. albicans to nitrogen starvation and feeding with the infection-relevant nitrogen sources arginine and bovine serum albumin (BSA), representing amino acids and proteins, respectively. The response to nitrogen starvation was marked by an immediate repression of protein synthesis and an up-regulation of general amino acid permeases, as well as an up-regulation of autophagal processes in its later stages. Feeding with arginine led to a fast reduction in expression of general permeases for amino acids and to resumption of protein synthesis. The response to BSA feeding was generally slower, and was additionally characterized by an up-regulation of oligopeptide transporter genes. From time-series data, we inferred network interaction models for genes relevant in nitrogen detection and uptake. Each individual network was found to be largely specific for the experimental condition (starvation or feeding with arginine or BSA). In addition, we detected several novel connections between regulator and effector genes, with putative roles in nitrogen uptake. We conclude that C. albicans adopts a particular nitrogen response network, defined by sets of specific gene-gene connections for each environmental condition. All together, they form a grid of possible gene regulatory networks, increasing the transcriptional flexibility of C. albicans.


Ocean source and optical property estimation from explicit and implicit algorithms.
We solve an inverse problem of ocean optics for estimating spatially dependent absorption and scattering coefficients and for determining sources such as fluorescence, bioluminescence, or Raman scattering. The solution requires in situ measurement of the downward and upward plane irradiances and scalar irradiances and a priori estimation of the angular shape of the volume scattering function. Both an explicit algorithm and an implicit one are developed from new two-stream radiative-transfer equations that utilize an asymptotic radiance approximation to close the set of equations. A comparison of numerical tests for the two algorithms is given.


Hallmarks of intestinal stem cells.
Intestinal stem cells (ISCs) are highly proliferative cells that fuel the continuous renewal of the intestinal epithelium. Understanding their regulatory mechanisms during tissue homeostasis is key to delineating their roles in development and regeneration, as well as diseases such as bowel cancer and inflammatory bowel disease. Previous studies of ISCs focused mainly on the position of these cells along the intestinal crypt and their capacity for multipotency. However, evidence increasingly suggests that ISCs also exist in distinct cellular states, which can be an acquired rather than a hardwired intrinsic property. In this Review, we summarise the recent findings into how ISC identity can be defined by proliferation state, signalling crosstalk, epigenetics and metabolism, and propose an update on the hallmarks of ISCs. We further discuss how these properties contribute to intestinal development and the dynamics of injury-induced regeneration.


Assessment of the exposure to heavy metals in Griffon vultures (Gyps fulvus) from the Iberian Peninsula.
Griffon vultures (Gyps fulvus), by virtue of their position at the top of the food chain and as obligate scavengers, are at risk of accumulating and concentrating heavy metals in their tissues and may be more predisposed to their toxic effects. The aim of this study is to investigate heavy metal concentrations in Griffon vultures in Portugal and Catalonia, Spain and to determine if heavy metal concentrations in the blood of weak and/or injured Griffon vultures admitted to wildlife rehabilitation centres (WRC) reflect contamination profiles in the local, free-living and outwardly healthy population. Whole-blood samples taken from 121 Griffon vultures caught in the wild or admitted to WRC in Portugal and Catalonia, Spain were examined for cadmium (Cd), mercury (Hg) and lead (Pb) by inductively coupled plasma mass spectrometry (ICP-MS). Cd and Hg were not detected in most samples (98.3% and 95%, respectively), while Pb was detected in all birds in concentrations ranging between 4.97 and 300.23 µg/dl. Birds admitted to WRC had significantly lower Pb concentrations (24.15 ± 15.07 and 25.98 ± 18.04 µg/dl in Portugal and Catalonia, Spain, respectively) than animals caught in the wild (29.67 ± 13.19 and 42.22 ± 50.08 µg/dl in Portugal and Catalonia, Spain, respectively) (p<0.05). This may be explained by the fact that malnutrition was the main cause of admission of Griffon vultures to WRC, as ingestion has been described as the most significant pathway for Pb exposure in raptors. Therefore Griffon vultures admitted to WRC do not seem to be representative of the local, free-flying populations, so it remains necessary to continue catching when one intends to monitor Pb exposure in this species. The population of vultures captured in Catalonia, Spain showed the highest mean blood Pb concentration, perhaps due to the municipal rubbish dump located near the feeding station, with rubbish providing a significant fraction of their trophic needs. The ingestion of game meat with bullet fragments in carcasses or with Pb shots embedded in their flesh could also be the cause of the high blood Pb concentrations found in some vultures. The potential risk of Pb exposure in Griffon vulture populations must be given consideration, since most individuals evaluated had Pb concentrations between 20 and 100µg/dl, which is considered to be subclinical exposure to Pb, and which is above the threshold level at which Pb can affect antioxidant system in this species (15 µg/dl).


Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site.
Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates.