ALBERT

Description: This study assessed the concentrations of cadmium in the gills, livers and muscles of a commercially important tilapia fish (Sarotherodon melanotheron) from Aby Lagoon in Adiaké, Côte d’Ivoire, between January and December, 2010. The organisms were grouped into two composite samples (juvenile and adult) of five individuals. Levels of cadmium were determined in tissues using Perkin-Elmer (AAnalyst 200) Atomic Absorption Spectrophotometry (AAS) after a digestion method. Fish muscle appeared to have a significantly higher tendency to accumulate cadmium (1.19–5.18 µg/g dw) while gills and livers had minimum concentrations (0.07–1.32 and 0.12–1.25 µg/g dw). This study has revealed that the concentrations of Cd in Sarotherodon melanotheron muscle tissue were above the maximum acceptable concentrations for human consumption, thus precautions need to be taken in order to prevent future contamination.

Description: Monitoring of progress towards the Millennium Development Goal (MDG) drinking water target relies on classification of water sources as “improved” or “unimproved” as an indicator for water safety. We adjust the current Joint Monitoring Programme (JMP) estimate by accounting for microbial water quality and sanitary risk using the only-nationally representative water quality data currently available, that from the WHO and UNICEF “Rapid Assessment of Drinking Water Quality”. A principal components analysis (PCA) of national environmental and development indicators was used to create models that predicted, for most countries, the proportions of piped and of other-improved water supplies that are faecally contaminated; and of these sources, the proportions that lack basic sanitary protection against contamination. We estimate that 1.8 billion people (28% of the global population) used unsafe water in 2010. The 2010 JMP estimate is that 783 million people (11%) use unimproved sources. Our estimates revise the 1990 baseline from 23% to 37%, and the target from 12% to 18%, resulting in a shortfall of 10% of the global population towards the MDG target in 2010. In contrast, using the indicator “use of an improved source” suggests that the MDG target for drinking-water has already been achieved. We estimate that an additional 1.2 billion (18%) use water from sources or systems with significant sanitary risks. While our estimate is imprecise, the magnitude of the estimate and the health and development implications suggest that greater attention is needed to better understand and manage drinking water safety.

Description: Schizophrenia is a very common psychiatric disorder. However, its etiology and pathogenesis is still unknown. Current theory saying that neurotransmitter imbalance such as serotonin or dopamine only provides limited effectiveness in schizophrenia treatment by drugs changing serotonin and dopamine concentration. Despite of such treatment, majority of schizophrenia patients still have very poor prognosis. Thus, the neurotransmitter imbalance theory is not correct. Here, I propose that schizophrenia is actually a TH2 dominant autoimmune disorder. The candidate of autoantigen could be acetylcholine receptors of CNS. My theory can explain the positive as well as negative symptoms of schizophrenia. By microarray analysis of PBMCS, one-tenth of the total 519 significantly expressed genes are immune-related genes. Among them, TH2 related genes are significantly up-regulated including IL-4, histidine decarboxylase, aldehyde dehydrogenase, CCR9, IgE Fc receptor, GATA2, serotonin receptor, phospholipase A2, and prostaglandin D2 synthase. Besides, TH1 and TH17 related genes are down-regulated including CXCL5, cathepsin C, and neutrophil related S100 binding proteins. The new theory sheds a light to better control this detrimental illness. Anti-inflammatory agents could be used to manage schizophrenia in the near future.

Description: Aim: To assess suicide mortality in comparison to traffic accidents and homicide deaths in Germany in the year 2010 and to compare years of life lost (YLL) due to these unnatural deaths. Methods: Mortality data were provided by the Federal Statistical Office giving death rates (related to 100,000 inhabitants) and proportions (related to 100 deaths of individuals) for suicide, traffic accidents and homicide as well as YLL data. Results: A total of 14,441 unnatural deaths (suicide, traffic accidents, homicide) were reported in 2010 in Germany. Of those, 10,021 subjects (69.4%) committed suicide, 3,942 (27.3%) died in traffic accidents, 478 (3.3%) were murdered. Suicide death rates were by far the highest, with rates for men (18.6) three times higher than for women (6.1). For both sexes, suicide rates increased with age, whereas suicide as a proportion of all causes of death was higher in younger age groups. In both sexes, suicide was the leading cause of YLL (men: 314 YLL, women: 90 YLL). Conclusions: Suicide is the leading cause of unnatural death and YLL. The sex- and age- specific patterns in suicide mortality call for different action plans to target high risk groups.

Description: The objective of this cross-sectional questionnaire study was to assess associations of a self-report index of sun protection habit strength with sunscreen use in sporting environments and outdoor physical activity. Participants (n = 234) in field hockey, soccer, tennis and surf sports in Queensland, Australia, completed a self-administered survey on sun protection during organized sport, and during general outdoor physical activity during 2005/2006. The sun protection habit strength index was dichotomized into two categories. Multinomial logistic regression analyses assessed the associations of low versus high sun protection habit strength with three categories of sunscreen use (no or rare use; inadequate use; and adequate use). Compared to participants with low sun protection habit strength, those with high sun protection habit strength had significantly greater odds of any sunscreen use during organized sport and during general outdoor physical activity. This association was strongest for adequate sunscreen use in both settings. In conclusion, this study suggests that the measure of sun protection habit strength is a potentially useful assessment tool for future sun protection studies.

Description: Animal models are often used to obtain a better understanding of psychiatric, neurodegenerative, and neurodevelopmental disorders. Despite many years of research, these models have not led to many novel therapies or treatments. Translating results between species will always be difficult, and it is argued that inappropriate statistical analyses, failure to identify the experimental unit, lack of random assignment to treatment conditions, and unblinded assessment of outcomes contribute to the low rate of translating preclinical in vivo studies into successful therapies. It is known that these shortcomings can generate biased estimates, too many false positives and false negatives, and unreproducible results. These issues have been raised repeatedly, but have largely gone unheeded by scientists. Two recommendations are made to improve the situation.

Description: Mobile Platform Informatics (MPI) and Smartphone Informatics (SPI) methods like Mobile Image Ratiometry (MIR) are potentially transformative point-of-use instantaneous analysis tools that are useful across a variety of industries. In agriculture, MIR-compatible immuno test strips allow early detection of a number of biotic stressors before devastating crop losses occur. Here we describe a low-cost and easy-to-use Smartphone and/or tablet-based protocol (Mobile Assay Inc., www.mobileassay.com) for the detection and on-sight instantaneous analysis of B. cinerea, a fungus that causes significant damage to a variety of plants and flowers. Early detection and tracking of the B. cinerea fungus before the visible gray mold appears has the potential to increase agricultural productivity especially in the developing world.

Description: Here we show a new interaction mechanism of colliding population waves. It provides a stable coexistence of two similar but different species competing for the same limiting resource during their asexual propagation in a limited homogeneous environment under constant conditions. The revealed mechanism opens new opportunities in conservation biology.

Description: Two erectoid hominids from Sarstedt prompted a detailed examination of the course of the impressions of the Arteria meningea media and their characteristics within the line of hominidae.

Description: Genomic Replikin CountsTM of Infectious Salmon Anemia Virus (ISAV) in Canada Exceed the Counts in Lethal Outbreaks in Norway, Chile, and Scotland. Real-Time Tracking of the Evolution of the ISAV Genome and the Resultant Replikins Solid Phase ISAV Vaccine Make ISAV Pandemic Prevention Possible.

Description: Background: The modeling of interactions among transcription factors (TFs) and their respective target genes (TGs) into transcriptional regulatory networks is important for the complete understanding of regulation of biological processes. In the case of human TF-TG interactions, there is no database at present that explicitly provides such information even though many databases containing human TF-TG interaction data have been available. In an effort to provide researchers with a repository of TF-TG interactions from which such interactions can be directly extracted, we present here the Human Transcriptional Regulation Interactions database (HTRIdb).Description: The HTRIdb is an open-access database of experimentally validated interactions among human TFs and their TGs. HTRIdb can be searched via a user-friendly web interface and the retrieved TF-TG interactions data and the associated protein-protein interactions can be downloaded or interactively visualized as a network using the Cytoscape Web software. Moreover, users can improve the database quality by uploading their own interactions and indicating inconsistencies in the data. So far, HTRIdb has been populated with 283 TFs that regulate 11886 genes, totaling 18160 TF-TG interactions. HTRIdb is freely available at http://www.lbbc.ibb.unesp.br/htri.Conclusions: HTRIdb is a powerful user-friendly tool from which human experimentally validated TF-TG interactions can be easily extracted and used to construct transcriptional regulation interaction networks enabling researchers to decipher the regulation of biological processes.

Description: Genome-wide association studies (GWAS) have become a standard method for finding genetic variations that contribute to common, complex diseases. Recently, it is suggested that these diseases may be caused by epistatic interactions of multiple genetic variations. Although tens of software tools have been developed for epistasis detection, few are able to infer pathway importance from the identified epistatic interactions. AntEpiSeeker is originally an algorithm for detecting epistatic interactions in case-control studies, using a two-stage ant colony optimization (ACO) algorithm. We have developed AntEpiSeeker2.0, which extends the AntEpiSeeker algorithm to inference of epistasis-associated pathways, based on a natural use of the ACO pheromones. By looking at pheromone distribution across pathways, epistasis-associated pathways can be easily identified. The effectiveness of AntEpiSeeker2.0 in inferring epistasis-associated pathways is demonstrated through a simulation study and a real data application. AntEpiSeeker 2.0 was designed to provide efficient inference of epistasis-associated pathways based on ant colony optimization and is freely available at http://lambchop.ads.uga.edu/antepiseeker2/.

Description: Micro-relief heterogeneity can lead to substantial variability in microclimate and hence niche opportunities on a small scale. We explored the relationship between plant species richness and small-scale heterogeneity of micro-relief on the subtropical island of La Palma, Canary Islands. Overall, we sampled 40 plots in laurel and pine forests at four altitudinal bands. Species richness was recorded separately for various growth forms (i.e., mosses, herbaceous and woody plants). Site conditions such as altitude, slope, aspect, and tree density were measured. Micro-relief heterogeneity was characterized by surface structure and a subsequently derived surface heterogeneity index. The effect of micro-relief heterogeneity on species richness was analysed by means of linear mixed effect models and variance partitioning. Effects of micro-relief heterogeneity on species richness varied considerably between growth forms. While moss richness was affected significantly by micro-relief heterogeneity, herbaceous and woody plants richness responded mainly to larger-scale site conditions such as aspect and tree density. Our results stress the importance of small-scale relief heterogeneity for the explanation of spatial patterns of species richness. This poses new challenges as small-scale heterogeneity is largely underrepresented, e.g. with regard to its application in species distribution models.

Description: The aim of this study was to determine the prevalence of suicidal ideation in patients who were tested for HIV-infection and whether along with their HIV status, age and gender influenced their risk for suicidal ideation. The sample consisted of 189 patients who attended a voluntary HIV counseling and testing clinic (VCT) at a general state hospital in Durban, South Africa. Their mean age at baseline was 34.2 years, with an age range of between 16–79 years. Seropositivity, age and gender were significantly associated with suicidal ideation. The majority of these patients were in the younger age group, and young males had a 1.8 times higher risk for suicidal ideation than females. Although risk factors for seropositive-related suicidal ideation can be complex and multi-factorial, this study identified a young age and male gender as important high risk factors in the sample studied. It is recommended that all, but especially young male HIV-infected patients seen at a VCT clinic be screened for suicidal ideation and that early intervention to prevent subsequent suicides or suicidal attempts be included in pre- and post-test HIV counseling.

Description: The next generation Nature Reviews Microbiology 10, 157 (2012). doi:10.1038/nrmicro2759 A better understanding of the factors that affect children's desire to follow a career in science is vital if we are to inspire the next generation of scientists.

Description: Bacterial pathogenesis: Controlling Fic proteins Nature Reviews Microbiology 10, 160 (2012). doi:10.1038/nrmicro2757 Author: Sheilagh Molloy A general mechanism for controlling the adenylylation activity of Fic proteins has been identified.

Description: Cellular microbiology: An unconventional exit for Brucella Nature Reviews Microbiology 10, 160 (2012). doi:10.1038/nrmicro2749 Author: Rachel David Brucella abortus hijacks autophagy components to complete its life cycle.

Description: Bacterial genomics: Universal bacterial barcode Nature Reviews Microbiology 10, 161 (2012). doi:10.1038/nrmicro2754 Author: Andrew Jermy Although analysis of 16S ribosomal RNA has revolutionized the ability to classify bacteria and understand their phylogenetic relationships, it is less useful for classifying related strains of bacteria that share similar or identical 16S rRNA gene sequences but exhibit distinct properties. To address this, Jolley

Description: Viral infection: Promiscuous packaging Nature Reviews Microbiology 10, 161 (2012). doi:10.1038/nrmicro2755 Author: Andrew Jermy The high error rate of viral polymerases allows viruses to rapidly adapt to a new host, and each replication cycle results in a heterogeneous population of viruses with distinct genetic content. Routh et al. used an unbiased next-generation sequencing approach to look at the

Description: Biofilms: Biofilms take shape Nature Reviews Microbiology 10, 162 (2012). doi:10.1038/nrmicro2756 Author: Sheilagh Molloy Phenol-soluble modulins have a key role in the structuring and detachment of Staphylococcus aureus biofilms.

Description: Adapting to domesticity Nature Reviews Microbiology 10, 163 (2012). doi:10.1038/nrmicro2752 Author: Adam J. Reid This month's Genome Watch highlights new insights into the impact of food production on the evolution of microorganisms.

Description: In the news Nature Reviews Microbiology 10, 164 (2012). doi:10.1038/nrmicro2760 Our monthly round up of infectious diseases news, which this month includes the spread of a new virus affecting livestock in Europe, the H5N1 controversy and a report that mortality from malaria may be much higher than was previously suspected.

Description: Bacterial pathogenesis: UPEC helps host to exfoliate Nature Reviews Microbiology 10, 159 (2012). doi:10.1038/nrmicro2758 Author: Andrew Jermy UPEC pore-forming toxin α-haemolysin (HlyA) stimulates the proteolysis of host proteins involved in cell adhesion, resulting in uroepithelial cell exfoliation.

Description: A bacterial siren song: intimate interactions between Neisseria and neutrophils Nature Reviews Microbiology 10, 178 (2012). doi:10.1038/nrmicro2713 Authors: Alison K. Criss & H. Steven Seifert Neisseria gonorrhoeae and Neisseria meningitidis are Gram-negative bacterial pathogens that are exquisitely adapted for growth at human mucosal surfaces and for efficient transmission between hosts. One factor that is essential to neisserial pathogenesis is the interaction between the bacteria and neutrophils, which are

Description: Phage biology: T4 to TA, checkmate Nature Reviews Microbiology 10, 160 (2012). doi:10.1038/nrmicro2748 Author: Andrew Jermy Phage T4 encodes an antitoxin that is active against multiple Escherichia coli toxins.

Description: ppGpp: magic beyond RNA polymerase Nature Reviews Microbiology 10, 203 (2012). doi:10.1038/nrmicro2720 Authors: Zachary D. Dalebroux & Michele S. Swanson During stress, bacteria undergo extensive physiological transformations, many of which are coordinated by ppGpp. Although ppGpp is best known for enhancing cellular resilience by redirecting the RNA polymerase (RNAP) to certain genes, it also acts as a signal in many other cellular processes in bacteria.

Description: Structural insights into the coupling of virion assembly and rotavirus replication Nature Reviews Microbiology 10, 165 (2012). doi:10.1038/nrmicro2673 Authors: Shane D. Trask, Sarah M. McDonald & John T. Patton Viral replication is rapid and robust, but it is far from a chaotic process. Instead, successful production of infectious progeny requires that events occur in the correct place and at the correct time. Rotaviruses (segmented double-stranded RNA viruses of the Reoviridae family) seem to

Description: Genome analyses highlight the different biological roles of cellulases Nature Reviews Microbiology 10, 227 (2012). doi:10.1038/nrmicro2729 Authors: Felix Mba Medie, Gideon J. Davies, Michel Drancourt & Bernard Henrissat Cellulolytic enzymes have been the subject of renewed interest owing to their potential role in the conversion of plant lignocellulose to sustainable biofuels. An analysis of ∼1,500 complete bacterial genomes, presented here, reveals that ∼40% of the genomes of sequenced bacteria encode at least one

Description: Host response: Phagocytosis runs like clockwork Nature Reviews Microbiology 10, 162 (2012). doi:10.1038/nrmicro2751 Author: Christina Tobin Kåhrström In Drosophila melanogaster, phagocytosis of specific bacteria is regulated by a circadian protein.

Description: From self sufficiency to dependence: mechanisms and factors important for autotransporter biogenesis Nature Reviews Microbiology 10, 213 (2012). doi:10.1038/nrmicro2733 Authors: Denisse L. Leyton, Amanda E. Rossiter & Ian R. Henderson Autotransporters are a superfamily of proteins that use the type V secretion pathway for their delivery to the surface of Gram-negative bacteria. At first glance, autotransporters look to contain all the functional elements required to promote their own secretion: an amino-terminal signal peptide to mediate

Description: Virophages question the existence of satellites Nature Reviews Microbiology 10, 234 (2012). doi:10.1038/nrmicro2676-c3 Authors: Christelle Desnues & Didier Raoult In a recent Comment (Virophages or satellite viruses? Nature Rev. Microbiol.9 762–763(2011)), Mart Krupovic and Virginija Cvirkaite-Krupovic argued that the recently described virophages, Sputnik and Mavirus, should be classified as satellite viruses. In a response, to which Krupovic and

Description: Evolution: Co-evolution promotes innovation Nature Reviews Microbiology 10, 161 (2012). doi:10.1038/nrmicro2753 Author: Christina Tobin Kåhrström The interaction between a viral ligand and its cellular receptor is highly specific and limits host range. A recent paper describes a mutant form of bacteriophage λ that targets an alternative receptor after co-evolution with Escherichia coli. When phage cI26 was cultured with E.

Description: Towards a more comprehensive classification of satellite viruses Nature Reviews Microbiology 10, 234 (2012). doi:10.1038/nrmicro2676-c4 Authors: Mart Krupovic & Virginija Cvirkaite-Krupovic Our recent Comment on the nature and place of the so-called virophages in the viral world (Virophages or satellite viruses? Nature Rev. Microbiol.9 762–763 (2011)) has caught the attention of researchers favouring the virophage concept and initiated a debate on this

Description: Computational tools for the synthetic design of biochemical pathways Nature Reviews Microbiology 10, 191 (2012). doi:10.1038/nrmicro2717 Authors: Marnix H. Medema, Renske van Raaphorst, Eriko Takano & Rainer Breitling As the field of synthetic biology is developing, the prospects for de novo design of biosynthetic pathways are becoming more and more realistic. Hence, there is an increasing need for computational tools that can support these efforts. A range of algorithms has been developed

Description: Natural agricultural production functions in open system, where energy and matter are exchanged freely between geosphere (especially pedosphere), biosphere, and atmosphere. The self regulation of biophysical processes in these spheres is crucial for global sustainability. However, modern farming practices have stressed the system to the extent that damaged C, N, and P cycles are threatening catastrophic consequences. High food-wastage coupled with high food price, high soil fertility zones but low crop productivity, and highly productive irrigated farming marred with ecological disasters are examples of global paradoxes associated with modern farming. High incidence of pesticide residues in soil and water bodies, low use efficiency of agricultural inputs, vulnerability to climate, and low conversion of energy by crops leaving high amount of residues and their subsequent burden on environment, and hunger and malnutrition in many parts of the world are threatening civilizations to crumble. Nanotechnology promises to break these vicious cycles, because technology is based on applying exact amounts of inputs for use by the crops, and only when they are required. Some of the examples are: nanofabricating nutrient ions to improve nutrient use efficiency, targeted use of nano-pesticides, holding of water and then releasing it at the time of crop need by nps, forecasting and elimination of diseases, packaging of food to improve shelf-life, protecting food during storage, DNA nanotechnology, smart treatment delivery systems, bioanalytical nanosensors, bioselective surfaces, nanobioprocessing, protection of the environment by the reduction and conversion of agricultural materials into valuable products, design and development of new nanocatalysts to convert vegetable oils into biobased fuels and biodegradable industrial solvents, and controlled ecological life support system.

Description: Importance of rare taxa for bacterial diversity in the rhizosphere of Bt- and conventional maize varieties The ISME Journal 7, 37 (January 2013). doi:10.1038/ismej.2012.77 Authors: Anja B Dohrmann, Meike Küting, Sebastian Jünemann, Sebastian Jaenicke, Andreas Schlüter & Christoph C Tebbe

Description: Dispersal of thermophilic Desulfotomaculum endospores into Baltic Sea sediments over thousands of years The ISME Journal 7, 72 (January 2013). doi:10.1038/ismej.2012.83 Authors: Júlia Rosa de Rezende, Kasper Urup Kjeldsen, Casey R J Hubert, Kai Finster, Alexander Loy & Bo Barker Jørgensen

Description: Phylogenetic stratigraphy in the Guerrero Negro hypersaline microbial mat The ISME Journal 7, 50 (January 2013). doi:10.1038/ismej.2012.79 Authors: J Kirk Harris, J Gregory Caporaso, Jeffrey J Walker, John R Spear, Nicholas J Gold, Charles E Robertson, Philip Hugenholtz, Julia Goodrich, Daniel McDonald, Dan Knights, Paul Marshall, Henry Tufo, Rob Knight & Norman R Pace

Description: Metaproteogenomic insights beyond bacterial response to naphthalene exposure and bio-stimulation The ISME Journal 7, 122 (January 2013). doi:10.1038/ismej.2012.82 Authors: María-Eugenia Guazzaroni, Florian-Alexander Herbst, Iván Lores, Javier Tamames, Ana Isabel Peláez, Nieves López-Cortés, María Alcaide, Mercedes V Del Pozo, José María Vieites, Martin von Bergen, José Luis R Gallego, Rafael Bargiela, Arantxa López-López, Dietmar H Pieper, Ramón Rosselló-Móra, Jesús Sánchez, Jana Seifert & Manuel Ferrer

Description: This article focuses on the psychosocial work environment of immigrant cleaners at a Danish workplace. Today, many cleaners working in Danish cleaning jobs are women from the established immigrant communities, but also labour migrants from the newer EU member states have found their way to the cleaning industry. Studies have drawn attention to immigrants’ low position in the cleaning industry and their increased risk of work injuries. This article is based on a case study of an intervention called “Make a Difference” designed to improve the work environment among cleaners at a multi-ethnic workplace. We used semi-structured interviews, photo logs, observation and participation to investigate how the cleaners experienced their work environment. The cleaners reported an overload of heavy work, related to the concept of a classroom’s “readiness for cleaning”, and they expressed strained social relations and communication in addition to a lack of social recognition and invisibility at the workplace, a school. We analysed these psychosocial work environmental problems by investigating the different forms of social relationships and communication within the group of cleaners, and between the cleaners and the teachers and pupils at the school. Moreover, we discussed why the intervention, based on training of language and cleaning skills and social interaction, only partially improved the cleaners’ psychosocial work environment problems. In this article, we argue that social divisions based on ethnicity between the new and the established group of cleaners, combined with their marginal position and poor work organisation at the school, reinforced the cleaners’ experiences of psychosocial work environment problems. This article suggests that increased effort towards social inclusion at work and improved work organisation, especially for the new labour migrants from newer EU-countries, should be considered.

Description: The risk to public health from the large number of dog stools present on streets of urban areas is cause for concern. Dog faeces may be a serious hazard because they may contain microorganisms that are both pathogenic to humans and resistant to several classes of antibiotics. The aim of this study was to evaluate the potential for zoonotic infections and for the presence of antibiotic resistant bacteria in canine faeces which contaminates the urban environment. A total of 418 canine faecal samples were collected from streets in seven areas of Bari, Southern Italy. We have isolated multi-drug resistant Enterococci and meticillin-resistant Staphylococcus aureus from these dog faecal samples. The presence of the resistant bacteria in an urban environment may represent a public health hazard which requires control measures by competent authorities. No Salmonella, Yersinia or Campylobacter species were isolated. Giardia cysts were detected in 1.9% of the samples. The predominant Enterococcus species were E. faecium (61.6%), E. gallinarum (23.3%) and E. casseliflavus (5.5%). Other species, including E. faecalis were also isolated. These strains were resistant to clindamycin (86.3%), tetracycline (65.7%), erythromycin (60.27%) and ampicillin (47.9%). High-level aminoglycoside resistance (HLAR) was found in 65.7% of enterococci. Resistance to three or more antibiotics and six or more antibiotics were observed in 67.12% and 38.4% of Enterococcus spp., respectively. Resistance to vancomycin and teicoplanin was not detected in any of the Enterococcus spp. isolated. Methicillin-resistant Staphylococcus aureus was isolated in 0.7% of the faecal samples. Canine faeces left on the streets may represent a risk factor for transmission of microorganisms and a reservoir of multidrug- resistant bacteria thus contributing to the spread of resistance genes into an urban area.

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 Insulin stimulates glucose uptake through the membrane translocation of GLUT4 and GLUT1. Peroxisome proliferator-activated receptor γ (PPARγ) enhances insulin sensitivity. Here, we demonstrate that insulin stimulates GLUT4 and GLUT1 translocation, and glucose uptake, by activating the signaling pathway involving nicotinic acid adenine dinucleotide phosphate (NAADP), a calcium mobilizer, in adipocytes. We also demonstrate that PPARγ mediates insulin sensitization by enhancing NAADP production through upregulation of CD38, the only enzyme identified for NAADP synthesis. Insulin produced NAADP by both CD38-dependent and -independent pathways, whereas PPARγ produced NAADP by CD38-dependent pathway. Blocking the NAADP signaling pathway abrogated both insulin-stimulated and PPARγ-induced GLUT4 and GLUT1 translocation, thereby inhibiting glucose uptake. CD38 knockout partially inhibited insulin-stimulated glucose uptake. However, CD38 knockout completely blocked PPARγ-induced glucose uptake in adipocytes and PPARγ-mediated amelioration of glucose tolerance in diabetic mice. These results demonstrated that the NAADP signaling pathway is a critical molecular target for PPARγ-mediated insulin sensitization. Graphical abstract Highlights ► Insulin induces glucose uptake via NAADP-mediated calcium increase ► PPARγ mediates insulin sensitization by upregulating the NAADP-producing enzyme CD38 ► PPARγ agonists ameliorate glucose tolerance by CD38 upregulation

Description: Available online 27 December 2012 Publication year: 2012 Source: Cell Reports Enveloped viruses have developed various adroit mechanisms to invade their host cells. This process requires one or more viral envelope glycoprotein to achieve cell attachment and membrane fusion. Members of the Flaviviridae such as flaviviruses possess only one envelope glycoprotein, E, whereas pestiviruses and hepacivirus encode two glycoproteins, E1 and E2. Although E2 is involved in cell attachment, it has been unclear which protein is responsible for membrane fusion. We report the crystal structures of the homodimeric glycoprotein E2 from the pestivirus bovine viral diarrhea virus 1 (BVDV1) at both neutral and low pH. Unexpectedly, BVDV1 E2 does not have a class II fusion protein fold, and at low pH the N-terminal domain is disordered, similarly to the intermediate postfusion state of E2 from sindbis virus, an alphavirus. Our results suggest that the pestivirus and possibly the hepacivirus fusion machinery are unlike any previously observed. Graphical abstract Highlights ► Structure of the major antigenically dominant protein of BVDV ► The overall fold of BVDV E2 shows no similarity to the class II fusion proteins ► At low pH, BVDV E2 N-terminal domain is disordered ► Entry mechanism of BVDV is probably applicable to hepatitis C virus

Description: Background: Trypanosoma cruzi, the causal agent of Chagas Disease, affects more than 16 million people in Latin America. The clinical outcome of the disease results from a complex interplay between environmental factors and the genetic background of both the human host and the parasite. However, knowledge of the genetic diversity of the parasite, is currently limited to a number of highly studied loci. The availability of a number of genomes from different evolutionary lineages of T. cruzi provides an unprecedented opportunity to look at the genetic diversity of the parasite at a genomic scale. Results: Using a bioinformatic strategy, we have clustered T. cruzi sequence data available in the public domain and obtained multiple sequence alignments in which one or two alleles from the reference CL-Brener were included. These data covers 4 major evolutionary lineages (DTUs): TcI, TcII, TcIII, and the hybrid TcVI. Using these set of alignments we have identified 288,957 high quality single nucleotide polymorphisms and 1,480 indels. In a reduced re-sequencing study we were able to validate ~ 97% of high-quality SNPs identified in 47 loci. Analysis of how these changes affect encoded protein products showed a 0.77 ratio of synonymous to non-synonymous changes in the T. cruzi genome. We observed 113 changes that introduce or remove a stop codon, some causing significant functional changes, and a number of tri-allelic and tetra-allelic SNPs that could be exploited in strain typing assays. Based on an analysis of the observed nucleotide diversity we show that the T. cruzi genome contains a core set of genes that are under apparent purifying selection. Interestingly, orthologs of known druggable targets show statistically significant lower nucleotide diversity values. Conclusions: This study provides the first look at the genetic diversity of T. cruzi at a genomic scale. The analysis covers an estimated ~ 60% of the genetic diversity present in the population, providing an essential resource for future studies on the development of new drugs and diagnostics, for Chagas Disease. These data is available through the TcSNP database (http://snps.tcruzi.org).

Description: Background: MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by targeting mRNAs for translation repression or mRNA degradation. Although many miRNAs have been discovered and studied in human and mouse, few studies focused on porcine miRNAs, especially in genome wide. Results: Here, we adopted computational approaches including support vector machine (SVM) and homology searching to make a global scanning on the pre-miRNAs of pigs. In our study, we built the SVM-based porcine pre-miRNAs classifier with a sensitivity of 100%, a specificity of 91.2% and a total prediction accuracy of 95.6%, respectively. Moreover, 2204 novel porcine pre-miRNA candidates were found by using SVM-based pre-miRNAs classifier. Besides, 116 porcine pre-miRNA candidates were detected by homology searching. Conclusions: We identified the porcine pre-miRNA in genome-wide through computational approaches by utilizing the data sets of pigs and set up the porcine pre-miRNAs library which may provide us a global scanning on the pre-miRNAs of pigs in genome level and would benefit subsequent experimental research on porcine miRNA functional and expression analysis.

Description: Background: Rhizobium tropici CIAT 899 and Rhizobium sp. PRF 81 are alpha-Proteobacteria that establish nitrogen-fixing symbioses with a range of legume hosts. These strains are broadly used in commercial inoculants for application to common bean (Phaseolus vulgaris) in South America and Africa. Both strains display intrinsic resistance to several abiotic stressful conditions such as low soil pH and high temperatures, which are common in tropical environments, and to several antimicrobials, including pesticides. The genetic determinants of these interesting characteristics remain largely unknown. Results: Genome sequencing revealed that CIAT 899 and PRF 81 share a highly-conserved symbiotic plasmid (pSym) that is present also in Rhizobium leucaenae CFN 299, a rhizobium displaying a similar host range. This pSym seems to have arisen by a co-integration event between two replicons. Remarkably, three distinct nodA genes were found in the pSym, a characteristic that may contribute to the broad host range of these rhizobia. Genes for biosynthesis and modulation of plant-hormone levels were also identified in the pSym. Analysis of genes involved in stress response showed that CIAT 899 and PRF 81 are well equipped to cope with low pH, high temperatures and also with oxidative and osmotic stresses. Interestingly, the genomes of CIAT 899 and PRF 81 had large numbers of genes encoding drug-efflux systems, which may explain their high resistance to antimicrobials. Genome analysis also revealed a wide array of traits that may allow these strains to be successful rhizosphere colonizers, including surface polysaccharides, uptake transporters and catabolic enzymes for nutrients, diverse iron-acquisition systems, cell wall-degrading enzymes, type I and IV pili, and novel T1SS and T5SS secreted adhesins. Conclusions: Availability of the complete genome sequences of CIAT 899 and PRF 81 may be exploited in further efforts to understand the interaction of tropical rhizobia with common bean and other legume hosts.

Description: Ecological studies of suicide and self-harm have established the importance of area variables (e.g., deprivation, social fragmentation) in explaining variations in suicide risk. However, there are likely to be unobserved influences on risk, typically spatially clustered, which can be modeled as random effects. Regression impacts may be biased if no account is taken of spatially structured influences on risk. Furthermore a default assumption of linear effects of area variables may also misstate or understate their impact. This paper considers variations in suicide outcomes for small areas across England, and investigates the impact on them of area socio-economic variables, while also investigating potential nonlinearity in their impact and allowing for spatially clustered unobserved factors. The outcomes are self-harm hospitalisations and suicide mortality over 6,781 Middle Level Super Output Areas.

Description: As the number of cancer survivors treated with radiation as a part of their therapy regimen is constantly increasing, so is concern about radiation-induced cancers. This increases the need for therapeutic and mitigating agents against secondary neoplasias. Development and efficacy testing of these agents requires not only extensive in vitro assessment, but also a set of reliable animal models of radiation-induced carcinogenesis. The laboratory mouse (Mus musculus) remains one of the best animal model systems for cancer research due to its molecular and physiological similarities to man, small size, ease of breeding in captivity and a fully sequenced genome. This work reviews relevant M. musculus inbred and F1 hybrid animal models and methodologies of induction of radiation-induced leukemia, thymic lymphoma, breast, and lung cancer in these models. Where available, the associated molecular pathologies are also included.

Description: Background: The objective of the research was to evaluate the current effectiveness of Ciprofloxacin on the uropathogens prevalent in infected urines of a cross-section of patients in Karachi, Pakistan.FindingsAn observational study conducted in a private diagnostic laboratory and its branches in key areas of Karachi City from February 2010 to July 2011. A total of 2963 consecutive urine samples were cultured on chocolate agar, CLED medium and selective EMB agar. Growth of possible uropathogens was noted, and compared retrospectively with earlier lab data of suggestive urine cultures (n = 1997) recorded during January 2009 and December 2009. The isolates were identified using routine procedures and the API 20 system and evaluated for their sensitivity to ciprofloxacin by Kirby-Bauer disk diffusion method. Data was subjected to statistical analysis on SPSS version 16. Out of the present-day culture-positive urines, 2409 (80.4%) yielded gram-negative rods, and 554 (18.5%) gram-positive cocci. E.coli (43.1%) was most frequent, followed by Klebsiella pneumoniae (22.4%) and Staphylococcus aureus (15.5%). 57.2% of the Gram-negative bacteria and 48.7% of the Gram-positive isolates were resistant to ciprofloxacin. In the earlier (2009) screening, 39% of Gram-negative rods and 48% of Gram-positive cocci were indifferent to the drug. Conclusions: A decrease in bacterial susceptibility of uropathogens to ciprofloxacin, a commonly prescribed drug in our population, is underlined, occurring possibly due to overuse pressure. Empirical initial treatment with ciprofloxacin would be inadequate in more than half of UTI cases, thereby counseling increased C/S testing of urines to provide existing sensitivity data for apt drug prescription.

Description: Background: Data accuracy and completeness are crucial for ensuring both the correctness and epidemiological relevance of a given data set. In this study we evaluated a clinical register in the administrative district of Marburg-Biedenkopf, Germany, for these criteria. Methods: The register contained data gathered from a comprehensive integrated breast-cancer network from three hospitals that treated all included incident cases of malignant breast cancer in two distinct time periods from 1996--97 (N=389) and 2003--04 (N=488). To assess the accuracy of this data, we compared distributions of risk, prognostic, and predictive factors with distributions from established secondary databases to detect any deviations from these [prime][prime]true[prime][prime] population parameters. To evaluate data completeness, we calculated epidemiological standard measures as well as incidence-mortality-ratios (IMRs). Results: In total, 12% (13 of 109) of the variables exhibited inaccuracies: 9% (5 out of 56) in 1996--97 and 15% (8 out of 53) in 2003--04. In contrast to raw, unstandardized incidence rates, (in-) directly age-standardized incidence rates showed no systematic deviations. Our final completeness estimates were IMR=36% (1996--97) and IMR=43% (2003--04). Conclusion: Overall, the register contained accurate, complete, and correct data. Regional differences accounted for detected inaccuracies. Demographic shifts occurred. Age-standardized measures indicate an acceptable degree of completeness. The IMR method of measuring completeness was inappropriate for incidence-based data registers. For the rising number of population-based health-care networks, further methodological advancements are necessary. Correct and epidemiologically relevant data are crucial for clinical and health-policy decision-making.

Description: Background: Patients increasingly turn to the Internet for information on medical conditions, including clinical news and treatment options. In recent years, an online patient community has arisen alongside the rapidly expanding world of social media, or "Web 2.0." Twitter provides real-time dissemination of news, information, personal accounts and other details via a highly interactive form of social media, and has become an important online tool for patients. This medium is now considered to play an important role in the modern social community of online, "wired" cancer patients. Results: Fifty-one highly influential "power accounts" belonging to cancer patients were extracted from a dataset of 731 Twitter accounts with cancer terminology in their profiles. In accordance with previously established methodology, "power accounts" were defined as those Twitter accounts with 500 or more followers. We extracted data on the cancer patient (female) with the most followers to study the specific relationships that existed between the user and her followers, and found that the majority of the examined tweets focused on greetings, treatment discussions, and other instances of psychological support. These findings went against our hypothesis that cancer patients' tweets would be centered on the dissemination of medical information and similar "newsy" details. Conclusions: At present, there exists a rapidly evolving network of cancer patients engaged in information exchange via Twitter. This network is valuable in the sharing of psychological support among the cancer community.

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 Controversy has recently arisen over the role of sirtuins in metazoan aging. In this issue of Cell Reports , Banerjee et al. demonstrate that Drosophila Sir2 is necessary for life span extension in response to dietary restriction and that its overexpression in the fat body increases the life span.

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson’s disease and Huntington’s disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans. Graphical abstract Highlights ► Sirtuin 2 (SIRT2) inhibition is neuroprotective in two HD mouse models ► SIRT2 inhibitor treatment markedly reduces huntingtin aggregates in HD mouse brain ► SIRT2 is a promising therapeutic target for neurological protein aggregation disorders

Description: Background: Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague--Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR. Results: Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners. Conclusions: The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on telomere length was not observed in exercised rats, indicating that voluntary exercise may buffer against the progressive changes in telomere length caused by alterations in maternal care early in life. In future, larger sample sizes will be needed to validate results obtained in the present study and obtain a more accurate representation of the effect that psychological stress and voluntary exercise have on telomere length.

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 Planar cell polarity (PCP) refers to the collective orientation of cells within the epithelial plane. We show that progenitor cells forming the ducts of the embryonic pancreas express PCP proteins and exhibit an active PCP pathway. Planar polarity proteins are acquired at embryonic day 11.5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal that tridimensional organization and collective communication of cells are needed in the pancreatic epithelium in order to generate appropriate numbers of endocrine cells. Graphical abstract Highlights ► PCP proteins are restricted to progenitor cells in the embryonic pancreas ► The PCP core components Celsr2 and Celsr3 control endocrine cell differentiation ► This effect is mediated by the JNK pathway

Description: Background: Graph-based modularity analysis has emerged as an important tool to study the functional organization of biological networks. However, few methods are available to study state-dependent changes in network modularity using biological activity data. We develop a weighting scheme, based on metabolic flux data, to adjust the interaction distances in a reaction-centric graph model of a metabolic network. The weighting scheme was combined with a hierarchical module assignment algorithm featuring the preservation of metabolic cycles to examine the effects of cellular differentiation and enzyme inhibitions on the functional organization of adipocyte metabolism. Results: Our analysis found that the differences between various metabolic states primarily involved the assignment of two specific reactions in fatty acid synthesis and glycerogenesis. Our analysis also identified cyclical interactions between reactions that are robust with respect to metabolic state, suggesting possible co-regulation. Comparisons based on cyclical interaction distances between reaction pairs suggest that the modular organization of adipocyte metabolism is stable with respect to the inhibition of an enzyme, whereas a major physiological change such as cellular differentiation leads to a more substantial reorganization. Conclusion: Taken together, our results support the notion that network modularity is influenced by both the connectivity of the network's components as well as the relative engagements of the connections.

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 MicroRNAs (miRNAs) are small, noncoding RNAs that inhibit translation and promote mRNA decay. The levels of mature miRNAs are the result of different rates of transcription, processing, and turnover. The noncanonical polymerase Gld2 has been implicated in the stabilization of miR-122, possibly through catalyzing 3′ monoadenylation; however, there is little evidence that this relationship is one of cause and effect. Here, we biochemically characterize Gld2’s involvement in miRNA monoadenylation and its effect on miRNA stability. We find that Gld2 directly monoadenylates and stabilizes specific miRNA populations in human fibroblasts and that sensitivity to monoadenylation-induced stability depends on nucleotides in the miRNA 3′ end. These results establish a mechanism of miRNA stability and resulting posttranscriptional gene regulation. Graphical abstract Highlights ► Gld2 monoadenylates specific microRNAs (miRNAs) ► Monoadenylation stabilizes miRNA subpopulations and prolongs their activity ► Sensitivity to monoadenylation and stability depends on nucleotides in the miRNA 3′ end

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 In the cytoplasm, the correct delivery of membrane proteins is an essential and highly regulated process. The posttranslational targeting of the important tail-anchor membrane (TA) proteins has recently been under intense investigation. A specialized pathway, called the guided entry of TA proteins (GET) pathway in yeast and the transmembrane domain recognition complex (TRC) pathway in vertebrates, recognizes endoplasmic-reticulum-targeted TA proteins and delivers them through a complex series of handoffs. An early step is the formation of a complex between Sgt2/SGTA, a cochaperone with a presumed ubiquitin-like-binding domain (UBD), and Get5/UBL4A, a ubiquitin-like domain (UBL)-containing protein. We structurally characterize this UBD/UBL interaction for both yeast and human proteins. This characterization is supported by biophysical studies that demonstrate that complex formation is mediated by electrostatics, generating an interface that has high-affinity with rapid kinetics. In total, this work provides a refined model of the interplay of Sgt2 homologs in TA targeting. Graphical abstract Highlights ► Sgt2 homologs contain dimerization motifs that are novel UBDs ► The UBL of Get5 homologs has features that distinguish it from other UBLs ► Complex formation of Sgt2 and Get5 includes a conserved and dynamic interface ► The system can rapidly discriminate between other UBL pathways

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 Chimera formation after blastocyst injection or morula aggregation is the principal functional assay of the developmental potential of mouse embryonic stem cells (ESCs). This property, which demonstrates functional equivalence between ESCs and the preimplantation epiblast, is not shared by epiblast stem cell (EpiSC) lines. Here, we show that EpiSCs derived either from postimplantation embryos or from ESCs in vitro readily generate chimeras when grafted to postimplantation embryos in whole embryo culture. EpiSC derivatives integrate and differentiate to derivatives of all three embryonic germ layers and primordial germ cells. In contrast, grafted ESCs seldom proliferate in postimplantation embryos, and fail to acquire the identity of their host-derived neighbors. EpiSCs do not incorporate efficiently into embryonic day 8.5 embryos, a stage by which pluripotency has been lost. Thus, chimera formation by EpiSCs requires a permissive environment, the postimplantation epiblast, and demonstrates functional equivalence between this cell type and EpiSCs. Graphical abstract Highlights ► Epiblast stem cells (EpiSCs) form chimeras when injected into postimplantation epiblast ► Embryonic stem cells do not form postimplantation chimeras ► EpiSCs do not integrate if they are injected after gastrulation

Description: 27 December 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 6 An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155 −/− mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4 + and CD8 + T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses. Graphical abstract Highlights ► miR-155 promotes and miR-146a inhibits both CD4+ and CD8+ T cell antitumor responses ► DKO mice reveal epistasis between miR-155 and miR-146a during tumor immunity ► miR-155 regulation of IFNγ involves repression of its target Ship1 in T cells

Description: Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors Nature Communications 3, 1329 (2012). doi:10.1038/ncomms2339 Authors: Manuela Rossol, Matthias Pierer, Nora Raulien, Dagmar Quandt, Undine Meusch, Kathrin Rothe, Kristin Schubert, Torsten Schöneberg, Michael Schaefer, Ute Krügel, Sanela Smajilovic, Hans Bräuner-Osborne, Christoph Baerwald & Ulf Wagner

Description: Background: A novel herbal formulation LI10903F, alternatively known as LOWAT was developed based on its ability to inhibit adipogenesis and lipogenesis in 3T3-L1 adipocytes model. The clinical efficacy and tolerability of LI10903F were evaluated in an eight-week, randomized, double-blind, placebo-controlled, clinical trial in 50 human subjects with body mass index (BMI) between 30 and 40 kg/m2 (clinical trial registration number: ISRCTN37381706). Participants were randomly assigned to either a placebo or LI10903F group. Subjects in the LI10903F group received 300 mg of herbal formulation thrice daily, while subjects in the placebo group received 300 mg of placebo capsules thrice daily. All subjects were provided a standard diet (2,000 kcal daily) and participated in a moderate exercise of 30 min walk for five days a week. Additionally, the safety of this herbal formulation was evaluated by a series of acute, sub-acute toxicity and genotoxicity studies in animals and cellular models. Results: After eight weeks of supplementation, statistically significant net reductions in body weight (2.49 kg; p=0.00005) and BMI (0.96 kg/m2; p=0.00004) were observed in the LI10903F group versus placebo group. Additionally, significant increase in serum adiponectin concentration (p=0.0076) and significant decrease in serum ghrelin concentration (p=0.0066) were found in LI10903F group compared to placebo group. Adverse events were mild and were equally distributed between the two groups. Interestingly, LI10903F showed broad spectrum safety in a series of acute, sub-acute toxicity and genotoxicity studies. Conclusions: Results from the current research suggest that LI10903F or LOWAT is well-tolerated, safe and effective for weight management.

Description: Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila Nature Communications 3, 1312 (2012). doi:10.1038/ncomms2278 Authors: Seongsoo Lee, Ji-Wu Wang, Wendou Yu & Bingwei Lu

Description: Atomic-scale engineering of magnetic anisotropy of nanostructures through interfaces and interlines Nature Communications 3, 1313 (2012). doi:10.1038/ncomms2316 Authors: S. Ouazi, S. Vlaic, S. Rusponi, G. Moulas, P. Buluschek, K. Halleux, S. Bornemann, S. Mankovsky, J. Minár, J.B. Staunton, H. Ebert & H. Brune

Description: Land use and land cover (LULC) information is an important component influencing watershed modeling with regards to hydrology and water quality in the river basin. In this study, the sensitivity of the Soil and Water Assessment Tool (SWAT) model to LULC datasets with three points in time and three levels of detail was assessed in a coastal subtropical watershed located in Southeast China. The results showed good agreement between observed and simulated values for both monthly and daily streamflow and monthly NH4+-N and TP loads. Three LULC datasets in 2002, 2007 and 2010 had relatively little influence on simulated monthly and daily streamflow, whereas they exhibited greater effects on simulated monthly NH4+-N and TP loads. When using the two LULC datasets in 2007 and 2010 compared with that in 2002, the relative differences in predicted monthly NH4+-N and TP loads were −11.0 to −7.8% and −4.8 to −9.0%, respectively. There were no significant differences in simulated monthly and daily streamflow when using the three LULC datasets with ten, five and three categories. When using LULC datasets from ten categories compared to five and three categories, the relative differences in predicted monthly NH4+-N and TP loads were −6.6 to −6.5% and −13.3 to −7.3%, respectively. Overall, the sensitivity of the SWAT model to LULC datasets with different points in time and levels of detail was lower in monthly and daily streamflow simulation than in monthly NH4+-N and TP loads prediction. This research provided helpful insights into the influence of LULC datasets on watershed modeling.

Description: Background: The -493G/T polymorphism in the microsomal triglyceride transfer protein (MTP) gene is associated with lower serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and longevity in several populations, but the results are inconsistent in different racial/ethnic groups. The current study was to investigate the plausible association of MTP -493G/T polymorphism with serum lipid levels and longevity in Zhuang long-lived families residing in Bama area, a famous home of longevity in Guangxi, China. Methods: The MTP -493G/T was genotyped by PCR-restriction fragment length polymorphism in 391 Bama Zhuang long-lived families (BLF, n = 1467, age 56.60 +/- 29.43 years) and four control groups recruited from Bama and out-of-Bama area with or without a familial history of exceptional longevity: Bama non-long-lived families (BNLF, n = 586, age 44.81 +/- 26.83 years), Bama non-Zhuang long-lived families (BNZLF, n = 444, age 52.09 +/- 31.91 years), Pingguo long-lived families (PLF, n = 658, age 50.83 +/- 30.30 years), and Pingguo non-long-lived families (PNLF, n = 539, age 38.74 +/- 24.69 years). Correlation analyses between genotypes and serum lipid levels and longevity were then performed. Results: No particularly favorable lipoprotein and clinical phenotypes were seen in BLF as compared to general families in the same area. Instead, the levels of total cholesterol (TC), TG, LDL-C, and the prevalence of dyslipidemia were significantly higher in the three Bama families as compared to the two non-Bama families (P 〈 0.01 for all). There were no differences in the allelic and genotypic frequencies among the tested cohorts (P 〉 0.05 for all), but the TT genotype tended to enrich in the three long-lived cohorts from both areas. In addition, the individuals harboring TT genotype exhibited lower LDL-C and TC levels in the overall populations and Bama populations with a region- and sex-specific pattern. Multiple linear regression analyses unraveled that LDL-C levels were correlated with genotypes in Bama combined population, BNLF, and the total population (P 〈 0.05 for each) but not in Pingguo populations; TC and HDL-C levels were correlated with genotypes in Bama combined population and BLF, respectively (P 〈 0.05 for each). Conclusions: MTP -493G/T polymorphism may play an important role in fashioning the serum lipid profiles of Bama populations, despite no direct association between MTP -493G/T and longevity was detected.

Description: Background: RNA interference (RNAi) becomes an increasingly important and effective genetic tool to study the function of target genes by suppressing specific genes of interest. This system approach helps identify signaling pathways and cellular phase types by tracking intensity and/or morphological changes of cells. The traditional RNAi screening scheme, in which one siRNA is designed to knockdown one specific mRNA target, needs a large library of siRNAs and turns out to be time-consuming and expensive. Results: In this paper, we propose a conceptual model, called compressed sensing RNAi (csRNAi), which employs the unique combination of group of small interfering RNAs (siRNAs) to knockdown a much larger size of genes. This strategy is based on the fact that one gene can be partially bound with several small interfering RNAs (siRNAs) and conversely, one siRNA can bind to a few genes with distinct binding affinity. This model constructs a multi-to-multi correspondence between siRNAs and their targets, with siRNAs much fewer than mRNA targets, compared with the conventional scheme. Mathematically this problem involves an underdetermined system of equations (linear or nonlinear), which is ill-posed in general. However, the recently developed compressed sensing (CS) theory can solve this problem. We present a mathematical model to describe the csRNAi system based on both CS theory and biological concerns. To build this model, we first search nucleotide motifs in a target gene set. Then we propose a machine learning based method to find the effective siRNAs with novel features, such as image features and speech features to describe an siRNA sequence. Numerical simulations show that we can reduce the siRNA library to one third of that in the conventional scheme. In addition, the features to describe siRNAs outperform the existing ones substantially. Conclusions: This csRNAi system is very promising in saving both time and cost for large-scale RNAi screening experiments which may benefit the biological research with respect to cellular processes and pathways.

Description: Background: Copy number variations (CNVs) are genomic structural variants that are found in healthy populations and have been observed to be associated with disease susceptibility. Existing methods for CNV detection are often performed on a sample-by-sample basis, which is not ideal for large datasets where common CNVs must be estimated by comparing the frequency of CNVs in the individual samples. Here we describe a simple and novel approach to locate genome-wide CNVs common to a specific population, using human ancestry as the phenotype. Results: We utilized our previously published Genome Alteration Detection Analysis (GADA) algorithm to identify common ancestry CNVs (caCNVs) and built a caCNV model to predict population structure. We identified a 73 caCNV signature using a training set of 225 healthy individuals from European, Asian, and African ancestry. The signature was validated on an independent test set of 300 individuals with similar ancestral background. The error rate in predicting ancestry in this test set was 2% using the 73 caCNV signature. Among the caCNVs identified, several were previously confirmed experimentally to vary by ancestry. Our signature also contains a caCNV region with a single microRNA (MIR270), which represents the first reported variation of microRNA by ancestry. Conclusions: We developed a new methodology to identify common CNVs and demonstrated its performance by building a caCNV signature to predict human ancestry with high accuracy. The utility of our approach could be extended to large case--control studies to identify CNV signatures for other phenotypes such as disease susceptibility and drug response.

Description: Background: Understanding demographic histories, such as divergence time, patterns of gene flow, and population size changes, in ecologically diverging lineages provide implications for the process and maintenance of population differentiation by ecological adaptation. This study addressed the demographic histories in two independently derived lineages of flood-resistant riparian plants and their non-riparian relatives [Ainsliaea linearis (riparian) and A. apiculata (non-riparian); A. oblonga (riparian) and A. macroclinidioides (non-riparian); Asteraceae] using an isolation-with-migration (IM) model based on variation at 10 nuclear DNA loci. Results: The highest posterior probabilities of the divergence time parameters were estimated to be ca. 25,000 years ago for A. linearis and A. apiculata and ca. 9000 years ago for A. oblonga and A. macroclinidioides, although the confidence intervals of the parameters had broad ranges. The likelihood ratio tests detected evidence of historical gene flow between both riparian/non-riparian species pairs. The riparian populations showed lower levels of genetic diversity and a significant reduction in effective population sizes compared to the non-riparian populations and their ancestral populations. Conclusions: This study showed the recent origins of flood-resistant riparian plants, which are remarkable examples of plant ecological adaptation. The recent divergence and genetic signatures of historical gene flow among riparian/non-riparian species implied that they underwent morphological and ecological differentiation within short evolutionary timescales and have maintained their species boundaries in the face of gene flow. Comparative analyses of adaptive divergence in two sets of riparian/non-riparian lineages suggested that strong natural selection by flooding had frequently reduced the genetic diversity and size of riparian populations through genetic drift, possibly leading to fixation of adaptive traits in riparian populations. The two sets of riparian/non-riparian lineages showed contrasting patterns of gene flow and genetic differentiation, implying that each lineage showed different degrees of reproductive isolation and that they had experienced unique evolutionary and demographic histories in the process of adaptive divergence.

Description: Background: HIV/AIDS has several means of transmission. Exposure to blood and other body fluids is a very important means of transmission. Healthcare workers are exposed to this disease mainly due to the nature of their work. This is an exploration of the perceptions of healthcare workers of the University of Gondar Hospital. Methods: Based on purposive sampling seven healthcare workers were selected from different departments in the hospital so that they could reflect on their perceptions. The selected healthcare workers were asked about the risks related to their work, their experience of HIV related hazards and their general views on the transmission of HIV. The main themes were identified for analysis and the views were summarized under the themes. Results: All the respondents were aware of the risk of acquiring HIV in healthcare settings. Some had experienced accidents that made them take post-exposure prophylaxis, and most witnessed accidents like needle-stick injuries to their colleagues. They also expressed their feelings that their workplace was not the best place to work at. Conclusion: Health professionals are well aware of the possibility of HIV transmission associated with their practice. Accidents like needle stick injuries are apparently common; and at the same time, the practice of healthcare workers towards using universal precautions looks poor.

Description: Background: Members of the family Syngnathidae share a unique reproductive mode termed male pregnancy. Males carry eggs in specialised brooding structures for several weeks and release free-swimming offspring. Here we describe a systematic investigation of pre-release development in syngnathid fishes, reviewing available data for 17 species distributed across the family. This work is complemented by in-depth examinations of the straight-nosed pipefish Nerophis ophidion, the black-striped pipefish Syngnathus abaster, and the potbellied seahorse Hippocampus abdominalis. Results: We propose a standardised classification of early syngnathid development that extends from the activation of the egg to the release of newborn. The classification consists of four developmental periods -- early embryogenesis, eye development, snout formation, and juvenile -- which are further divided into 11 stages. Stages are characterised by morphological traits that are easily visible in live and preserved specimens using incident-light microscopy. Conclusions: Our classification is derived from examinations of species representing the full range of brooding-structure complexity found in the Syngnathidae, including tail-brooding as well as trunk-brooding species, which represent independent evolutionary lineages. We chose conspicuous common traits as diagnostic features of stages to allow for rapid and consistent staging of embryos and larvae across the entire family. In view of the growing interest in the biology of the Syngnathidae, we believe that the classification proposed here will prove useful for a wide range of studies on the unique reproductive biology of these male-brooding fish.

Description: Background: Maize is a major crop plant, grown for human and animal nutrition, as well as a renewable resource forbioenergy. When looking at the problems of limited fossil fuels, the growth of the world's population or theworld's climate change, it is important to find ways to increase the yield and biomass of maize and to studyhow it reacts to specific abiotic and biotic stress situations. Within the OPTIMAS systems biology projectmaize plants were grown under a large set of controlled stress conditions, phenotypically characterised andplant material was harvested to analyse the effect of specific environmental conditions or developmentalstages. Transcriptomic, metabolomic, ionomic and proteomic parameters were measured from the same plantmaterial allowing the comparison of results across different omics domains. A data warehouse wasDescriptionThe OPTIMAS Data Warehouse (OPTIMAS-DW) is a comprehensive data collection for maize and integratesdata from different data domains such as transcriptomics, metabolomics, ionomics, proteomics andphenomics. Within the OPTIMAS project, a 44K oligo chip was designed and annotated to describe thefunctions of the selected unigenes. Several treatment- and plant growth stage experiments were performed andmeasured data were filled into data templates and imported into the data warehouse by a Java based importtool. A web interface allows users to browse through all stored experiment data in OPTIMAS-DW includingall data domains. Furthermore, the user can filter the data to extract information of particular interest. All datacan be exported into different file formats for further data analysis and visualisation. The data analysisintegrates data from different data domains and enables the user to find answers to different systems biologyquestions. Finally, maize specific pathway information is provided. Conclusions: With OPTIMAS-DW a data warehouse for maize was established, which is able to handle different datadomains, comprises several analysis results that will support researchers within their work and supportssystems biological research in particular. The system is available athttp://www.optimas-bioenergy.org/optimas_dw.

Description: Background: Health control beliefs were postulated to be associated with health behaviour. However, the results of studies assessing these associations suggest that they might not be universal. Among young adults associations have been reported, but, the evidence is limited. The objective of this analysis was to re-examine these associations in a sample of university students in Germany.FindingsData from a multicentre cross-sectional study among university students in North Rhine-Westphalia, Germany was used (N=3,306). The Multidimensional Health Locus of Control Scale with three dimensions (one internal and two external) and six aspects of health behaviour (smoking habits, alcohol use, drug consumption, being over-/ or underweight, physical activity, and importance of healthy nutrition) were evaluated. Students with stronger internal locus of control scores paid more attention to healthy nutrition and displayed a higher level of physical activity. Individuals with a stronger belief in health professionals were less likely to use drugs and paid more attention to healthy nutrition. Furthermore, higher scores in the second external locus of control dimension (beliefs in luck or chance) were associated with a higher likelihood of current smoking, lower physical activity and less attention to healthy nutrition. Conclusions: Students engaged more strongly in unhealthy behaviour if they believed that luck determines health. In contrast, believing in having control over one's own health was associated with more healthy behaviour. These findings support the need to consider health control beliefs while designing preventive strategies in this specific population.

Description: Available online 29 December 2012 Publication year: 2012 Source: FEBS Open Bio A water-soluble selenoxide (DHS ox ) having a five-membered ring structure enables rapid and selective conversion of cysteinyl SH groups in a polypeptide chain into SS bonds in a wide pH and temperature range. It was previously demonstrated that the second-order rate constants for the SS formation with DHS ox would be proportional to the number of the free SH groups present in the substrate if there is no steric congestion around the SH groups. In the present study, kinetics of the SS formation with DHS ox was extensively studied at pH 4–10 and 25°C by using reduced ribonuclease A, recombinant hirudin variant (CX-397), insulin A- and B-chains, and relaxin A-chain, which have two to eight cysteine residues, as polythiol substrates. The obtained rate constants showed stochastic SS formation behaviors under most conditions. However, the rate constants for CX-397 at pH 8.0 and 10.0 were not proportional to the number of the free SH groups, suggesting that the SS intermediate ensembles possess densely packed structures under weakly basic conditions. The high two-electron redox potential of DHS ox (375 mV at 25°C) compared to L-cystine supported the high ability of DHS ox for SS formation in a polypeptide chain. Interestingly, the rate constants of the SS formation jumped up at a pH around the p K a value of the cysteinyl SH groups. The SS formation velocity was slightly decreased by addition of a denaturant due probably to the interaction between the denaturant and the peptide. The stochastic behaviors as well as the absolute values of the second-order rate constants in comparison to dithiothreitol (DTT red ) are useful to probe the chemical reactivity and conformation, hence the folding, of polypeptide chains. Graphical abstract Highlights ▸ DHS ox was applied as a SS-forming reagent for five polythiol peptides and DTT red . ▸ The SS formation velocities depend on the kind of substrate and solvent conditions. ▸ The SS-formation rate constants are proportional to the number of free SH groups. ▸ Folded structures and SH p K a modify the stochastic nature and absolute values of the rate constants. ▸ DHS ox is a useful probe of chemical reactivity and intermediate structures in oxidative protein folding.

Description: Background: In higher eukaryotes, gene expression is regulated at different levels. In particular, 3[prime]UTRs play a central role in translation, stability and subcellular localization of transcripts. In recent years, the development of high throughput sequencing techniques has facilitated the acquisition of transcriptional data at a genome wide level. However, annotation of the 3[prime] ends of genes is still incomplete, thus limiting the interpretation of the data generated. For example, we have previously reported two different genes, ADD2 and CPEB3, with conserved 3[prime]UTR alternative isoforms not annotated in the current versions of Ensembl and RefSeq human databases. Results: In order to evaluate the existence of other conserved 3[prime] ends not annotated in these databases we have now used comparative genomics and transcriptomics across several vertebrate species. In general, we have observed that 3[prime]UTR conservation is lost after the end of the mature transcript. Using this change in conservation before and after the 3[prime] end of the mature transcripts we have shown that many conserved ends were still not annotated. In addition, we used orthologous transcripts to predict 3[prime]UTR extensions and validated these predictions using total RNA sequencing data. Finally, we used this method to identify not annotated 3[prime] ends in rats and dogs. As a result, we report several hundred novel 3[prime]UTR extensions in rats and a few thousand in dogs. Conclusions: The methods presented here can efficiently facilitate the identification of not-yet-annotated conserved 3[prime]UTR extensions. The application of these methods will increase the confidence of orthologous gene models across vertebrates.

Description: Background: For selection and evaluation of potential biomarkers, inclusion of already published information is of utmost importance. In spite of significant advancements in text- and data-mining techniques, the vast knowledge space of biomarkers in biomedical text has remained unexplored. Existing named entity recognition approaches are not sufficiently selective for the retrieval of biomarker information from the literature. The purpose of this study was to identify textual features that enhance the effectiveness of biomarker information retrieval for different indication areas and diverse end user perspectives. Methods: A biomarker terminology was created and further organized into six concept classes. Performance of this terminology was optimized towards balanced selectivity and specificity. The information retrieval performance using the biomarker terminology was evaluated based on various combinations of the terminology's six classes. Further validation of these results was performed on two independent corpora representing two different neurodegenerative diseases. Results: The current state of the biomarker terminology contains 119 entity classes supported by 1890 different synonyms. The result of information retrieval shows improved retrieval rate of informative abstracts, which is achieved by including clinical management terms and evidence of gene/protein alterations (e.g. gene/protein expression status or certain polymorphisms) in combination with disease and gene name recognition. When additional filtering through other classes (e.g. diagnostic or prognostic methods) is applied, the typical high number of unspecific search results is significantly reduced. The evaluation results suggest that this approach enables the automated identification of biomarker information in the literature. A demo version of the search engine SCAIView, including the biomarker retrieval, is made available to the public through http://www.scaiview.com/scaiview-academia.html. Conclusions: The approach presented in this paper demonstrates that using a dedicated biomarker terminology for automated analysis of the scientific literature maybe helpful as an aid to finding biomarker information in text. Successful extraction of candidate biomarkers information from published resources can be considered as the first step towards developing novel hypotheses. These hypotheses will be valuable for the early decision-making in the drug discovery and development process.

Description: Background: Pineapple (Ananas comosus) is a tropical fruit crop of significant commercial importance. Although the physiological changes that occur during pineapple fruit development have been well characterized, little is known about the molecular events that occur during the fruit ripening process. Understanding the molecular basis of pineapple fruit ripening will aid the development of new varieties via molecular breeding or genetic modification. In this study we developed a 9277 element pineapple microarray and used it to profile gene expression changes that occur during pineapple fruit ripening. Results: Microarray analyses identified 271 unique cDNAs differentially expressed at least 1.5-fold between the mature green and mature yellow stages of pineapple fruit ripening. Among these 271 sequences, 184 share significant homology with genes encoding proteins of known function, 53 share homology with genes encoding proteins of unknown function and 34 share no significant homology with any database accession. Of the 237 pineapple sequences with homologs, 160 were up-regulated and 77 were down-regulated during pineapple fruit ripening. DAVID Functional Annotation Cluster (FAC) analysis of all 237 sequences with homologs revealed confident enrichment scores for redox activity, organic acid metabolism, metalloenzyme activity, glycolysis, vitamin C biosynthesis, antioxidant activity and cysteine peptidase activity, indicating the functional significance and importance of these processes and pathways during pineapple fruit development. Quantitative real-time PCR analysis validated the microarray expression results for nine out of ten genes tested. Conclusions: This is the first report of a microarray based gene expression study undertaken in pineapple. Our bioinformatic analyses of the transcript profiles have identified a number of genes, processes and pathways with putative involvement in the pineapple fruit ripening process. This study extends our knowledge of the molecular basis of pineapple fruit ripening and non-climacteric fruit ripening in general.

Description: Background: Accumulation of extracellular matrix (ECM) and increased matrix metalloproteinase (MMP) activity are hallmarks of liver fibrosis. The aim of the present study was to develop a model of liver fibrosis combining ex vivo tissue culture of livers from CCl4 treated animals with an ELISA detecting a fragment of type III collagen generated in vitro by MMP-9 (C3M), known to be associated with liver fibrosis and to investigate cAMP modulation of MMP activity and liver tissue turnover in this model.FindingsIn vivo: Rats were treated for 8 weeks with CCl4/Intralipid. Liver slices were cultured for 48 hours. Levels of C3M were determined in the supernatants of slices cultured without treatment, treated with GM6001 (positive control) or treated with IBMX (phosphodiesterase inhibitor). Enzymatic activity of MMP-2 and MMP-9 were studied by gelatin zymography.Ex vivo: The levels of serum C3M increased 77% in the CCl4-treated rats at week 8 (p 〈 0.01); Levels of C3M increased significantly by 100% in fibrotic liver slices compared to controls after 48 hrs (p 〈 0.01). By adding GM6001 or IBMX to the media, C3M was restored to control levels. Gelatin zymography demonstrated CCl4-treated animals had highly increased MMP-9, but not MMP-2 activity, compared to slices derived from control animals. Conclusions: We have combined an ex vivo model of liver fibrosis with measurement of a biochemical marker of collagen degradation in the condition medium. This technology may be used to evaluate the molecular process leading to structural fibrotic changes, as collagen species are the predominant structural part of fibrosis. These data suggest that modulation of cAMP may play a role in regulation of collagen degradation associated with liver fibrosis.

Description: Background: Cia5a is a locus on rat chromosome 10 that regulates disease severity and joint damage in two models of rheumatoid arthritis, collagen- and pristane-induced arthritis (PIA). In this study, we aimed to identify cellular and molecular processes regulated by Cia5a using microarray-based gene expression analysis of synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia5a) congenics (mild non-erosive disease) rats. Results: Synovial tissues from six DA and eight DA.F344(Cia5a) rats were analyzed 21 days after the induction of PIA using the Illumina RatRef-12 BeadChip (21,922 genes) and selected data confirmed with qPCR. There was a significantly increased expression of pro-inflammatory mediators such as Il1b (5-fold), Il18 (3.9-fold), Cxcl1 (10-fold), Cxcl13 (7.5-fold) and Ccl7 (7.9-fold), and proteases like Mmp3 (23-fold), Mmp9 (32-fold), Mmp14 (4.4-fold) and cathepsins in synovial tissues from DA, with reciprocally reduced levels in congenics. mRNA levels of 47 members of the Spleen Tyrosine Kinase (Syk) pathway were significantly increased in DA synovial tissues compared with DA.F344(Cia5a), and included Syk (5.4-fold), Syk-activating receptors and interacting proteins, and genes regulated by Syk such as NFkB, and NAPDH oxidase complex genes. Nuclear receptors (NR) such as Rxrg, Pparg and Rev-erba were increased in the protected congenics, and so was the anti-inflammatory NR-target gene Scd1 (54-fold increase). Tnn (72-fold decrease) was the gene most significantly increased in DA. Conclusions: Analyses of gene expression in synovial tissues revealed that the arthritis severity locus Cia5a regulates the expression of key mediators of inflammation and joint damage, as well as the expression of members of the Syk pathway. This expression pattern correlates with disease severity and joint damage and along with the gene accounting for Cia5a could become a useful biomarker to identify patients at increased risk for severe and erosive disease. The identification of the gene accounting for Cia5a has the potential to generate a new and important target for therapy and prognosis.

Description: Background: Traditional candidate gene approach has been widely used for the study of complex diseases including obesity. However, this approach is largely limited by its dependence on existing knowledge of presumed biology of the phenotype under investigation. Our combined strategy of comparative genomics and chromosomal heritability estimate analysis of obesity traits, subscapular skinfold thickness and back-fat thickness in Korean cohorts and pig (Sus scrofa), may overcome the limitations of candidate gene analysis and allow us to better understand genetic predisposition to human obesity. Results: We found common genes including FTO, the fat mass and obesity associated gene, identified from significant SNPs by association studies of each trait. These common genes were related to blood pressure and arterial stiffness (P = 1.65E-05) and type 2 diabetes (P = 0.00578). Through the estimation of variance of genetic component (heritability) for each chromosome by SNPs, we observed a significant positive correlation (r = 0.479) between genetic contributions of human and pig to obesity traits. Furthermore, we noted that the phenotypic variance for obesity can be explained dominantly by chromosome 2, which is syntenic to pig chromosomes 3 and 15. Conclusions: Obesity genetics still awaits further discovery. Navigating syntenic regions suggests obesity candidate genes on chromosome 2 that are previously known to be associated with obesity-related diseases: MRPL33, PARD3B, ERBB4, STK39, and ZNF385B.

Description: Background: Phenotypic evolution in animals is thought to be driven in large part by differences in gene expression patterns, which can result from sequence changes in cis-regulatory elements (cis-changes) or from changes in the expression pattern or function of transcription factors (trans-changes). While isolated examples of trans-changes have been identified, the scale of their overall contribution to regulatory and phenotypic evolution remains unclear. Results: Here, we attempt to examine the prevalence of trans-effects and their potential impact on gene expression patterns in vertebrate evolution by comparing the function of identical human tissue-specific enhancer sequences in two highly divergent vertebrate model systems, mouse and zebrafish. Among 47 human conserved non-coding elements (CNEs) tested in transgenic mouse embryos and in stable zebrafish lines, at least one species-specific expression domain was observed in the majority (83%) of cases, and 36% presented dramatically different expression patterns between the two species. Although some of these discrepancies may be due to the use of different transgenesis systems in mouse and zebrafish, in some instances we found an association between differences in enhancer activity and changes in the endogenous gene expression patterns between mouse and zebrafish, suggesting a potential role for trans-changes in the evolution of gene expression. Conclusions: In total, our results: (i) serve as a cautionary tale for studies investigating the role of human enhancers in different model organisms, and (ii) suggest that changes in the trans environment may play a significant role in the evolution of gene expression in vertebrates.

Description: Background: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor andverbal tics. Although several genes have been suggested in the etiology of TS, the geneticmechanisms remain poorly understood. Methods: Using cytogenetics and FISH analysis, we identified an apparently balancedt(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). Inorder to map the breakpoints and to identify additional submicroscopic rearrangements, weperformed whole genome mate-pair sequencing and CGH-array analysis on DNA from theproband. Results: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of thechromosome 6q breakpoint, which has not been reported in controls. The deletion affectsthree genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deletedin a girl with autistic features and speech delay. The proband's mother, also a carrier of thetranslocation, was diagnosed with OCD and shares the deletion. We also describe a furtherpotentially related rearrangement which, while unmapped in Homo sapiens, was consistentwith the chimpanzee genome. Conclusions: We conclude that genome-wide sequencing at relatively low resolution can be used for theidentification of submicroscopic rearrangements.We also show that large rearrangements may escape detection using standard analysis ofwhole genome sequencing data. Our findings further provide a candidate region for TS andOCD on chromosome 6q16.

Description: Background: Secretoglobin 1A1 (SCGB 1A1), also called Clara cell secretory protein, is the most abundantly secreted protein of the airway. The SCGB1A1 gene has been characterized in mammals as a single copy in the genome. However, analysis of the equine genome suggested that horses might have multiple SCGB1A1 gene copies. Non-ciliated lung epithelial cells produce SCGB 1A1 during inhalation of noxious substances to counter airway inflammation. Airway fluid and lung tissue of horses with recurrent airway obstruction (RAO), a chronic inflammatory lung disease affecting mature horses similar to environmentally induced asthma of humans, have reduced total SCGB 1A1 concentration. Herein, we investigated whether horses have distinct expressed SCGB1A1 genes; whether the transcripts are differentially expressed in tissues and in inflammatory lung disease; and whether there is cell specific protein expression in tissues. Results: We identified three SCGB1A1 gene copies on equine chromosome 12, contained within a 512-kilobase region. Bioinformatic analysis showed that SCGB1A1 genes differ from each other by 8 to 10 nucleotides, and that they code for different proteins. Transcripts were detected for SCGB1A1 and SCGB1A1A, but not for SCGB1A1P. The SCGB1A1P gene had most inter-individual variability and contained a non-sense mutation in many animals, suggesting that SCGB1A1P has evolved into a pseudogene. Analysis of SCGB1A1 and SCGB1A1A sequences by endpoint-limiting dilution PCR identified a consistent difference affecting 3 bp within exon 2, which served as a gene-specific "signature". Assessment of gene- and organ-specific expression by semiquantitative RT-PCR of 33 tissues showed strong expression of SCGB1A1 and SCGB1A1A in lung, uterus, Fallopian tube and mammary gland, which correlated with detection of SCGB 1A1 protein by immunohistochemistry. Significantly altered expression of the ratio of SCGB1A1A to SCGB1A1 was detected in RAO-affected animals compared to controls, suggesting different roles for SCGB 1A1 and SCGB 1A1A in this inflammatory condition. Conclusions: This is the first report of three SCGB1A1 genes in a mammal. The two expressed genes code for proteins predicted to differ in function. Alterations in the gene expression ratio in RAO suggest cell and tissue specific regulation and functions. These findings may be important for understanding of lung and reproductive conditions.

Description: Background: To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method[prime]s potential value in the prediction of LN metastases. Methods: Axillary LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups. Results: In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex 〉3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex 〉3mm in B-mode and blue cortex in the elastogram, SP=99.3%). Conclusions: Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.

Description: Background: The use of food-grade Lactic Acid Bacteria (LAB) as DNA delivery vehicles represents an attractive strategy to deliver DNA vaccines at the mucosal surfaces as they are generally regarded as safe (GRAS). We previously showed that either native Lactococcus lactis (LL) or recombinant invasive LL expressing Fibronectin Binding Protein A of Staphylococcus aureus (LL-FnBPA+) or Internalin A of Listeria monocytogenes (LL-InlA+), were able to deliver and trigger DNA expression by epithelial cells, either in vitro or in vivo. InlA does not bind to its receptor, the murine E-cadherin, thus limiting the use of LL-InlA+in in vivo murine models. Moreover, FnBPA binds to its receptors, integrins, via fibronectin introducing another limiting factor. In order to avoid the limitations of LL-InlA+and LL-FnBPA+, a new L. lactis strain was engineered to produce a previously described mutated form of InlA (LL-mInlA+) allowing the binding of mInlA on murine E-cadherin. Results: After showing the expression of mInLA at the surface of LL-mInlA+strain, in vitro gentamycin survival assay in Caco-2 cells showed that LL-mInlA+is 1000 times more invasive than LL. LL-mInlA+invasivity was also validated by fluorescence microscopy. LL and LL-mInlA+were transformed with pValacBLG, a plasmid containing the cDNA of bovine beta-Lactoglobulin (BLG), resulting in strains LL-BLG and LL-mInlA+BLG. The plasmid transfer in vitro using LL-mInlA+BLG was increased 10 times compared to LL-BLG. Moreover, the number of mice producing BLG in isolated enterocytes after oral administration of LL-mInlA+BLG in vivo was slightly higher than after oral administration of LL-BLG. Conclusions: We confirmed in this study that the production of mInlA at the surface of L. lactis is a promising strategy for plasmid transfer in vitro and in vivo.

Description: Background: The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion. Methods: Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation. Results: Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes. Conclusions: MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

Description: Background: In eukaryotic cells, dynamin and flotillin are involved in processes such as endocytosis and lipid raft formation, respectively. Dynamin is a GTPase that exerts motor-like activity during the pinching off of vesicles, while flotillins are coiled coil rich membrane proteins with no known enzymatic activity. Bacteria also possess orthologs of both classes of proteins, but their function has been unclear. Results: We show that deletion of the single dynA or floT genes lead to no phenotype or a mild defect in septum formation in the case of the dynA gene, while dynA floT double mutant cells were highly elongated and irregularly shaped, although the MreB cytoskeleton appeared to be normal. DynA colocalizes with FtsZ, and the dynA deletion strain shows aberrant FtsZ rings in a subpopulation of cells. The mild division defect of the dynA deletion is exacerbated by an additional deletion in ezrA, which affects FtsZ ring formation, and also by the deletion of a late division gene (divIB), indicating that DynA affects several steps in cell division. DynA and mreB deletions generated a synthetic defect in cell shape maintenance, showing that MreB and DynA play non-epistatic functions in cell shape maintenance. TIRF microscopy revealed that FloT forms many dynamic membrane assemblies that frequently colocalize with the division septum. The deletion of dynA did not change the pattern of localization of FloT, and vice versa, showing that the two proteins play non redundant roles in a variety of cellular processes. Expression of dynamin or flotillin T in eukaryotic S2 cells revealed that both proteins assemble at the cell membrane. While FloT formed patch structures, DynA built up tubulated structures extending away from the cells. Conclusions: Bacillus subtilis dynamin ortholog DynA plays a role during cell division and in cell shape maintenance. It shows a genetic link with flotillin T, with both proteins playing non-redundant functions at the cell membrane, where they assemble even in the absence of any bacterial cofactor.

Description: Background: To derive post-genomic, neutral insight into the peptidoglycan (PG) distribution among organisms, we mined 1,644 genomes listed in the Carbohydrate-Active Enzymes database for the presence of a minimal 3-gene set that is necessary for PG metabolism. This gene set consists of one gene from the glycosyltransferase family GT28, one from family GT51 and at least one gene belonging to one of five glycoside hydrolase families (GH23, GH73, GH102, GH103 and GH104). Results: None of the 103 Viruses or 101 Archaea examined possessed the minimal 3-gene set, but this set was detected in 1/42 of the Eukarya members (Micromonas sp., coding for GT28, GT51 and GH103) and in 1,260/1,398 (90.1%) of Bacteria, with a 100% positive predictive value for the presence of PG. Pearson correlation test showed that GT51 family genes were significantly associated with PG with a value of 0.963 and a p value less than 10-3. This result was confirmed by a phylogenetic comparative analysis showing that the GT51-encoding gene was significantly associated with PG with a Pagel's score of 60 and 51 (percentage of error close to 0%). Phylogenetic analysis indicated that the GT51 gene history comprised eight loss and one gain events, and suggested a dynamic on-going process. Conclusions: Genome analysis is a neutral approach to explore prospectively the presence of PG in uncultured, sequenced organisms with high predictive values.

Description: Background: Toxin complex (Tc) family proteins were first identified as insecticidal toxins in Photorhabdus luminescens and have since been found in a wide range of bacteria. The genome of Yersinia pestis, the causative agent of bubonic plague, contains a locus that encodes the Tc protein homologues YitA, YitB, YitC, and YipA and YipB. Previous microarray data indicate that the Tc genes are highly upregulated by Y. pestis while in the flea vector; however, their role in the infection of fleas and pathogenesis in the mammalian host is unclear. Results: We show that the Tc proteins YitA and YipA are highly produced by Y. pestis while in the flea but not during growth in brain heart infusion (BHI) broth at the same temperature. Over-production of the LysR-type regulator YitR from an exogenous plasmid increased YitA and YipA synthesis in broth culture. The increase in production of YitA and YipA correlated with the yitR copy number and was temperature-dependent. Although highly synthesized in fleas, deletion of the Tc proteins did not alter survival of Y. pestis in the flea or prevent blockage of the proventriculus. Furthermore, YipA was found to undergo post-translational processing and YipA and YitA are localized to the outer membrane of Y. pestis. YitA was also detected by immunofluorescence microscopy on the surface of Y. pestis. Both YitA and YipA are produced maximally at low temperature but persist for several hours after transfer to 37[degree sign]C. Conclusions: Y. pestis Tc proteins are highly expressed in the flea but are not essential for Y. pestis to stably infect or produce a transmissible infection in the flea. However, YitA and YipA localize to the outer membrane and YitA is exposed on the surface, indicating that at least YitA is present on the surface when Y. pestis is transmitted into the mammalian host from the flea.

Description: Background: Fermentative bacteria offer the potential to convert lignocellulosic waste-streams into biofuels such as hydrogen (H2) and ethanol. Current fermentative H2 and ethanol yields, however, are below theoretical maxima, vary greatly among organisms, and depend on the extent of metabolic pathways utilized. For fermentative H2 and/or ethanol production to become practical, biofuel yields must be increased. We performed a comparative meta-analysis of (i) reported end-product yields, and (ii) genes encoding pyruvate metabolism and end-product synthesis pathways to identify suitable biomarkers for screening a microorganism's potential of H2 and/or ethanol production, and to identify targets for metabolic engineering to improve biofuel yields. Our interest in H2 and/or ethanol optimization restricted our meta-analysis to organisms with sequenced genomes and limited branched end-product pathways. These included members of the Firmicutes, Euryarchaeota, and Thermotogae. Results: Bioinformatic analysis revealed that the absence of genes encoding acetaldehyde dehydrogenase and bifunctional acetaldehyde/alcohol dehydrogenase (AdhE) in Caldicellulosiruptor, Thermococcus, Pyrococcus, and Thermotoga species coincide with high H2 yields and low ethanol production. Organisms containing genes (or activities) for both ethanol and H2 synthesis pathways (i.e. Caldanaerobacter subterraneus subsp. tengcongensis, Ethanoligenens harbinense, and Clostridium species) had relatively uniform mixed product patterns. The absence of hydrogenases in Geobacillus and Bacillus species did not confer high ethanol production, but rather high lactate production. Only Thermoanaerobacter pseudethanolicus produced relatively high ethanol and low H2 yields. This may be attributed to presence of genes encoding proteins that promote NADH production. Lactate dehydrogenase and pyruvate:formate lyase are not conducive for ethanol and/or H2 production. While the type(s) of encoded hydrogenases appear to have little impact on H2 production in organisms that do not encode ethanol producing pathways, they do influence reduced end-product yields in those that do. Conclusions: Here we show that composition of genes encoding pathways involved in pyruvate catabolism and end-product synthesis pathways can be used to approximate potential end-product distribution patterns. We have identified a number of genetic biomarkers for streamlining ethanol and H2 producing capabilities. By linking genome content, reaction thermodynamics, and end-product yields, we offer potential targets for optimization of either ethanol or H2 yields through metabolic engineering.

Description: Background: Endolysins produced by bacteriophages lyse bacteria, and are thus considered a novel type of antimicrobial agent. Several endolysins from Bacillus phages or prophages have previously been characterized and used to target Bacillus strains that cause disease in animals and humans. B. thuringiensis phage BtCS33 is a Siphoviridae family phage and its genome has been sequenced and analyzed. In the BtCS33 genome, orf18 was found to encode an endolysin protein (PlyBt33). Results: Bioinformatic analyses showed that endolysin PlyBt33 was composed of two functional domains, the N-terminal catalytic domain and the C-terminal cell wall binding domain. In this study, the entire endolysin PlyBt33, and both the N- and C-termini,were expressed in Escherichia coli and then purified. The lytic activities of PlyBt33 and its N-terminus were tested on bacteria. Both regions exhibited lytic activity, although PlyBt33 showed a higher lytic activity than the N-terminus. PlyBt33 exhibited activity against all Bacillus strains tested from five different species, but was not active against Gram-negative bacteria. Optimal conditions for PlyBt33 reactivity were pH 9.0 and 50[degree sign]C. PlyBt33 showed high thermostability, with 40% of initial activity remaining following 1 h of treatment at 60[degree sign]C. The C-terminus of PlyBt33 bound to B. thuringiensis strain HD-73 and Bacillus subtilis strain 168. This cell wall binding domain might be novel, as its amino acid sequence showed little similarity to previously reported endolysins. Conclusions: PlyBt33 showed potential as a novel antimicrobial agent at a relatively high temperature and had a broad lytic spectrum within the Bacillus genus. The C-terminus of PlyBt33 might be a novel kind of cell wall binding domain.

Description: Background: In plants, the multistep phosphorelay signaling pathway mediates responses to environmental factors and plant hormones. This system is composed of three successive partners: hybrid Histidine-aspartate Kinases (HKs), Histidine-containing Phosphotransfer proteins (HPts), and Response Regulators (RRs). Among the third partners, B-type RR family members are the final output elements of the pathway; they act as transcription factors and clearly play a pivotal role in the early response to cytokinin in Arabidopsis. While interactions studies between partners belonging to the multistep phosphorelay system are mainly focused on protagonists involved in cytokinin or ethylene pathways, very few reports are available concerning partners of osmotic stress signaling pathway. Results: In Populus, we identified eight B-type RR proteins, RR12-16, 19, 21 and 22 in the Dorskamp genotype. To assess HPt/B-type RR interactions and consequently determine potential third partners in the osmosensing multistep phosphorelay system, we performed global yeast two-hybrid (Y2H) assays in combination with Bimolecular Fluorescence Complementation (BiFC) assays in plant cells. We found that all B-type RRs are able to interact with HPt predominant partners (HPt2, 7 and 9) of HK1, which is putatively involved in the osmosensing pathway. However, different profiles of interaction are observed depending on the studied HPt. HPt/RR interactions displayed a nuclear localization, while the nuclear and cytosolic localization of HPt and nuclear localization of RR proteins were validated. Although the nuclear localization of HPt/RR interaction was expected, this work constitutes the first evidence of such an interaction in plants. Furthermore, the pertinence of this partnership is reinforced by highlighting a co-expression of B-type RR transcripts and the other partners (HK1 and HPts) belonging to a potential osmosensing pathway. Conclusion: Based on the interaction studies between identified B-type RR and HPt proteins, and the co-expression analysis of transcripts of these potential partners in poplar organs, our results favor the model that RR12, 13, 14, 16 and 19 are able to interact with the main partners of HK1, HPt2, 7 and 9, and this HPt/RR interaction occurs within the nucleus. On the whole, the five B-type RRs of interest could be third protagonists putatively involved in the osmosensing signaling pathway in Populus.

Description: Background: A measles outbreak was detected at Ndanga Hospital in Zaka district Masvingo Province on the 5th of May 2010 and there were five deaths. Source of infection was not known and an investigation was carried out to determine factors associated with contracting measles in Zaka district.Materials and methodsA 1:1 unmatched case control study was conducted. A case was a person residing in Zaka district who developed signs and symptoms of measles or tested IgM positive from 06 May 2010 to 30 August 2010. A control was a person residing in the same community who did not have history of signs and symptoms of measles during the same period. A structured interviewer administered questionnaire (translated into shona) was used to solicit information from cases and controls. Ethical consideration like written consent from all participants, respect and confidentiality were observed. Permission to carry out the study was obtained from the medical research Council of Zimbabwe and the provincial Medical Directors Masvingo. Epi info was used to calculate frequencies, odds ratios and perform logistic regression to control for confounding variables.FindingsA total of 110 cases and 110 controls were recruited. Most cases (63.03%) were from the apostolic sect while 44.7% of controls were from orthodox churches. Contact with a measles case [AOR= 41.14, 95% CI (7.47-226.5)],being unvaccinated against measles [AOR= 3.96, 95%CI (2.58-6.08)] and not receiving additional doses of measles vaccine [AOR 5.48, 95% CI (2.16-11.08)] were independent risk factor for contracting measles . Measles vaccination coverage for Zaka district was 75%. The median duration for seeking treatment after onset of illness was three days (Q1=2; Q3=7). There were no emergency preparedness plans in place. Conclusion: This outbreak occurred due to a large number of unvaccinated children and a boarding school that facilitated person to person transmission. We recommend mandatory vaccination for all children before enrolling into schools. As a result of the study one day training on outbreak management and surveillance was done with all District Nursing Officers and Environmental Health Officers in personnel in the province.