Illicit trade in marine fish catch and its effects on ecosystems and people worldwide.

Illegal, unreported, and unregulated fishing is widespread; it is therefore likely that illicit trade in marine fish catch is also common worldwide. We combine ecological-economic databases to estimate the magnitude of illicit trade in marine fish catch and its impacts on people. Globally, between 8 and 14 million metric tons of unreported catches are potentially traded illicitly yearly, suggesting gross revenues of US$9 to US$17 billion associated with these catches. Estimated loss in annual economic impact due to the diversion of fish from the legitimate trade system is US$26 to US$50 billion, while losses to countries' tax revenues are between US$2 and US$4 billion. Country-by-country estimates of these losses are provided in the Supplementary Materials. We find substantial likely economic effects of illicit trade in marine fish catch, suggesting that bold policies and actions by both public and private actors are needed to curb this illicit trade.

Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans.

Emerging knowledge suggests that post-traumatic stress disorder (PTSD) pathophysiology is linked to the patients' epigenetic changes, but comprehensive studies examining genome-wide methylation have not been performed. In this study, we examined genome-wide DNA methylation in peripheral whole blood in combat veterans with and without PTSD to ascertain differentially methylated probes. Discovery was initially made in a training sample comprising 48 male Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) veterans with PTSD and 51 age/ethnicity/gender-matched combat-exposed PTSD-negative controls. Agilent whole-genome array detected ~5600 differentially methylated CpG islands (CpGI) annotated to ~2800 differently methylated genes (DMGs). The majority (84.5%) of these CpGIs were hypermethylated in the PTSD cases. Functional analysis was performed using the DMGs encoding the promoter-bound CpGIs to identify networks related to PTSD. The identified networks were further validated by an independent test set comprising 31 PTSD+/29 PTSD- veterans. Targeted bisulfite sequencing was also used to confirm the methylation status of 20 DMGs shown to be highly perturbed in the training set. To improve the statistical power and mitigate the assay bias and batch effects, a union set combining both training and test set was assayed using a different platform from Illumina. The pathways curated from this analysis confirmed 65% of the pool of pathways mined from training and test sets. The results highlight the importance of assay methodology and use of independent samples for discovery and validation of differentially methylated genes mined from whole blood. Nonetheless, the current study demonstrates that several important epigenetically altered networks may distinguish combat-exposed veterans with and without PTSD.

An Entrustable Professional Activity (EPA)-Based Framework to Prepare Fourth-Year Medical Students for Internal Medicine Careers.

The purpose of the fourth year of medical school remains controversial. Competing demands during this transitional phase cause confusion for students and educators. In 2014, the Association of American Medical Colleges (AAMC) released 13 Core Entrustable Professional Activities for Entering Residency (CEPAERs). A committee comprising members of the Clerkship Directors in Internal Medicine and the Association of Program Directors in Internal Medicine applied these principles to preparing students for internal medicine residencies. The authors propose a curricular framework based on five CEPAERs that were felt to be most relevant to residency preparation, informed by prior stakeholder surveys. The critical areas outlined include entering orders, forming and answering clinical questions, conducting patient care handovers, collaborating interprofessionally, and recognizing patients requiring urgent care and initiating that care. For each CEPAER, the authors offer suggestions about instruction and assessment of competency. The fourth year of medical school can be rewarding for students, while adequately preparing them to begin residency, by addressing important elements defined in the core entrustable activities. Thus prepared, new residents can function safely and competently in supervised postgraduate settings.

Bridging Systems Medicine and Patient Needs.

While there is widespread consensus on the need both to change the prevailing research and development (R&D) paradigm and provide the community with an efficient way to personalize medicine, ecosystem stakeholders grapple with divergent conceptions about which quantitative approach should be preferred. The primary purpose of this position paper is to contrast these approaches. The second objective is to introduce a framework to bridge simulation outputs and patient outcomes, thus empowering the implementation of systems medicine.

Systems cancer medicine: towards realization of predictive, preventive, personalized and participatory (P4) medicine.

A grand challenge impeding optimal treatment outcomes for patients with cancer arises from the complex nature of the disease: the cellular heterogeneity, the myriad of dysfunctional molecular and genetic networks as results of genetic (somatic) and environmental perturbations. Systems biology, with its holistic approach to understanding fundamental principles in biology, and the empowering technologies in genomics, proteomics, single-cell analysis, microfluidics and computational strategies, enables a comprehensive approach to medicine, which strives to unveil the pathogenic mechanisms of diseases, identify disease biomarkers and begin thinking about new strategies for drug target discovery. The integration of multidimensional high-throughput 'omics' measurements from tumour tissues and corresponding blood specimens, together with new systems strategies for diagnostics, enables the identification of cancer biomarkers that will enable presymptomatic diagnosis, stratification of disease, assessment of disease progression, evaluation of patient response to therapy and the identification of reoccurrences. Whilst some aspects of systems medicine are being adopted in clinical oncology practice through companion molecular diagnostics for personalized therapy, the mounting influx of global quantitative data from both wellness and diseases is shaping up a transformational paradigm in medicine we termed 'predictive', 'preventive', 'personalized', and 'participatory' (P4) medicine, which requires new strategies, both scientific and organizational, to enable bringing this revolution in medicine to patients and to the healthcare system. P4 medicine will have a profound impact on society - transforming the healthcare system, turning around the ever escalating costs of healthcare, digitizing the practice of medicine and creating enormous economic opportunities for those organizations and nations that embrace this revolution.

Dietary antioxidant intake is associated with the prevalence but not incidence of age-related hearing loss.

OBJECTIVES: Diet is one of the few modifiable risk factors for age-related hearing loss. We aimed to examine the link between dietary and supplement intakes of antioxidants, and both the prevalence and 5-year incidence of measured hearing loss. DESIGN: Cross-sectional and 5-year longitudinal analyses. SETTING: Blue Mountains, Sydney, Australia. PARTICIPANTS: 2,956 Blue Mountains Hearing Study participants aged 50+ at baseline, examined during 1997-9 to 2002-4. MEASUREMENTS: Age-related hearing loss was measured and defined as the pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz >25 dB HL. Dietary data were collected in a semi-quantitative food frequency questionnaire, and intakes of α-carotene; ß-carotene; ß-cryptoxanthin; lutein and zeaxanthin; lycopene; vitamins A, C and E; iron and zinc were calculated. RESULTS: After adjusting for age, sex, smoking, education, occupational noise exposure, family history of hearing loss, history of diagnosed diabetes and stroke, each standard deviation (SD) increase in dietary vitamin E intake was associated with a 14% reduced likelihood of prevalent hearing loss, odds ratio, OR, 0.86 (95% confidence interval, CI, 0.78-0.98). Those in the highest quintile of dietary vitamin A intake had a 47% reduced risk of having moderate or greater hearing loss (>40 dB HL) compared to those in the lowest quintile of intake, multivariable-adjusted OR 0.53 (CI 0.30-0.92), P for trend = 0.04. However, dietary antioxidant intake was not associated with the 5-year incidence of hearing loss. CONCLUSIONS: Dietary vitamin A and vitamin E intake were significantly associated with the prevalence of hearing loss. However, dietary antioxidant intake did not increase the risk of incident hearing loss. Further large, prospective studies are warranted to assess these relationships in older adults.

Towards predictive stochastic dynamical modeling of cancer genesis and progression.

Based on an innovative endogenous network hypothesis on cancer genesis and progression we have been working towards a quantitative cancer theory along the systems biology perspective. Here we give a brief report on our progress and illustrate that combing ideas from evolutionary and molecular biology, mathematics, engineering, and physics, such quantitative approach is feasible.

Meta-analysis of gene expression in human pancreatic islets after in vitro expansion.

Pancreatic islet transplantation as a potential cure for type 1 diabetes (T1D) cannot be scaled up due to a scarcity of human pancreas donors. In vitro expansion of beta-cells from mature human pancreatic islets provides an alternative source of insulin-producing cells. The exact nature of the expanded cells produced by diverse expansion protocols and their potential for differentiation into functional beta-cells remain elusive. We performed a large-scale meta-analysis of gene expression in human pancreatic islet cells, which were processed using three different previously described protocols for expansion and for which redifferentiation was attempted. All three expansion protocols induced dramatic changes in the expression profiles of pancreatic islets; many of these changes are shared among the three protocols. Attempts at redifferentiation of expanded cells induce a limited number of gene expression changes. Nevertheless, these fail to restore a pancreatic islet-like gene expression pattern. Comparison with a collection of public microarray datasets confirmed that expanded cells are highly comparable to mesenchymal stem cells. Genes induced in expanded cells are also enriched for targets of transcription factors important for pluripotency induction. The present data increase our understanding of the active pathways in expanded and redifferentiated islets. Knowledge of the mesenchymal stem cell potential may help development of drug therapeutics to restore beta-cell mass in T1D patients.

DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis.

Epigenetic inactivation of tumor suppressor genes is a common feature in human cancer. Promoter hypermethylation and histone deacetylation are reversible epigenetic mechanisms associated with transcriptional regulation. DNA methyltransferases (DNMT1 and DNMT3b) regulate and maintain promoter methylation and are overexpressed in human cancer. We performed whole-genome microarray analysis to identify genes with altered expression after RNAi-induced suppression of DNMT in a glioblastoma multiforme (GBM) cell line. We then identified genes with both decreased expression and evidence of promoter CpG island hypermethylation in GBM tissue samples using a combined whole-genome microarray transcriptome analysis in conjunction with a promoter array analysis after DNA immunoprecipitation with anti-5-methylcytidine. DNMT1 and 3b knockdown resulted in the restored expression of 308 genes that also contained promoter region hypermethylation. Of these, 43 were also found to be downregulated in GBM tissue samples. Three downregulated genes with hypermethylated promoters and restored expression in response to acute DNMT suppression were assayed for methylation changes using bisulfite sequence analysis of the promoter region after chronic DNMT suppression. Restoration of gene expression was not associated with changes in promoter region methylation, but rather with changes in histone methylation and chromatin conformation. Two of the identified genes exhibited growth suppressive activity in in vitro assays. Combining targeted genetic manipulations with comprehensive genomic and expression analyses provides a potentially powerful new approach for identifying epigenetically regulated genes in GBM.

Learning to care for spiritual needs: connecting spiritually.

Despite mandates to provide spiritual care, confusion persists among nurses about spirituality, spiritual needs, and related roles. To discover how practicing nurses acquire knowledge for spiritual care, the authors chose a grounded theory design. They constantly compared and analyzed verbatim transcribed interview data to find the core variable, categories, and properties. Connection, manifesting as a state, act, or process, appeared throughout the data. Categories emerged as Needing Connection, Nurturing Connection, Learning Connection, and Living Connection. Nurses used a cyclical, intertwined, and progressive learning process of opening to, struggling with, and making connections between numerous discrete personal and professional experiences. Shifting attention between these interconnected experiences fueled knowledge acquisition. Whether referring to how nurses learn, what they do, or with whom, the theory Connecting Spiritually joined categories into a cumulative experiential learning process that explained how nurses learn to care for spiritual needs.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

Robustness, stability and efficiency of phage lambda genetic switch: dynamical structure analysis.

Based on the dynamical structure theory for complex networks recently developed by one of us and on the physical-chemical models for gene regulation, developed by Shea and Ackers in the 1980's, we formulate a direct and concise mathematical framework for the genetic switch controlling phage lambda life cycles, which naturally includes the stochastic effect. The dynamical structure theory states that the dynamics of a complex network is determined by its four elementary components: The dissipation (analogous to degradation), the stochastic force, the driving force determined by a potential, and the transverse force. The potential may be interpreted as a landscape for the phage development in terms of attractive basins, saddle points, peaks and valleys. The dissipation gives rise to the adaptivity of the phage in the landscape defined by the potential: The phage always has the tendency to approach the bottom of the nearby attractive basin. The transverse force tends to keep the network on the equal-potential contour of the landscape. The stochastic fluctuation gives the phage the ability to search around the potential landscape by passing through saddle points. With molecular parameters in our model fixed primarily by the experimental data on wild-type phage and supplemented by data on one mutant, our calculated results on mutants agree quantitatively with the available experimental observations on other mutants for protein number, lysogenization frequency, and a lysis frequency in lysogen culture. The calculation reproduces the observed robustness of the phage lambda genetic switch. This is the first mathematical description that successfully represents such a wide variety of major experimental phenomena. Specifically, we find: (1) The explanation for both the stability and the efficiency of phage lambda genetic switch is the exponential dependence of saddle point crossing rate on potential barrier height, a result of the stochastic motion in a landscape; and (2) The positive feedback of cI repressor gene transcription, enhanced by the CI dimer cooperative binding, is the key to the robustness of the phage lambda genetic switch against mutations and fluctuations in kinetic parameter values.

Lung function, asthma symptoms, and quality of life for children in public housing in Boston: a case-series analysis.

BACKGROUND: Children in urban public housing are at high risk for asthma, given elevated environmental and social exposures and suboptimal medical care. For a multifactorial disease like asthma, design of intervention studies can be influenced by the relative prevalence of key risk factors. To better understand risk factors for asthma morbidity in the context of an environmental intervention study, we conducted a detailed baseline evaluation of 78 children (aged 4-17 years) from three public housing developments in Boston. METHODS: Asthmatic children and their caregivers were recruited between April 2002 and January 2003. We conducted intake interviews that captured a detailed family and medical history, including questions regarding asthma symptom severity, access to health care, medication usage, and psychological stress. Quality of life was evaluated for both the child and caregiver with an asthma-specific scale. Pulmonary function was measured with a portable spirometer, and allergy testing for common indoor and outdoor allergens was conducted with skin testing using the prick puncture method. Exploratory linear and logistic regression models evaluating predictors of respiratory symptoms, quality of life, and pulmonary function were conducted using SAS. RESULTS: We found high rates of obesity (56%) and allergies to indoor contaminants such as cockroaches (59%) and dust mites (59%). Only 36% of children with persistent asthma reported being prescribed any daily controller medication, and most did not have an asthma action plan or a peak flow meter. One-time lung function measures were poorly correlated with respiratory symptoms or quality of life, which were significantly correlated with each other. In multivariate regression models, household size, body mass index, and environmental tobacco smoke exposure were positively associated with respiratory symptom severity (p < 0.10). Symptom severity was negatively associated with asthma-related quality of life for the child and the caregiver, with caregiver (but not child) quality of life significantly influenced by caregiver stress and whether the child was in the intensive care unit at birth. CONCLUSION: Given the elevated prevalence of multiple risk factors, coordinated improvements in the social environment, the built environment, and in medical management would likely yield the greatest health benefits in this high-risk population.

Calculating biological behaviors of epigenetic states in the phage lambda life cycle.

The biology and behavior of bacteriophage lambda regulation have been the focus of classical investigations of molecular control of gene expression. Both qualitative and quantitative aspects of this behavior have been systematically characterized experimentally. Complete understanding of the robustness and stability of the genetic circuitry for the lysis-lysogeny switch remains an unsolved puzzle. It is an excellent test case for our understanding of biological behavior of an integrated network based on its physical, chemical, DNA, protein, and functional properties. We have used a new approach to non-linear dynamics to formulate a new mathematical model, performed a theoretical study on the phage lambda life cycle, and solved the crucial part of this puzzle. We find a good quantitative agreement between the theoretical calculation and published experimental observations in the protein number levels, the lysis frequency in the lysogen culture, and the lysogenization frequency for mutants of O(R). We also predict the desired robustness for the lambda genetic switch. We believe that this is the first successful example in the quantitative calculation of robustness and stability of the phage lambda regulatory network, one of the simplest and most well-studied regulatory systems.

Doppel-induced cerebellar degeneration in transgenic mice.

Doppel (Dpl) is a paralog of the mammalian prion protein (PrP); it is abundant in testes but expressed at low levels in the adult central nervous system. In two Prnp-deficient (Prnp(0/0)) mouse lines (Ngsk and Rcm0), Dpl overexpression correlated with ataxia and death of cerebellar neurons. To determine whether Dpl overexpression, rather than the dysregulation of genes neighboring the Prn gene complex, was responsible for the ataxic syndrome, we placed the mouse Dpl coding sequence under the control of the Prnp promoter and produced transgenic (Tg) mice on the Prnp(0/0)-ZrchI background (hereafter referred to as ZrchI). ZrchI mice exhibit neither Dpl overexpression nor cerebellar degeneration. In contrast, Tg(Dpl)ZrchI mice showed cerebellar granule and Purkinje cell loss; the age of onset of ataxia was inversely proportional to the levels of Dpl protein. Crosses of Tg mice overexpressing wild-type PrP with two lines of Tg(Dpl)ZrchI mice resulted in a phenotypic rescue of the ataxic syndrome, while Dpl overexpression was unchanged. Restoration of PrP expression also rendered the Tg(Dpl) mice susceptible to prion infection, with incubation times indistinguishable from non-Tg controls. Whereas the rescue of Dpl-induced neurotoxicity by coexpression of PrP argues for an interaction between the PrP and Dpl proteins in vivo, the unaltered incubation times in Tg mice overexpressing Dpl in the central nervous system suggest that Dpl is unlikely to be involved in prion formation.

A new approach to decoding life: systems biology.

Systems biology studies biological systems by systematically perturbing them (biologically, genetically, or chemically); monitoring the gene, protein, and informational pathway responses; integrating these data; and ultimately, formulating mathematical models that describe the structure of the system and its response to individual perturbations. The emergence of systems biology is described, as are several examples of specific systems approaches.

Understanding the adaptation of Halobacterium species NRC-1 to its extreme environment through computational analysis of its genome sequence.

The genome of the halophilic archaeon Halobacterium sp. NRC-1 and predicted proteome have been analyzed by computational methods and reveal characteristics relevant to life in an extreme environment distinguished by hypersalinity and high solar radiation: (1) The proteome is highly acidic, with a median pI of 4.9 and mostly lacking basic proteins. This characteristic correlates with high surface negative charge, determined through homology modeling, as the major adaptive mechanism of halophilic proteins to function in nearly saturating salinity. (2) Codon usage displays the expected GC bias in the wobble position and is consistent with a highly acidic proteome. (3) Distinct genomic domains of NRC-1 with bacterial character are apparent by whole proteome BLAST analysis, including two gene clusters coding for a bacterial-type aerobic respiratory chain. This result indicates that the capacity of halophiles for aerobic respiration may have been acquired through lateral gene transfer. (4) Two regions of the large chromosome were found with relatively lower GC composition and overrepresentation of IS elements, similar to the minichromosomes. These IS-element-rich regions of the genome may serve to exchange DNA between the three replicons and promote genome evolution. (5) GC-skew analysis showed evidence for the existence of two replication origins in the large chromosome. This finding and the occurrence of multiple chromosomes indicate a dynamic genome organization with eukaryotic character.

Substitution model of sequence evolution for the human immunodeficiency virus type 1 subtype B gp120 gene over the C2-V5 region.

Phylogenetic analyses frequently rely on models of sequence evolution that detail nucleotide substitution rates, nucleotide frequencies, and site-to-site rate heterogeneity. These models can influence hypothesis testing and can affect the accuracy of phylogenetic inferences. Maximum likelihood methods of simultaneously constructing phylogenetic tree topologies and estimating model parameters are computationally intensive, and are not feasible for sample sizes of 25 or greater using personal computers. Techniques that initially construct a tree topology and then use this non-maximized topology to estimate ML substitution rates, however, can quickly arrive at a model of sequence evolution. The accuracy of this two-step estimation technique was tested using simulated data sets with known model parameters. The results showed that for a star-like topology, as is often seen in human immunodeficiency virus type 1 (HIV-1) subtype B sequences, a random starting topology could produce nucleotide substitution rates that were not statistically different than the true rates. Samples were isolated from 100 HIV-1 subtype B infected individuals from the United States and a 620 nt region of the env gene was sequenced for each sample. The sequence data were used to obtain a substitution model of sequence evolution specific for HIV-1 subtype B env by estimating nucleotide substitution rates and the site-to-site heterogeneity in 100 individuals from the United States. The method of estimating the model should provide users of large data sets with a way to quickly compute a model of sequence evolution, while the nucleotide substitution model we identified should prove useful in the phylogenetic analysis of HIV-1 subtype B env sequences.