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Environmental changes associated with global warming create new opportunities for pathogen and parasite transmission in Arctic wildlife. As an apex predator ranging over large, remote areas, changes in pathogens and parasites in polar bears are a useful indicator of changing transmission dynamics in Arctic ecosystems. We examined prevalence and risk factors associated with exposure to parasites and viral and bacterial pathogens in Chukchi Sea polar bears. Serum antibodies to six pathogens were detected and prevalence increased between 1987–1994 and 2008–2017 for five: Toxoplasma gondii, Neospora caninum, Francisella tularensis, Brucella abortus/suis, and canine distemper virus. Although bears have increased summer land use, this behavior was not associated with increased exposure. Higher prevalence of F. tularensis, Coxiella burnetii, and B. abortus/suis antibodies in females compared to males, however, could be associated with terrestrial denning. Exposure was related to diet for several pathogens indicating increased exposure in the food web. Elevated white blood cell counts suggest a possible immune response to some pathogens. Given that polar bears face multiple stressors in association with climate change and are a subsistence food, further work is warranted to screen for signs of disease. [ABSTRACT FROM AUTHOR]

IntroductionThe demand for spinal fusion surgery has increased over the last decades. Health care providers should take costs and cost-effectiveness of these surgeries into account. Open transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF) are two widely used techniques for spinal fusion. Earlier research revealed that TLIF is associated with less blood loss, shorter surgical time and sometimes shorter length of hospital stay, while effectiveness of both techniques on back and/or leg pain are equal. Therefore, TLIF could result in lower costs and be more cost-effective than PLIF. This is the first systematic review comparing direct and indirect (partial) economic evaluations of TLIF with PLIF in adults with lumbar spondylolisthesis. Furthermore, methodological quality of included studies was assessed.MethodsSearches were conducted in eight databases for reporting on eligibility criteria; TLIF or PLIF, lumbar spondylolisthesis or lumbar instability, and cost. Costs were converted to United States Dollars with reference year 2020. Study quality was assessed using the bias assessment tool of the Cochrane Handbook for Systematic Reviews of Interventions, the Level of Evidence guidelines of the Oxford Centre for Evidence-based Medicine and the Consensus Health Economic Criteria (CHEC) list.ResultsOf a total of 693 studies, 16 studies were included. Comparison of TLIF and PLIF could only be made indirectly, since no study compared TLIF and PLIF directly. There was a large heterogeneity in health care and societal perspective costs due to different in-, and exclusion criteria, baseline characteristics and the use of costs or charges in calculations. Health care perspective costs, calculated with hospital costs, ranged from $15,867-$43,217 in TLIF-studies and $32,662 in one PLIF-study. Calculated with hospital charges, it ranged from $8,964-$51,469 in TLIF-studies and $21,838-$93,609 in two PLIF-studies. Societal perspective costs and cost-effectiveness, only mentioned in TLIF-studies, ranged from $5,702/QALY-$48,538/QALY and $50,092/QALY-$90,977/QALY, respectively. Overall quality of studies was low.ConclusionsThis systematic review shows that TLIF and PLIF are expensive techniques. Moreover, firm conclusions about the preferable technique, based on (partial) economic evaluations, cannot be drawn due to limited studies and heterogeneity. Randomized prospective trials and full economical evaluations with direct TLIF and PLIF comparison are needed to obtain high levels of evidence. Furthermore, development of guidelines to perform adequate economic evaluations, specified for the field of interest, will be useful to minimize heterogeneity and maximize transferability of results.Trial registrationProspero-database registration number: CRD42020196869.

BackgroundThe recently developed Social Exclusion Index for Health Surveys (SEI-HS) revealed particularly strong social exclusion in non-Western immigrant groups compared to the native Dutch population. To qualify such results, cross-cultural validation of the SEI-HS in non-Western immigrant groups is called for.MethodsA sequential explanatory mixed methods design was used, employing quantitative data from the Netherlands Public Health Monitor along with qualitative interviews. Data from 1,803 adults aged 19 years or older of Surinamese, 1,009 of Moroccan and 1,164 of Turkish background and 19,318 native Dutch living in the four largest cities in the Netherlands were used to test the factorial structure of the SEI-HS and differential item functioning across immigrant groups. Additionally, 52 respondents with a high score on the SEI-HS and from different background were interviewed on the item content of the SEI-HS and subjective feelings of exclusion. For each SEI-HS item the semantic, conceptual and contextual connotations were coded and compared between the immigrant groups and native Dutch.ResultsHigh levels of social exclusion were found in 20.0% of the urban population of Surinamese origin, 20.9% of Moroccan, 28.7% of Turkish and 4.2% of native Dutch origin. The 4-factor structure of the SEI-HS was confirmed in all three immigrant groups. None of the items demonstrated substantial differential item functioning in relation to immigration background. The interviews uncovered some methodological shortcomings, but these did not substantially impact the observed excess of social exclusion in immigrant groups.ConclusionsThe present study provides evidence in support of the validity of the SEI-HS in adults of Surinamese, Moroccan and Turkish background and confirms the major social exclusion of these immigrant groups in the main cities in the Netherlands. Policy measures to enhance social inclusion and reduce exclusion are urgently needed.

RNA interference (RNAi)-based technology shows great potential for use in agriculture, particularly for management of costly insect pests. In the decade since the insecticidal effects of environmentally-introduced RNA were first reported, this treatment has been applied to several types of insect pests. Through the course of those efforts, it has become apparent that different insects exhibit a range of sensitivity to environmentally-introduced RNAs. The variation in responses across insect is not well-understood, with differences in the underlying RNAi mechanisms being one explanation. This study evaluates eight proteins among three agricultural pests whose responses to environmental RNAi are known to differ: western corn rootworm (Diabrotica virgifera virgifera), fall armyworm (Spodoptera frugiperda), and southern green stink bug (Nezara viridula). These proteins have been identified in various organisms as centrally involved in facilitating the microRNA- and small interfering-RNA-mediated interference responses. Various bioinformatics tools, as well as gene expression profiling, were used to identify and evaluate putative homologues for characteristics that may contribute to the differing responses of these insects, such as the absence of critical functional domains within expressed sequences, the absence of entire gene sequences, or unusually low or undetectable expression of critical genes. Though many similarities were observed, the number of isoforms and expression levels of double-stranded RNA-binding and argonaute proteins varied across insect. Differences among key RNAi machinery genes of these three pests may impact the function of their RNAi pathways, and therefore, their respective responses to exogenous RNAs.

INTRODUCTION: Social exclusion is considered a major factor in the causation and maintenance of health inequalities, but its measurement in health research is still in its infancy. In the Netherlands the Institute for Social Research (SCP) developed an instrument to measure the multidimensional concept of social exclusion in social and economic policy research. Here, we present a method to construct a similar measure of social exclusion using available data from public health surveys. METHODS: Analyses were performed on data from the health questionnaires that were completed by 20,877 adults in the four largest cities in the Netherlands. From each of the four questionnaires we selected the items that corresponded to those of the SCP-instrument. These were entered into a nonlinear canonical correlation analysis. The measurement properties of the resulting indices and dimension scales were assessed and compared to the SCP-instrument. RESULTS: The internal consistency of the indices and most of the dimension scales were adequate and the internal structure of the indices was as expected. Both generalisabiliy and construct validity were good: in all datasets strong associations were found between the index and a number of known risk factors of social exclusion. A limitation of content validity was that the dimension "lack of normative integration" could not be measured, because no relevant items were available. CONCLUSIONS: Our findings indicate that a measure for social exclusion can be constructed with available health questionnaires. This provides opportunities for application in public health surveillance systems in the Netherlands and elsewhere in the world.

Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates.Tenofovir and adefovir only differ by an extra CH3-moiety in tenofovir, introducing a center of chirality at the carbon atom linking the purine group with the phosphates. (R)-Tenofovir (and not (S)-tenofovir) binds significantly better to HBV-RT than adefovir. "Single hit" mutations in HBV-RT associated with adefovir resistance may affect the affinity for tenofovir, but to a level that is insufficient for tenofovir resistance. The RT-Surface protein gene overlap in the HBV genome provides an additional genetic constraint that limits the mutational freedom required to generate drug-resistance. Different pockets near the nucleotide binding motif (YMDD) in HBV-RT can bind nucleotides and nucleotide analogues with different affinities and specificities.The difference in binding affinity of tenofovir (more than two orders of magnitude in terms of local concentration), a 30x higher dosage of the (R)-tenofovir enantiomer as compared to conformational isomeric or rotameric adefovir, and the constrained mutational space due to gene overlap in HBV may explain the absence of resistance mutations after 6 years of tenofovir monotherapy. In addition, the computational methodology applied here may guide the development of antiviral drugs with better resistance profiles.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that re-emerged in 2004 and has caused massive outbreaks in recent years. The lack of a licensed vaccine or treatment options emphasize the need to obtain more insight into the viral life cycle and CHIKV-host interactions. Infectious cDNA clones are important tools for such studies, and for mechanism of action studies on antiviral compounds. Existing CHIKV cDNA clones are based on a single genome from an individual clinical isolate, which is expected to have evolved specific characteristics in response to the host environment, and possibly also during subsequent cell culture passaging. To obtain a virus expected to have the general characteristics of the recent E1-226V CHIKV isolates, we have constructed a new CHIKV full-length cDNA clone, CHIKV LS3, based on the consensus sequence of their aligned genomes. Here we report the characterization of this synthetic virus and a green fluorescent protein-expressing variant (CHIKV LS3-GFP). Their characteristics were compared to those of natural strain ITA07-RA1, which was isolated during the 2007 outbreak in Italy. In cell culture the synthetic viruses displayed phenotypes comparable to the natural isolate, and in a mouse model they caused lethal infections that were indistinguishable from infections with a natural strain. Compared to ITA07-RA1 and clinical isolate NL10/152, the synthetic viruses displayed similar sensitivities to several antiviral compounds. 3-deaza-adenosine was identified as a new inhibitor of CHIKV replication. Cyclosporin A had no effect on CHIKV replication, suggesting that cyclophilins -opposite to what was found for other +RNA viruses- do not play an essential role in CHIKV replication. The characterization of the consensus sequence-based synthetic viruses and their comparison to natural isolates demonstrated that CHIKV LS3 and LS3-GFP are suitable and representative tools to study CHIKV-host interactions, screen for antiviral compounds and unravel their mode of action.

The hepatitis B virus (HBV) genome encodes the X protein (HBx), a ubiquitous transactivator that is required for HBV replication. Expression of the HBx protein has been associated with the development of HBV infection-related hepatocellular carcinoma (HCC). Previously, we generated a 3D structure of HBx by combined homology and ab initio in silico modelling. This structure showed a striking similarity to the human thymine DNA glycosylase (TDG), a key enzyme in the base excision repair (BER) pathway. To further explore this finding, we investigated whether both proteins interfere with or complement each other's functions. Here we show that TDG does not affect HBV replication, but that HBx strongly inhibits TDG-initiated base excision repair (BER), a major DNA repair pathway. Inhibition of the BER pathway may contribute substantially to the oncogenic effect of HBV infection.

Orthohepadnavirus (mammalian hosts) and avihepadnavirus (avian hosts) constitute the family of Hepadnaviridae and differ by their capability and inability for expression of protein X, respectively. Origin and functions of X are unclear. The evolutionary analysis at issue of X indicates that present strains of orthohepadnavirus started to diverge about 25,000 years ago, simultaneously with the onset of avihepadnavirus diversification. These evolutionary events were preceded by a much longer period during which orthohepadnavirus developed a functional protein X while avihepadnavirus evolved without X. An in silico generated 3D-model of orthohepadnaviral X protein displayed considerable similarity to the tertiary structure of DNA glycosylases (key enzymes of base excision DNA repair pathways). Similarity is confined to the central domain of MUG proteins with the typical DNA-binding facilities but without the capability of DNA glycosylase enzymatic activity. The hypothetical translation product of a vestigial X reading frame in the genome of duck hepadnavirus could also been folded into a DNA glycosylase-like 3D-structure. In conclusion, the most recent common ancestor of ortho- and avihepadnavirus carried an X sequence with orthology to the central domain of DNA glycosylase.

Honest advertisement models posit that only individuals in good health can produce and/or maintain ornamental traits. Even though disease has profound effects on condition, few studies have experimentally tested its effects on trait expression and even fewer have identified a mechanistic basis for these effects. Recent evidence suggests that black and white, but not grey, plumage colors of black-capped chickadees (Poecile atricapillus) are sexually selected. We therefore hypothesized that birds afflicted with avian keratin disorder, a condition that affects the beak and other keratinized tissues, would show reduced expression of black and white, but not grey, color. UV-vis spectrometry of black-capped chickadees affected and unaffected by avian keratin disorder revealed spectral differences between them consistent with this hypothesis. To elucidate the mechanistic bases of these differences, we used scanning electron microscopy (SEM), electron-dispersive x-ray spectroscopy (EDX) and a feather cleaning experiment. SEM showed extreme feather soiling in affected birds, and EDX revealed that this was most likely from external sources. Experimentally cleaning the feathers increased color expression of ornamental feathers of affected, but not unaffected, birds. These data provide strong evidence that black and white color is an honest indicator in chickadees, and that variation in feather dirtiness, likely due to differences in preening behavior is a mechanism for this association.

BACKGROUND: Probiotics can be used to stimulate or regulate epithelial and immune cells of the intestinal mucosa and generate beneficial mucosal immunomodulatory effects. Beneficial effects of specific strains of probiotics have been established in the treatment and prevention of various intestinal disorders, including allergic diseases and diarrhea. However, the precise molecular mechanisms and the strain-dependent factors involved are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we aimed to identify gene loci in the model probiotic organism Lactobacillus plantarum WCFS1 that modulate the immune response of host dendritic cells. The amounts of IL-10 and IL-12 secreted by dendritic cells (DCs) after stimulation with 42 individual L. plantarum strains were measured and correlated with the strain-specific genomic composition using comparative genome hybridisation and the Random Forest algorithm. This in silico "gene-trait matching" approach led to the identification of eight candidate genes in the L. plantarum genome that might modulate the DC cytokine response to L. plantarum. Six of these genes were involved in bacteriocin production or secretion, one encoded a bile salt hydrolase and one encoded a transcription regulator of which the exact function is unknown. Subsequently, gene deletions mutants were constructed in L. plantarum WCFS1 and compared to the wild-type strain in DC stimulation assays. All three bacteriocin mutants as well as the transcription regulator (lp_2991) had the predicted effect on cytokine production confirming their immunomodulatory effect on the DC response to L. plantarum. Transcriptome analysis and qPCR data showed that transcript level of gtcA3, which is predicted to be involved in glycosylation of cell wall teichoic acids, was substantially increased in the lp_2991 deletion mutant (44 and 29 fold respectively). CONCLUSION: Comparative genome hybridization led to the identification of gene loci in L. plantarum WCFS1 that modulate the immune response of DCs.

BACKGROUND: Genomic data release for the grapevine has increased exponentially in the last five years. The Vitis vinifera genome has been sequenced and Vitis EST, transcriptomic, proteomic, and metabolomic tools and data sets continue to be developed. The next critical challenge is to provide biological meaning to this tremendous amount of data by annotating genes and integrating them within their biological context. We have developed and validated a system of Grapevine Molecular Networks (VitisNet). METHODOLOGY/PRINCIPAL FINDINGS: The sequences from the Vitis vinifera (cv. Pinot Noir PN40024) genome sequencing project and ESTs from the Vitis genus have been paired and the 39,424 resulting unique sequences have been manually annotated. Among these, 13,145 genes have been assigned to 219 networks. The pathway sets include 88 "Metabolic", 15 "Genetic Information Processing", 12 "Environmental Information Processing", 3 "Cellular Processes", 21 "Transport", and 80 "Transcription Factors". The quantitative data is loaded onto molecular networks, allowing the simultaneous visualization of changes in the transcriptome, proteome, and metabolome for a given experiment. CONCLUSIONS/SIGNIFICANCE: VitisNet uses manually annotated networks in SBML or XML format, enabling the integration of large datasets, streamlining biological functional processing, and improving the understanding of dynamic processes in systems biology experiments. VitisNet is grounded in the Vitis vinifera genome (currently at 8x coverage) and can be readily updated with subsequent updates of the genome or biochemical discoveries. The molecular network files can be dynamically searched by pathway name or individual genes, proteins, or metabolites through the MetNet Pathway database and web-portal at http://metnet3.vrac.iastate.edu/. All VitisNet files including the manual annotation of the grape genome encompassing pathway names, individual genes, their genome identifier, and chromosome location can be accessed and downloaded from the VitisNet tab at http://vitis-dormancy.sdstate.org.