Four erroneous beliefs thwarting more trustworthy research.

A range of problems currently undermines public trust in biomedical research. We discuss four erroneous beliefs that may prevent the biomedical research community from recognizing the need to focus on deserving this trust, and thus which act as powerful barriers to necessary improvements in the research process

Geology of the Molina Member of the Wasatch Formation, Piceance Basin, Colorado

The Molina Member of the Wasatch Formation has been cored in order to assess the presence/absence and character of microbial communities in the deep subsurface. Geological study of the Molina Member was undertaken in support of the microbiological tasks of this project, for the purposes of characterizing the host strata and of assessing the potential for post-depositional introduction of microbes into the strata. The Molina Member comprises a sandy fluvial unit within a formation dominated by mudstones. Sandy to conglomeratic deposits of braided and meandering fluvial systems are present on the western and eastern margins of the basin respectively, although the physical and temporal equivalence of these systems cannot be proven. Distal braided facies of planar-horizontal bedded sandstones are recognized on the western margin of the basin. Natural fractures are present in all Molina sandstones, commonly as apparent shear pairs. Core from the 1-M-18 well contains natural fractures similar to those found in outcrops, and has sedimentological affinities to the meandering systems of the eastern margin of the basin. The hydrologic framework of the Molina, and thus any potential post-depositional introduction of microbes into the formation, should have been controlled by approximately east-west flow through the natural fracture system, the geometries and extent of the sandstones in which the fractures occur, and hydraulic gradient. Migration to the well site, from outcropping recharge areas at the edge of the basin, could have started as early as 40 million years ago if the cored strata are connected to the eastern sedimentary system

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer

The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies

Global human footprint on the linkage between biodiversity and ecosystem functioning in reef fishes

Copyright: © 2011 Mora et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Difficulties in scaling up theoretical and experimental results have raised controversy over the consequences of biodiversity loss for the functioning of natural ecosystems. Using a global survey of reef fish assemblages, we show that in contrast to previous theoretical and experimental studies, ecosystem functioning (as measured by standing biomass) scales in a non-saturating manner with biodiversity (as measured by species and functional richness) in this ecosystem. Our field study also shows a significant and negative interaction between human population density and biodiversity on ecosystem functioning (i.e., for the same human density there were larger reductions in standing biomass at more diverse reefs). Human effects were found to be related to fishing, coastal development, and land use stressors, and currently affect over 75% of the world's coral reefs. Our results indicate that the consequences of biodiversity loss in coral reefs have been considerably underestimated based on existing knowledge and that reef fish assemblages, particularly the most diverse, are greatly vulnerable to the expansion and intensity of anthropogenic stressors in coastal areas

Clostridium difficile infection.

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota

Public health genomics capacity assessment: readiness for large-scale pathogen genomic surveillance in Canada’s public health laboratories

Abstract Background Along with rapid diagnostic testing, contact tracing, and public health measures, an effective pandemic response incorporates genomics-based surveillance. Large-scale SARS-CoV-2 genome sequencing is a crucial component of the global response to COVID-19. Characterizing the state of genomics readiness among Canada’s public health laboratories was necessary to inform strategic planning and deployment of capacity-building resources in the early stages of the pandemic. Methods We used a qualitative study design and focus group discussions, encompassing both technical and leadership perspectives, to perform an in-depth evaluation of the state of pathogen genomics readiness in Canada. Results We found substantial diversity in the state of readiness for SARS-CoV-2 genomic surveillance across Canada. Despite this variability, we identified common barriers and needs in the areas of specimen access, data flow and sharing, computing infrastructure, and access to highly qualified bioinformatics personnel. Conclusions These findings enable the strategic prioritization and deployment of resources to increase Canada’s ability to perform effective public health genomic surveillance for COVID-19 and prepare for future emerging infectious diseases. They also provide a unique qualitative research model for use in capacity building

Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries

OBJECTIVES: The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. METHODS: Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. RESULTS: ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. CONCLUSIONS: There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made

Model-based probe set optimization for high-performance microarrays

A major challenge in microarray design is the selection of highly specific oligonucleotide probes for all targeted genes of interest, while maintaining thermodynamic uniformity at the hybridization temperature. We introduce a novel microarray design framework (Thermodynamic Model-based Oligo Design Optimizer, TherMODO) that for the first time incorporates a number of advanced modelling features: (i) A model of position-dependent labelling effects that is quantitatively derived from experiment. (ii) Multi-state thermodynamic hybridization models of probe binding behaviour, including potential cross-hybridization reactions. (iii) A fast calibrated sequence-similarity-based heuristic for cross-hybridization prediction supporting large-scale designs. (iv) A novel compound score formulation for the integrated assessment of multiple probe design objectives. In contrast to a greedy search for probes meeting parameter thresholds, this approach permits an optimization at the probe set level and facilitates the selection of highly specific probe candidates while maintaining probe set uniformity. (v) Lastly, a flexible target grouping structure allows easy adaptation of the pipeline to a variety of microarray application scenarios. The algorithm and features are discussed and demonstrated on actual design runs. Source code is available on request

Vesicoureteral Reflux and Other Urinary Tract Malformations in Mice Compound Heterozygous for Pax2 and Emx2

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2+/−;Emx2+/− mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2+/−;Emx2+/− embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans

An Assessment of Mobile Predator Populations along Shallow and Mesophotic Depth Gradients in the Hawaiian Archipelago.

Large-bodied coral reef roving predators (sharks, jacks, snappers) are largely considered to be depleted around human population centers. In the Hawaiian Archipelago, supporting evidence is primarily derived from underwater visual censuses in shallow waters (=30?m). However, while many roving predators are present or potentially more abundant in deeper strata (30-100?m+), distributional information remains sparse. To partially fill that knowledge gap, we conducted surveys in the remote Northwestern Hawaiian Islands (NWHI) and populated Main Hawaiian Islands (MHI) from 2012-2014 using baited remote underwater stereo-video. Surveys between 0-100?m found considerable roving predator community dissimilarities between regions, marked conspicuous changes in species abundances with increasing depth, and largely corroborated patterns documented during shallow water underwater visual censuses, with up to an order of magnitude more jacks and five times more sharks sampled in the NWHI compared to the MHI. Additionally, several species were significantly more abundant and larger in mesophotic versus shallow depths, which remains particularly suggestive of deep-water refugia effects in the MHI. Stereo-video extends the depth range of current roving predator surveys in a more robust manner than was previously available, and appears to be well-suited for large-scale roving predator work in the Hawaiian Archipelago