Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.

Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.

Friends or Foes? Emerging Impacts of Biological Toxins.

Toxins are substances produced from biological sources (e.g., animal, plants, microorganisms) that have deleterious effects on a living organism. Despite the obvious health concerns of being exposed to toxins, they are having substantial positive impacts in a number of industrial sectors. Several toxin-derived products are approved for clinical, veterinary, or agrochemical uses. This review sets out the case for toxins as 'friends' that are providing the basis of novel medicines, insecticides, and even nucleic acid sequencing technologies. We also discuss emerging toxins ('foes') that are becoming increasingly prevalent in a range of contexts through climate change and the globalisation of food supply chains and that ultimately pose a risk to health.

Spatial variation in microbial communities associated with sea-ice algae in Commonwealth Bay, East Antarctica.

Antarctic sea-ice forms a complex and dynamic system that drives many ecological processes in the Southern Ocean. Sea-ice microalgae and their associated microbial communities are understood to influence nutrient flow and allocation in marine polar environments. Sea-ice microalgae and their microbiota can have high seasonal and regional (>1000 km2) compositional and abundance variation, driven by factors modulating their growth, symbiotic interactions and function. In contrast, our knowledge of small-scale variation in these communities is limited. Understanding variation across multiple scales and its potential drivers is critical for informing on how multiple stressors impact sea-ice communities and the functions they provide. Here, we characterized bacterial communities associated with sea-ice microalgae and the potential drivers that influence their variation across a range of spatial scales (metres to >10 kms) in a previously understudied area in Commonwealth Bay, East Antarctica where anomalous events have substantially and rapidly expanded local sea-ice coverage. We found a higher abundance and different composition of bacterial communities living in sea-ice microalgae closer to the shore compared to those further from the coast. Variation in community structure increased linearly with distance between samples. Ice thickness and depth to the seabed were found to be poor predictors of these communities. Further research on the small-scale environmental drivers influencing these communities is needed to fully understand how large-scale regional events can affect local function and ecosystem processes.

ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance.

PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research. METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations. RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified. CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.

Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

OBJECTIVES: Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom. DESIGN AND PATIENTS: Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated. MEASUREMENTS: Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed. RESULTS: Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results. CONCLUSIONS: Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

Desalination Discharge Influences the Composition of Reef Invertebrate and Fish Assemblages.

Large-scale desalination is used increasingly to address growing freshwater demands and climate uncertainty. Discharge of hypersaline brine from desalination operations has the potential to impact marine ecosystems. Here, we used a 7-year Multiple-Before-After-Control-Impact experiment to test the hypothesis that hypersaline discharge from reverse osmosis desalination alters temperate reef communities. Using replicated, video-based, timed searches at eight sites, we sampled fish and invertebrate assemblages before, during, and after the discharge of hypersaline brine. We found that the composition of fish assemblages was significantly altered out to 55 m while the composition of invertebrate assemblages was altered out to 125 m from the outlet during hypersaline discharge. Fish richness and functional diversity increased around the outlet, while the invertebrate assemblages were no less diverse than those on reference reefs. Differences in faunal assemblages between outlet and reference sites during discharging included changes in the frequency of occurrence of both common and rare reef biota. Overall, we found the influence of hypersaline discharge on temperate reef biota to be spatially localized, with the reefs around the outlet continuing to support rich and diverse faunal communities. In some cases, therefore, the marine environmental consequences of large-scale, well-designed, desalination operations may be appropriately balanced against the positive benefits of improved water security.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Evaluating the social and ecological effectiveness of partially protected marine areas.

Marine protected areas (MPAs) are a primary tool for the stewardship, conservation, and restoration of marine ecosystems, yet 69% of global MPAs are only partially protected (i.e., are open to some form of fishing). Although fully protected areas have well-documented outcomes, including increased fish diversity and biomass, the effectiveness of partially protected areas is contested. Partially protected areas may provide benefits in some contexts and may be warranted for social reasons, yet social outcomes often depend on MPAs achieving their ecological goals to distinguish them from open areas and justify the cost of protection. We assessed the social perceptions and ecological effectiveness of 18 partially protected areas and 19 fully protected areas compared with 19 open areas along 7000 km of coast of southern Australia. We used mixed methods, gathering data via semistructured interviews, site surveys, and Reef Life (underwater visual census) surveys. We analyzed qualitative data in accordance with grounded theory and quantitative data with multivariate and univariate linear mixed-effects models. We found no social or ecological benefits for partially protected areas relative to open areas in our study. Partially protected areas had no more fish, invertebrates, or algae than open areas; were poorly understood by coastal users; were not more attractive than open areas; and were not perceived to have better marine life than open areas. These findings provide an important counterpoint to some large-scale meta-analyses that conclude partially protected areas can be ecologically effective but that draw this conclusion based on narrower measures. We argue that partially protected areas act as red herrings in marine conservation because they create an illusion of protection and consume scarce conservation resources yet provide little or no social or ecological gain over open areas. Fully protected areas, by contrast, have more fish species and biomass and are well understood, supported, and valued by the public. They are perceived to have better marine life and be improving over time in keeping with actual ecological results. Conservation outcomes can be improved by upgrading partially protected areas to higher levels of protection including conversion to fully protected areas.

Análisis de la Efectividad Social y Ecológica de las Áreas Marinas Parcialmente Protegidas Resumen Las áreas marinas protegidas (AMPs) son una herramienta importante para la administración, conservación y restauración de los ecosistemas marinos; sin embargo, el 69% de las AMPs mundiales solamente están parcialmente protegidas (es decir, están abiertas a alguna forma de pesca). Aunque las áreas completamente protegidas tienen resultados bien documentados, incluyendo el incremento en la diversidad de peces y la biomasa, la efectividad de las áreas parcialmente protegidas está en disputa. Puede que las áreas parcialmente protegidas se justifiquen por razones sociales, aunque los resultados sociales con frecuencia dependen de que las AMPs alcancen sus metas ecológicas para distinguirlas de las áreas abiertas y justificar el costo de la protección. Analizamos las percepciones sociales y la efectividad ecológica de 18 áreas parcialmente protegidas y 19 áreas completamente protegidas a lo largo de 7000 km de costa en el sur de Australia. Usamos métodos mixtos, recopilando información por medio de entrevistas semiestructuradas, encuestas en sitio y censos Reef Life (censos visuales submarinos). Analizamos los datos cualitativos de acuerdo con la teoría fundamentada y los datos cuantitativos con modelos lineales de efectos mixtos multivariados y univariados. No encontramos beneficios sociales o ecológicos para las áreas parcialmente protegidas en relación con las áreas abiertas en nuestro estudio. Las áreas parcialmente protegidas no tuvieron más peces, invertebrados o algas que las áreas abiertas; los usuarios de la costa tenían poco entendimiento de ellas; no eran más atractivas que las áreas abiertas; y no eran percibidas como albergues de mejor vida marina que las áreas abiertas. Estos hallazgos proporcionan un contrapunto importante a algunos metaanálisis a gran escala que concluyen que las áreas parcialmente protegidas pueden ser ecológicamente efectivas, pero llegan a esta conclusión con base en medidas más reducidas. Discutimos que las áreas parcialmente protegidas funcionan como pistas falsas para la conservación marina pues crean una ilusión de estar protegidas y consumen pocos recursos para la conservación, pero proporcionan poca o ninguna ganancia ecológica o social en comparación con las áreas abiertas. Las áreas completamente protegidas, al contrario, tienen más especies de peces y biomasa y están bien comprendidas, respaldadas y valoradas por el público. Este tipo de AMPs son percibidas como albergues de mejor vida marina y como en constante mejora con el tiempo al mantenerse en regla con los resultados ecológicos actuales. Los resultados de la conservación pueden mejorarse si se eleva a las áreas parcialmente protegidas a niveles más altos de protección incluyendo la conversión a áreas completamente protegidas.

MethylCal: Bayesian calibration of methylation levels.

Bisulfite amplicon sequencing has become the primary choice for single-base methylation quantification of multiple targets in parallel. The main limitation of this technology is a preferential amplification of an allele and strand in the PCR due to methylation state. This effect, known as 'PCR bias', causes inaccurate estimation of the methylation levels and calibration methods based on standard controls have been proposed to correct for it. Here, we present a Bayesian calibration tool, MethylCal, which can analyse jointly all CpGs within a CpG island (CGI) or a Differentially Methylated Region (DMR), avoiding 'one-at-a-time' CpG calibration. This enables more precise modeling of the methylation levels observed in the standard controls. It also provides accurate predictions of the methylation levels not considered in the controlled experiment, a feature that is paramount in the derivation of the corrected methylation degree. We tested the proposed method on eight independent assays (two CpG islands and six imprinting DMRs) and demonstrated its benefits, including the ability to detect outliers. We also evaluated MethylCal's calibration in two practical cases, a clinical diagnostic test on 18 patients potentially affected by Beckwith-Wiedemann syndrome, and 17 individuals with celiac disease. The calibration of the methylation levels obtained by MethylCal allows a clearer identification of patients undergoing loss or gain of methylation in borderline cases and could influence further clinical or treatment decisions.

Effect of Desalination Discharge on the Abundance and Diversity of Reef Fishes.

Global growth in desalination industries has increased the need for an evidence-based understanding of associated environmental impacts. We completed a seven-year assessment of the responses of fish assemblages to hypersaline discharge from the large Sydney Desalination Plant. At 12 times before, eight times during, and four times following the cessation of discharging hypersaline brine, we sampled reef fishes at two outlet sites and two close reference sites, as well as four reference sites that were located from 2-8 km from the outlet. At each site and each time of sampling, five 50 m video transects were used to sample reef fish assemblages. Following the commencement of discharging, there was a 279% increase in the abundance of fish around the outlet, which included substantially greater abundances of pelagic and demersal fish, as well as fishes targeted by recreational and commercial fishers. Following the cessation of discharge, abundances of fishes mostly returned to levels such that there was no longer a significant effect compared to the period prior to the commencement of the desalination plant's operations. Overall, our results demonstrate that well-designed marine infrastructure and processes used to support the growing demand for potable water can also enhance local fish abundances and species richness.

Variation in cownose ray Rhinoptera neglecta abundance and group size on the central east coast of Australia.

Here, we provide baseline information about the relative abundance and group size of the Australian cownose ray Rhinoptera neglecta on the central east coast of Australia. Using drone monitoring over 2 years, we completed 293 transects, each 2 km in length, at four locations distributed along c.100 km of coast. In total, 5979 R. neglecta were observed with overall relative abundance (±SE) of, 20.4 (±3.3) individuals per transect. The numbers of R. neglecta varied among locations, with the highest density found off the beach adjacent to the river mouth at Evans Head. The number of rays observed also decreased with increasing wind speed. While some of this relationship was probably associated with visibility, R. neglecta may also move offshore during strong winds. We found no evidence that R. neglecta was under significant threat. Additionally, our cost-effective surveys demonstrate the utility of aerial drones in fisheries conservation biology.

Habitat complexity effects on diversity and abundance differ with latitude: an experimental study over 20 degrees.

Habitat complexity is accepted as a general mechanism for increasing the abundance and diversity of communities. However, the circumstances under which complexity has the strongest effects are not clear. Over 20 degrees of Australia's east coast, we tested whether the effects of within-site structural habitat complexity on the diversity and community structure of sessile marine invertebrates was consistent over a latitudinal gradient where environmental conditions and species composition vary. We used experimental arrays with varied structural treatments to detect whether community cover, species richness, diversity and community composition (ß-diversity) changed with increasing complexity. Community response to complexity varied over latitude due to differences in species richness and community development. Increased complexity had the greatest positive effects on community cover and species richness at higher latitudes where recruitment and growth were low. At lower latitudes, community cover and species richness were higher overall and did not vary substantially between complexity treatments. Latitudinal variation in within-treatment ß-diversity relative to complexity further suggest divergent community responses. At higher latitudes, increased similarity in more complex treatments suggests community dominance of successful taxonomic groups. Despite limited effects on species richness and community cover at lower latitudes, ß-diversity was higher in more complex treatments, signifying potential positive effects of increased complexity at these sites. These results demonstrate the context-dependency of complexity effects in response to variation in species richness and community development and should be taken into consideration to help direct conservation and restoration efforts.

Latitudinal variation in the competition-colonisation trade-off reveals rate-mediated mechanisms of coexistence.

Theories of species coexistence often describe a trade-off between colonising and competitive abilities. In sessile marine invertebrates, this trade-off can manifest as trends in species distributions relative to the size of isolated patches of substrate. Based on their abilities to find available substrate and competitively exclude neighbours, good colonisers tend to dominate smaller patches, whereas better competitors tend to monopolise larger patches. In theory, species with equivalent colonising and competitive abilities should display similar distributions across patch sizes. We used patch size to observe this manifestation of the competition-colonisation trade-off over 20° of latitude. The trade-off was more readily observed at lower latitudes and was proportional to the 'ecological age' of communities (i.e. the degree of resource acquisition and likelihood of species interactions). Results suggest that ecological age may mediate the prominence of stochastic or deterministic coexistence mechanisms and will depend on the rate of ecological processes.

Corrigendum: Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs.

[This corrects the article DOI: 10.1093/biosci/biw180.].

Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs.

Reporting progress against targets for international biodiversity agreements is hindered by a shortage of suitable biodiversity data. We describe a cost-effective system involving Reef Life Survey citizen scientists in the systematic collection of quantitative data covering multiple phyla that can underpin numerous marine biodiversity indicators at high spatial and temporal resolution. We then summarize the findings of a continental- and decadal-scale State of the Environment assessment for rocky and coral reefs based on indicators of ecosystem state relating to fishing, ocean warming, and invasive species and describing the distribution of threatened species. Fishing impacts are widespread, whereas substantial warming-related change affected some regions between 2005 and 2015. Invasive species are concentrated near harbors in southeastern Australia, and the threatened-species index is highest for the Great Australian Bight and Tasman Sea. Our approach can be applied globally to improve reporting against biodiversity targets and enhance public and policymakers' understanding of marine biodiversity trends.

Using multispectral imaging flow cytometry to assess an in vitro intracellular Burkholderia thailandensis infection model.

The use of in vitro models to understand the interaction of bacteria with host cells is well established. In vitro bacterial infection models are often used to quantify intracellular bacterial load by lysing cell populations and subsequently enumerating the bacteria. Modern established techniques employ the use of fluorescence technologies such as flow cytometry, fluorescent microscopy, and/or confocal microscopy. However, these techniques often lack either the quantification of large data sets (microscopy) or use of gross fluorescence signal which lacks the visual confirmation that can provide additional confidence in data sets. Multispectral imaging flow cytometry (MIFC) is a novel emerging field of technology. This technology captures a bright field and fluorescence image of cells in a flow using a charged coupled device camera. It allows the analysis of tens of thousands of single cell images, making it an extremely powerful technology. Here MIFC was used as an alternative method of analyzing intracellular bacterial infection using Burkholderia thailandensis E555 as a model organism. It has been demonstrated that the data produced using traditional enumeration is comparable to data analyzed using MIFC. It has also been shown that by using MIFC it is possible to generate other data on the dynamics of the infection model rather than viable counts alone. It has been demonstrated that it is possible to inhibit the uptake of bacteria into mammalian cells and identify differences between treated and untreated cell populations. The authors believe this to be the first use of MIFC to analyze a Burkholderia bacterial species during intracellular infection. © 2016 Crown copyright. Published by Wiley Periodicals Inc. on behalf of ISAC.

Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation.

Wilms tumor and nephroblastomatosis are associated with syndromic conditions including hemihyperplasia. Hemihyperplasia is genetically heterogeneous and may be the result of genomic abnormalities seen in Beckwith-Wiedemann syndrome, mosaic chromosome or genomic abnormalities, or somatic point mutations. Somatic missense mutations affecting the PI3K-AKT-MTOR pathway result in segmental overgrowth and are present in numerous benign and malignant tumors. Here, we report a fourth patient with asymmetric overgrowth due to a somatic PIK3CA mutation who had nephroblastomatosis or Wilms tumor. Similar to two of three reported patients with a somatic PIK3CA mutation and renal tumors, he shared a PIK3CA mutation affecting codon 1047, presented at birth with asymmetric overgrowth, and had fibroadipose overgrowth. Codon 1047 is most commonly affected by somatic mutations in PIK3CA-related overgrowth spectrum (PROS). While the fibroadipose overgrowth phenotype appears to be common in individuals with PIK3CA mutations at codon 1047, individuals with a clinical diagnosis of Klippel-Trenaunay syndrome or isolated lymphatic malformation also had mutations affecting this amino acid. Screening for Wilms tumor in individuals with PROS-related hemihyperplasia may be considered and, until the natural history is fully elucidated in larger cohort studies, may follow guidelines for Beckwith-Wiedemann syndrome, or isolated hemihyperplasia. It is not known if the specific PIK3CA mutation, the mosaic distribution, or the clinical presentation affect the Wilms tumor or nephroblastomatosis risk in individuals with PROS. © 2016 Wiley Periodicals, Inc.

Elevated nutrients change bacterial community composition and connectivity: high throughput sequencing of young marine biofilms.

Biofilms are integral to many marine processes but their formation and function may be affected by anthropogenic inputs that alter environmental conditions, including fertilisers that increase nutrients. Density composition and connectivity of biofilms developed in situ (under ambient and elevated nutrients) were compared using 454-pyrosequencing of the 16S gene. Elevated nutrients shifted community composition from bacteria involved in higher processes (eg Pseudoalteromonas spp. invertebrate recruitment) towards more nutrient-tolerant bacterial species (eg Terendinibacter sp.). This may enable the persistence of biofilm communities by increasing resistance to nutrient inputs. A core biofilm microbiome was identified (predominantly Alteromonadales and Oceanospirillales) and revealed shifts in abundances of core microbes that could indicate enrichment by fertilisers. Fertiliser decreased density and connectivity within biofilms indicating that associations were disrupted perhaps via changes to energetic allocations within the core microbiome. Density composition and connectivity changes suggest nutrients can affect the stability and function of these important marine communities.

Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB.

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Optical and electrochemical methods for determining the effective area and charge density of conducting polymer modified electrodes for neural stimulation.

Neural stimulation is used in the cochlear implant, bionic eye, and deep brain stimulation, which involves implantation of an array of electrodes into a patient's brain. The current passed through the electrodes is used to provide sensory queues or reduce symptoms associated with movement disorders and increasingly for psychological and pain therapies. Poor control of electrode properties can lead to suboptimal performance; however, there are currently no standard methods to assess them, including the electrode area and charge density. Here we demonstrate optical and electrochemical methods for measuring these electrode properties and show the charge density is dependent on electrode geometry. This technique highlights that materials can have widely different charge densities but also large variation in performance. Measurement of charge density from an electroactive area may result in new materials and electrode geometries that improve patient outcomes and reduce side effects.