Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

Background: The HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype. Methods and results: We ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA. Conclusion: This study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders

Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans

Better methods are required to interpret the pathogenicity of disease-associated variants of uncertain significance (VUS), which cannot be actioned clinically. In this study, we explore the use of an animal model (Caenorhabditis elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a cilia gene associated with ciliopathies. CRISPR/Cas9 gene editing was used to generate homozygous knock-in C. elegans worm strains carrying TMEM67 patient variants engineered into the orthologous gene (mks-3). Quantitative phenotypic assays of sensory cilia structure and function (neuronal dye filling, roaming and chemotaxis assays) measured how the variants impacted mks-3 gene function. Effects of the variants on mks-3 function were further investigated by looking at MKS-3::GFP localization and cilia ultrastructure. The quantitative assays in C. elegans accurately distinguished between known benign (Asp359Glu, Thr360Ala) and known pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of eight missense VUS generated evidence that three are benign (Cys173Arg, Thr176Ile and Gly979Arg) and five are pathogenic (Cys170Tyr, His782Arg, Gly786Glu, His790Arg and Ser961Tyr). Results from worms were validated by a genetic complementation assay in a human TMEM67 knock-out hTERT-RPE1 cell line that tests a TMEM67 signalling function. We conclude that efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model for rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles

Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit

A recent surge in human mastadenovirus (HAdV) cases, including five deaths, amongst a haematopoietic stem cell transplant population led us to use whole genome sequencing (WGS) to investigate. We compared sequences from 37 patients collected over a 20-month period with sequences from GenBank and our own database of HAdVs. Maximum likelihood trees and pairwise differences were used to evaluate genotypic relationships, paired with the epidemiological data from routine infection prevention and control (IPC) records and hospital activity data. During this time period, two formal outbreaks had been declared by IPC, while WGS detected nine monophyletic clusters, seven were corroborated by epidemiological evidence and by comparison of single-nucleotide polymorphisms. One of the formal outbreaks was confirmed, and the other was not. Of the five HAdV-associated deaths, three were unlinked and the remaining two considered the source of transmission. Mixed infection was frequent (10%), providing a sentinel source of recombination and superinfection. Immunosuppressed patients harboring a high rate of HAdV positivity require comprehensive surveillance. As a consequence of these findings, HAdV WGS is being incorporated routinely into clinical practice to influence IPC policy contemporaneously

Evolution of star formation in the UKIDSS Ultra Deep Survey Field - I. Luminosity functions and cosmic star formation rate out to z = 1.6

We present new results on the cosmic star formation history in the Subaru/XMM–Newton Deep Survey (SXDS)–Ultra Deep Survey (UDS) field out to z = 1.6. We compile narrowband data from the Subaru Telescope and the Visible and Infrared Survey Telescope for Astronomy (VISTA) in conjunction with broad-band data from the SXDS and UDS, to make a selection of 5725 emission-line galaxies in 12 redshift slices, spanning 10 Gyr of cosmic time. We determine photometric redshifts for the sample using 11-band photometry, and use a spectroscopically confirmed subset to fine tune the resultant redshift distribution. We use the maximum-likelihood technique to determine luminosity functions in each redshift slice and model the selection effects inherent in any narrow-band selection statistically, to obviate the retrospective corrections ordinarily required. The deep narrow-band data are sensitive to very low star formation rates (SFRs), and allow an accurate evaluation of the faint end slope of the Schechter function, α. We find that α is particularly sensitive to the assumed faintest broad-band magnitude of a galaxy capable of hosting an emission line, and propose that this limit should be empirically motivated. For this analysis, we base our threshold on the limiting observed equivalent widths of emission lines in the local Universe. We compute the characteristic SFR of galaxies in each redshift slice, and the integrated SFR density, ρSFR. We find our results to be in good agreement with the literature and parametrize the evolution of the SFR density as ρSFR ∝ (1 + z)4.58 confirming a steep decline in star formation activity since z ∼ 1.6. Keywords: surveys – galaxies: evolution – galaxies: formation – galaxies: high-redshift – galaxies: star formation – cosmology: observations

Over 1200 drugs-related deaths and 190,000 opiate-user-years of follow-up : relative risks by sex and age-group

Heroin users/injectors' risk of drugs-related death by sex and current age is weakly estimated both in individual cohorts of under 1000 clients, 5000 person-years or 50 drugs-related deaths and when using cross-sectional data. A workshop in Cambridge analysed six cohorts who were recruited according to a common European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) protocol from drug treatment agencies in Barcelona, Denmark, Dublin, Lisbon, Rome and Vienna in the 1990s; and, as external reference, opiate-user arrestees in France and hepatitis C diagnosed ever-injectors in Scotland in 1993-2001, both followed by database linkage to December 2001. EMCDDA cohorts recorded approximately equal numbers of drugs-related deaths (864) and deaths from other non-HIV causes (865) during 106,152 person-years of follow-up. External cohorts contributed 376 drugs-related deaths (Scotland 195, France 181) and 418 deaths from non-HIV causes (Scotland 221, France 197) during 86,417 person-years of follow-up (Scotland 22,670, France 63,747). EMCDDA cohorts reported 707 drugs-related deaths in 81,367 man-years {8.7 per 1000 person-years, 95% CI: 8.1 to 9.4} but only 157 in 24,785 person-years for females {6.3 per 1000 person-years, 95% CI: 5.4 to 7.4}. Except in external cohorts, relative risks by current age-group were not particularly strong, and more modest in Poisson regression than in cross-sectional analyses: relative risk was 1.2 (95% CI: 1.0-1.4) for 35-44 year olds compared to 15-24 year 3 olds, but 1.4 for males (95%CI: 1.2-1.6), and dramatically lower at 0.44 after the first year of follow-up (95% CI: 0.37-0.52)

How large should whales be?

The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.Comment: 7 pages, 3 figures, 2 data table

imPlatelet classifier: image-converted RNA biomarker profiles enable blood-based cancer diagnostics

Liquid biopsies offer a minimally invasive sample collection, outperforming traditional biopsies employed for cancer evaluation. The widely used material is blood, which is the source of tumor-educated platelets. Here, we developed the imPlatelet classifier, which converts RNA-sequenced platelet data into images in which each pixel corresponds to the expression level of a certain gene. Biological knowledge from the Kyoto Encyclopedia of Genes and Genomes was also implemented to improve accuracy. Images obtained from samples can then be compared against standard images for specific cancers to determine a diagnosis. We tested imPlatelet on a cohort of 401 non-small cell lung cancer patients, 62 sarcoma patients, and 28 ovarian cancer patients. imPlatelet provided excellent discrimination between lung cancer cases and healthy controls, with accuracy equal to 1 in the independent dataset. When discriminating between noncancer cases and sarcoma or ovarian cancer patients, accuracy equaled 0.91 or 0.95, respectively, in the independent datasets. According to our knowledge, this is the first study implementing an image-based deep-learning approach combined with biological knowledge to classify human samples. The performance of imPlatelet considerably exceeds previously published methods and our own alternative attempts of sample discrimination. We show that the deep-learning image-based classifier accurately identifies cancer, even when a limited number of samples are available.publishedVersio

At what scale should we assess the health of pelagic habitats? Trade-offs between small-scale manageable pressures and the need for regional upscaling

Major planktonic lifeforms such as diatoms, dinoflagellates, meroplankton and holoplankton have recently shown significant and alarming changes in abundance - mainly downwards trends - around the northwest European shelf. This has major implications for food web connections and for ecosystem services including seafood provision and carbon storage. We have quantified these changes in abundance for 2006–2019/20 using a Plankton Index (PI) and show that the scale of spatial aggregation is critical to the ability of the PI to detect change, understand causal mechanisms, and provide advice to policymakers. We derived PI statistics in the Celtic and North Seas from data from the Continuous Plankton Recorder survey offshore and England’s Environment Agency inshore using three sets of spatial units: (i) Ecohydrodynamic (EHD) units based on hydro-biogeochemical modelling, (ii) ‘COMP4′ areas based on cluster analysis of satellite data for chlorophyll a and primary productivity, and (iii) English coastal and estuarine Water Framework Directive (WFD) waterbodies. For the largest scale areas, the EHD units (median size 87,000 km2), we find greater change in plankton communities than previously reported, suggesting that these shifts have continued and possibly intensified in recent years. The smaller-scale COMP4 areas (median size 6,700 km2) appear to encompass more spatially coherent changes in plankton community structure than EHD units; at this scale PI values indicate community shifts of greater magnitude. These COMP4 areas provide a reasonable compromise scale for linking offshore plankton communities to large-scale drivers of change such as climate warming. For inshore plankton communities, larger changes are detected at the smaller WFD waterbody scale (median size 11 km2). This scale allows direct links to coastal management measures and is more suitable for linking to land-sourced pressures. Recent integration of the UK’s OSPAR and WFD plankton monitoring data management enables the exploration of changes across spatial scales to develop a holistic understanding of ecosystem health. Regional-sea scale derivation of the PI for coastal waters provides a clear indication that changes are occurring, at least in phytoplankton communities, while localised PI statistics offer an additional layer of information which can be an important tool for linking to localised drivers of change including coastal anthropogenic pressures. Broadscale inshore zooplankton monitoring is needed to evaluate the coastal plankton community holistically; zooplankton communities offshore are also changing but these changes cannot currently be linked to coastal processes. Layering information across spatial scales provides a breadth of system-level understanding beyond what any one typology can provide