Publications by authors named "David Hunt"

293 Publications

Isolated 17, 20 Lyase Deficiency Secondary to a Novel CYB5A Variant: Comparison of Steroid Metabolomic Findings with Published Cases Provides Diagnostic Guidelines and Greater Insight into Its Biological Role.

Horm Res Paediatr 2021 Feb 24;93(7-8):483-496. Epub 2021 Feb 24.

Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.

Objective: The objective of this study was to report CYB5A deficiency, to discuss the contribution of steroid metabolomics to diagnosis and interpretation, and to highlight the presence of testicular microlithiasis.

Methods: Two siblings with ambiguous genitalia at birth were later found to carry novel CYB5A variants, with resulting isolated 17, 20 lyase deficiency. We compared urine steroid data obtained between birth and adulthood with that from other cases.

Results: Neonatal urine steroid profiles show a relative increase of 16-hydroxylated pregnenolone metabolites. Thereafter, there are no distinguishing features until puberty, when sex steroid deficiency drives gonadotrophin production, resulting in marked increases of 17-hydroxyprogesterone metabolites derived from the gonads. This excess may be revealed pre-pubertally by gonadotrophin stimulation testing. Novel findings are first, a considerable capacity for DHEA synthesis in the neonatal period compared to childhood and adulthood, suggesting that DHEAS production is much less dependent on CYB5A at birth; second, no consistent change in "backdoor pathway" intermediates; third, side chain cleavage of cortisol is largely unaffected, supporting the existence of a different lyase not dependent on CYB5A; fourth, increased 17-hydroxyprogesterone metabolites and very low androgen metabolites are diagnostic post-pubertally.

Conclusion: This is the fourth disease-causing variant in CYB5A in isolated 17, 20 lyase deficiency and the first associated with testicular microlithiasis. Establishing a biochemical diagnosis pre-pubertally should now be possible using urine steroid profiling, supported by synacthen and gonadotrophin stimulation testing. We recommend liquid chromatography-mass spectrometry/mass spectrometry rather than immunoassay for serum steroid analysis, early methaemoglobin measurement and surveillance should testicular microlithiasis be detected.
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http://dx.doi.org/10.1159/000512372DOI Listing
February 2021

Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse.

eNeuro 2021 Feb 15. Epub 2021 Feb 15.

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

In the hippocampus, the excitatory synapse between dentate granule cell axons - or mossy fibers (MF) - and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g. during exploratory behaviors) and bring CA3 pyramidal neurons above threshold. While frequency facilitation at this synapse is limited by endogenous activation of presynaptic metabotropic glutamate receptors, whether MF-PTP can be regulated in an activity-dependent manner is unknown. Here, using physiologically relevant patterns of mossy fiber stimulation in acute mouse hippocampal slices, we found that disrupting postsynaptic Ca dynamics increases MF-PTP, strongly suggesting a form of Ca-dependent retrograde suppression of this form of plasticity. PTP suppression requires a few seconds of MF bursting activity and Ca release from internal stores. Our findings raise the possibility that the powerful MF-CA3 synapse can negatively regulate its own strength not only during PTP-inducing activity typical of normal exploratory behaviors, but also during epileptic activity. The powerful mossy fiber-CA3 synapse exhibits strong forms of plasticity that are engaged during location-specific exploration, when dentate granule cells fire in bursts. While this synapse is well-known for its presynaptically-expressed LTP and LTD, much less is known about the robust changes that occur on a shorter time scale. How such short-term plasticity is regulated, in particular, remains poorly understood. Unexpectedly, an -like pattern of presynaptic activity induced robust post-tetanic potentiation (PTP) only when the postsynaptic cell was loaded with a high concentration of Ca buffer, indicating a form of Ca-dependent retrograde suppression of PTP. Such suppression may have profound implications for how environmental cues are encoded into neural assemblies, and for limiting network hyperexcitability during seizures.
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http://dx.doi.org/10.1523/ENEURO.0450-20.2021DOI Listing
February 2021

Impact of the first COVID-19 pandemic wave on the Scottish Multiple Sclerosis Register population.

Wellcome Open Res 2020 25;5:276. Epub 2020 Nov 25.

Anne Rowling Clinic, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

: The impact of the coronavirus disease 2019 (COVID-19) pandemic on people with multiple sclerosis (MS) is a major current concern, in particular the risk of death. Here we describe the impact of the first wave of COVID-19 infections (Mar 2020-July 2020) on the Scottish MS Register (SMSR) population, a cohort of 4702 individuals with MS, all newly diagnosed in the past decade. : We established a clinician alert system, linking the SMSR with the Electronic Communication of Surveillance in Scotland (ECOSS). This allows identification of patients within this cohort who had a positive SARS-CoV-2 PCR test. The SMSR was also linked to death records from National Records Scotland. : Of 4702 people with MS, 246 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR tests were performed, of which 17 were positive. The proportion of positive tests were similar to the general Scotland population (Observed PCR confirmed cases = 17, expected = 17.5, O/E = 0.97, 95% CI: 0.60 - 1.56, =.90). Between 1 March - 31 July 2020 12 individuals on the SMSR died, 5 of which were linked to COVID-19 (1 PCR confirmed, 4 clinical diagnoses without PCR confirmation). This number of COVID-19-related deaths was higher than expected (observed deaths = 5, expected deaths = 1.2, O/E = 4.03, 95% CI = 1.48 - 8.94, =.01). All COVID-19-related deaths in the SMSR occurred in individuals with advanced disability (Expanded Disability Status Scale ≥7), and no deaths occurred in patients receiving disease modifying therapy (DMT) therapies. : In this nationally comprehensive cohort of MS patients diagnosed in Scotland within the past 10 years, we observed similar rates of PCR-confirmed SARS-CoV-2 infection compared to the general Scottish population, but a small number of excess COVID-19 related deaths. These deaths occurred in individuals with advanced disability who were not receiving DMTs.
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http://dx.doi.org/10.12688/wellcomeopenres.16349.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848856PMC
November 2020

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia.

Eur Respir J 2021 Jan 21. Epub 2021 Jan 21.

Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Background: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigate relationships have been unsuitable for rare diseases.

Methods: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, twelve clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics.

Results: Disease severity at diagnosis measured by FEV z-score was (i) significantly worse in individuals with mutations compared to other gene mutations and (ii) better in those with mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV at diagnosis. Individuals with mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis.

Conclusions: This large scale multi-national study presents PCD as a syndrome with overlapping symptoms and variation in phenotype, according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies ( FEV worse with mutations), and identified new relationships, including FEV preservation with mutations and diversity of severity with mutations.
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http://dx.doi.org/10.1183/13993003.02359-2020DOI Listing
January 2021

Did Neandertals have large brains? Factors affecting endocranial volume comparisons.

Am J Phys Anthropol 2020 12 16;173(4):768-775. Epub 2020 Aug 16.

Smithsonian Institution, Washington, District of Columbia, USA.

Objectives: Common wisdom in paleoanthropology is that Neandertals had bigger brains than recent humans. Here we tested the hypothesis that there is no difference in brain size between Neandertals and recent humans while accounting for methodological variation and the makeup of both the Neandertal and recent human samples.

Materials And Methods: We examined endocranial volume (ECV) derived from virtually reconstructed endocasts of 11 Neandertals, six of which had associated femoral head diameters (FHD). Our recent human comparative dataset consisted of virtually measured ECV and associated FHD from 94 recent humans from the Robert J. Terry Anatomical Collection (63 male, 31 female). ECV of Neandertals and recent humans was compared using bootstrap resampling, repeating the analysis for two groupings of Neandertals (all and classic) and for three groupings of recent humans (all, males, and females). To examine brain size scaling, we completed an ordinary least squares regression of log (ECV) against log (FHD) for Neandertals and recent humans.

Results: The results of the bootstrap resampling analyses indicated that Neandertals only had significantly larger ECV when compared with recent human females. The regression between ECV and FHD suggested that Neandertals fall within the range of variation for larger humans.

Discussion: Our results demonstrate that Neandertals do not have uniquely large brains when compared with recent humans. Their brain size falls in the large end of the recent human range of variation, but does not exceed it. These results have implications for future research on Neandertal encephalization.
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http://dx.doi.org/10.1002/ajpa.24124DOI Listing
December 2020

Desire to eat and intake of 'insect' containing food is increased by a written passage: The potential role of familiarity in the amelioration of novel food disgust.

Appetite 2020 Dec 30;161:105088. Epub 2020 Dec 30.

Nutrition and Behaviour Unit, School of Psychological Science, University of Bristol, UK.

Over two studies we investigated the effect of various written interventions (passages) on the disgust response towards a food (falafels) which supposedly contained mealworm (insect) flour. Actually, participants (Study 1 N = 80, Study 2 N = 78) were given the same non-mealworm containing food in all conditions. Disgust was measured using: tactile sensitivity, food intake, liking and desire to eat. Results of Study 1 showed that a sustainability passage (sustainability advantages of entomophagy), but not a delicacy passage (oro-sensory qualities of insects), was effective in reducing disgust. In Study 2, contrary to prediction, a passage describing the sustainability and nutritional advantages entomophagy failed to reduce disgust - falafel intake, liking and desire to eat were decreased. However, a passage which described how mealworm flour is produced, did significantly reduce disgust. Taken together, these studies demonstrate that written passages can alter the disgust response, notably resulting in a maintenance of food intake. Interventions that increase the perception of familiarity of a novel food, but not logic-based arguments, may be a key driver of the amelioration of disgust. These results also support the suggestion that altering the ideational component of disgust can result in changes of distaste perception.
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http://dx.doi.org/10.1016/j.appet.2020.105088DOI Listing
December 2020

Visual opsin expression and morphological characterization of retinal photoreceptors in the pouched lamprey (Geotria australis, Gray).

J Comp Neurol 2020 Dec 18. Epub 2020 Dec 18.

School of Biological Sciences, The University of Western Australia, Perth, Western Australia, Australia.

Lampreys are extant members of the agnathan (jawless) vertebrates that diverged ~500 million years ago, during a critical stage of vertebrate evolution when image-forming eyes first emerged. Among lamprey species assessed thus far, the retina of the southern hemisphere pouched lamprey, Geotria australis, is unique, in that it possesses morphologically distinct photoreceptors and expresses five visual photopigments. This study focused on determining the number of different photoreceptors present in the retina of G. australis and whether each cell type expresses a single opsin class. Five photoreceptor subtypes were identified based on ultrastructure and differential expression of one of each of the five different visual opsin classes (lws, sws1, sws2, rh1, and rh2) known to be expressed in the retina. This suggests, therefore, that the retina of G. australis possesses five spectrally and morphologically distinct photoreceptors, with the potential for complex color vision. Each photoreceptor subtype was shown to have a specific spatial distribution in the retina, which is potentially associated with changes in spectral radiance across different lines of sight. These results suggest that there have been strong selection pressures for G. australis to maintain broad spectral sensitivity for the brightly lit surface waters that this species inhabits during its marine phase. These findings provide important insights into the functional anatomy of the early vertebrate retina and the selection pressures that may have led to the evolution of complex color vision.
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http://dx.doi.org/10.1002/cne.25092DOI Listing
December 2020

Agreement and predictive value of the Rockwood Clinical Frailty Scale at emergency department triage.

Emerg Med J 2020 Nov 10. Epub 2020 Nov 10.

Anaesthetics Department, Western Sussex Hospitals NHS Foundation Trust, Worthing, UK.

Aim: To determine the agreement and predictive value of emergency department (ED) triage nurse scoring of frailty using the Rockwood Clinical Frailty Scale (CFS) when compared with inpatient medical assessment using the same scale.

Methods: Prospective, dual-centre UK-based study over a 1-year period (1 April 2017 to 31 March 2018) of CFS recorded digitally at nursing triage on ED arrival and on hospital admission by a medical doctor. Inclusion criteria were emergency medical admission in those aged ≥65 staying at least one night in hospital with a CFS completed in both ED and at hospital admission. Agreement between ED triage nurse and inpatient hospital physician was assessed using a weighted Kappa statistic and Spearman's correlation coefficient. The ability of the ED to diagnose frailty (defined by a CFS ≥5) was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and receiver operating characteristic (ROC) curves. At both time points the ability of the CFS to predict inpatient mortality was also assessed.

Results: From 29 211 admissions aged ≥65 who stayed at least one night in hospital, 12 385 (42.3%) were referred from the ED. Of the ED referrals, 8568 cases (69.2%) were included with paired CFS performed. Median age was 84 (IQR 77 to 89) with an inpatient mortality of 6%. Median CFS in ED was 4 (3 to 5) and on hospital admission 5 (4 to 6). Agreement between the ED CFS and admission CFS was weak (Kappa 0.21, 95% CI 0.19 to 0.22, r 0.366). The area under the ROC curve (AUC) was 0.67 (95% CI 0.66 to 0.68) for the ED CFS ability to predict an admission CFS ≥5. To predict inpatient mortality the ED CFS AUC was 0.56 (0.53 to 0.59) and admission CFS AUC 0.70 (0.68 to 0.73).

Conclusion: Agreement between ED CFS and inpatient CFS was found to be weak. In addition the ability of ED CFS to predict clinically important outcomes was limited. NPV and PPV for ED CFS cut-off value of ≥5 were found to be low. Further work is required on the feasibility, clinical impact and appropriate tools for screening of frailty in EDs.
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http://dx.doi.org/10.1136/emermed-2019-208633DOI Listing
November 2020

Improving Blood Vessel Tortuosity Measurements via Highly Sampled Numerical Integration of the Frenet-Serret Equations.

IEEE Trans Med Imaging 2021 Jan 29;40(1):297-309. Epub 2020 Dec 29.

Measures of vascular tortuosity-how curved and twisted a vessel is-are associated with a variety of vascular diseases. Consequently, measurements of vessel tortuosity that are accurate and comparable across modality, resolution, and size are greatly needed. Yet in practice, precise and consistent measurements are problematic-mismeasurements, inability to calculate, or contradictory and inconsistent measurements occur within and across studies. Here, we present a new method of measuring vessel tortuosity that ensures improved accuracy. Our method relies on numerical integration of the Frenet-Serret equations. By reconstructing the three-dimensional vessel coordinates from tortuosity measurements, we explain how to identify and use a minimally-sufficient sampling rate based on vessel radius while avoiding errors associated with oversampling and overfitting. Our work identifies a key failing in current practices of filtering asymptotic measurements and highlights inconsistencies and redundancies between existing tortuosity metrics. We demonstrate our method by applying it to manually constructed vessel phantoms with known measures of tortuousity, and 9,000 vessels from medical image data spanning human cerebral, coronary, and pulmonary vascular trees, and the carotid, abdominal, renal, and iliac arteries.
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http://dx.doi.org/10.1109/TMI.2020.3025467DOI Listing
January 2021

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus.

Ann Neurol 2020 12 6;88(6):1244-1250. Epub 2020 Oct 6.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244-1250.
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http://dx.doi.org/10.1002/ana.25908DOI Listing
December 2020

Evaluating life history trade-offs through the presence of linear enamel hypoplasia at Pueblo Bonito and Hawikku: A biocultural study of early life stress and survival in the Ancestral Pueblo Southwest.

Am J Hum Biol 2020 Sep 14:e23506. Epub 2020 Sep 14.

Physical Anthropology Division, Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington, District of Columbia, USA.

Objectives: Due to the indelible nature of enamel, bioarchaeologists use linear enamel hypoplasia (LEH) to detect early investments in surviving stress and have identified an association between LEH presence and constraints in growth and maintenance as well as an increased susceptibility to future stress events. This study evaluates heterogenous frailty and susceptibility to death in relation to episodes of early life stress, as reflected by LEH presence, in the Ancestral Pueblo Southwest. This study hypothesizes that LEH presence will be associated with decreased survivorship and an increased likelihood of mortality in both samples.

Materials And Methods: This study uses two samples, one from Pueblo Bonito (A.D. 800-1200; n = 28) and the second from Hawikku (A.D. 1300-1680; n = 103). Kaplan-Meier survival analysis with a log-rank test was used to evaluate the effect of LEH presence on survivorship for the two samples.

Results: Survival analysis reveals statistically significant differences in mortality risk between individuals with and without LEH for the Hawikku sample, but no significant differences for the Pueblo Bonito sample.

Conclusion: The results demonstrate differences in the response to early life stress at the Hawikku and Pueblo Bonito sites, likely reflecting context. The Pueblo Bonito sample represents a high-status group, and survival following LEH may be the result of cultural buffering. Hawikku dates to a period associated with increased levels of disease and malnutrition as well as Spanish colonization. This environment may have exacerbated mortality risk for individuals in the region who survived early life stress and signifies the consequences of European colonialism in the New World.
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http://dx.doi.org/10.1002/ajhb.23506DOI Listing
September 2020

Interventions to reduce the time to diagnosis of brain tumours.

Cochrane Database Syst Rev 2020 09 4;9:CD013564. Epub 2020 Sep 4.

The Evidence-Based Medicine Consultancy Ltd, Bath, UK.

Background: Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available.

Objectives: To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions.

Search Methods: For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014.

Selection Criteria: We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non-randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour.

Data Collection And Analysis: Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author.

Main Results: We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic.

Authors' Conclusions: In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost-effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.
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http://dx.doi.org/10.1002/14651858.CD013564.pub2DOI Listing
September 2020

Validating Fluorescent Chrnb4.EGFP Mouse Models for the Study of Cone Photoreceptor Degeneration.

Transl Vis Sci Technol 2020 08 18;9(9):28. Epub 2020 Aug 18.

Centre for Ophthalmology and Visual Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.

Purpose: To validate the application of a known transgenic mouse line with green fluorescent cones (Chrnb4.EGFP) to study cone photoreceptor biology and function in health and disease.

Methods: Chrnb4.EGFP retinas containing GFP cones were compared with retinas without the GFP transgene via immunohistochemistry, quantitative real-time polymerase chain reaction, electroretinograms, and flow cytometry. The Chrnb4.EGFP line was backcrossed to the mouse models of cone degeneration, and , generating the new lines .GFP and .GFP, which were also studied as described.

Results: GFP expression spanned the length of the cone cell in the Chrnb4.EGFP line, as well as in the novel .GFP and .GFP lines. The effect of GFP expression showed no significant changes to outer nuclear layer cell death, cone-specific gene expression, and immune response activation. A temporal decrease in GFP expression over time was observed, but GFP fluorescence was still detected through flow cytometry as late as 6 months. Furthermore, a functional analysis of photopic and scotopic electroretinogram responses of the Chrnb4 mouse showed no significant difference between GFP and GFP mice, whereas electroretinogram recordings for the .GFP and .GFP lines matched previous reports from the original lines.

Conclusions: This study demonstrates that the Chrnb4.EGFP mouse can be a powerful tool to overcome the limitations of studying cone biology, including the use of this line to study different types of cone degeneration.

Translational Relevance: This work validates research tools that could potentially offer more reliable preclinical data in the development of treatments for cone-mediated vision loss conditions, shortening the gap to clinical translation.
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http://dx.doi.org/10.1167/tvst.9.9.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442867PMC
August 2020

Tracking down the White Plague. Chapter two: The role of endocranial abnormal blood vessel impressions and periosteal appositions in the paleopathological diagnosis of tuberculous meningitis.

PLoS One 2020 1;15(9):e0238444. Epub 2020 Sep 1.

Department of Anthropology, National Museum of Natural History, Smithsonian Institution, District of Columbia, Washington, D.C., United States of America.

Although endocranial abnormal blood vessel impressions (ABVIs) and periosteal appositions (PAs) have been considered as paleopathological diagnostic criteria for tuberculous meningitis (TBM) based on findings of previous studies, they are not pathognomonic for tuberculosis (TB). Therefore, their utilization in the paleopathological practice can be questioned, especially in consideration that most of the previous studies were not performed on identified skeletal collections but on osteoarchaeological material and did not include statistical data analysis. To fill the aforementioned research gap, for the first time, a macroscopic investigation was conducted on identified pre-antibiotic era skeletons from the Terry Collection. A sample set of 234 individuals who died of TB (TB group) and 193 individuals who died of non-tuberculous causes (NTB group) were examined. The frequency of ABVIs and PAs, as well as other probable TB-related lesions was recorded. To determine the significance of difference (if any) in the frequencies of ABVIs and PAs between the two groups, χ2 testing of our data was performed. We found that ABVIs, PAs, and their co-occurrence with each other and with other probable TB-related lesions were more common in the TB group than in the NTB group. In addition, the χ2 comparative frequencies of ABVIs and PAs revealed a statistically significant difference between individuals who died of TB and individuals who died of NTB causes. Our findings strengthen those of previous studies that ABVIs and PAs are not specific to TBM but can be of tuberculous origin. Therefore, they do have a diagnostic value in the identification of TB in human osteoarchaeological material, especially when they simultaneously occur with other probable TB-related lesions. Their prudent utilization provides paleopathologists with a stronger basis for diagnosing TB and consequently, a more sensitive means of assessing TB frequency in past human populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462305PMC
October 2020

Deep vein thrombosis protocol optimization to minimize healthcare worker exposure in coronavirus disease-2019.

J Vasc Surg Venous Lymphat Disord 2021 03 11;9(2):299-306. Epub 2020 Aug 11.

Department of Radiology, Massachusetts General Hospital, Boston, Mass.

Objective: There are no societal ultrasound (US) guidelines detailing appropriate patient selection for deep vein thrombosis (DVT) imaging in patients with COVID-19, nor are there protocol recommendations aimed at decreasing exposure time for US technologists. We aimed to provide COVID-19-specific protocol optimization recommendations limiting US technologist exposure while optimizing patient selection.

Methods: A novel two-pronged algorithm was implemented to limit the DVT US studies on patients with COVID-19 prospectively, which included direct physician communication with the care team and a COVID-19-specific imaging protocol was instated to reduce US technologist exposure. To assess the pretest risk of DVT, the sensitivity and specificity of serum d-dimer in 500-unit increments from 500 to 8000 ng/mL and a receiver operating characteristic curve to assess performance of serum d-dimer in predicting DVT was generated. Rates of DVT, pulmonary embolism, and scan times were compared using t-test and Fisher's exact test (before and after implementation of the protocol).

Results: Direct physician communication resulted in cancellation or deferral of 72% of requested examinations in COVID-19-positive patients. A serum d-dimer of >4000 ng/mL yielded a sensitivity of 80% and a specificity of 70% (95% confidence interval, 0.54-0.86) for venous thromboembolism. Using the COVID-19-specific protocol, there was a significant (50%) decrease in the scan time (P < .0001) in comparison with the conventional protocol.

Conclusions: A direct physician communication policy between imaging physician and referring physician resulted in deferral or cancellation of a majority of requested DVT US examinations. An abbreviated COVID-19-specific imaging protocol significantly decreased exposure time to the US technologist.
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http://dx.doi.org/10.1016/j.jvsv.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418643PMC
March 2021

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

Mult Scler Relat Disord 2020 Sep 2;44:102251. Epub 2020 Jun 2.

Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom; Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Department of Neurology, The Cleveland Clinic Abu Dhabi, United Arab Emirates. Electronic address:

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD).

Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model).

Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses.

Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.
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http://dx.doi.org/10.1016/j.msard.2020.102251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895306PMC
September 2020

DRM02, a novel phosphodiesterase-4 inhibitor with cutaneous anti-inflammatory activity.

Tissue Barriers 2020 Jul 1;8(3):1765633. Epub 2020 Jun 1.

Department of Physiology and Pharmacology, University of Western Ontario , London, Canada.

Chronic inflammatory skin disorders are frequently associated with impaired skin barrier function. Selective phosphodiesterase-4 (PDE4) inhibition constitutes an effective therapeutic strategy for the treatment of inflammatory skin diseases. We now report the pharmacological anti-inflammatory profile of DRM02, a novel pyrazolylbenzothiazole derivative with selective inhibitory activity toward PDE4 isoforms A, B and D. DRM02 treatment of cultured primary human and mouse epidermal keratinocytes interfered with pro-inflammatory cytokine production elicited by interleukin-1α and tumor necrosis factor-α. Similarly, DRM02 inhibited the production of pro-inflammatory cytokines by human peripheral blood mononuclear cells and cultured THP-1 monocyte-like cells, with IC values of 0.6-14 µM. These anti-inflammatory properties of DRM02 were associated with dose-dependent repression of nuclear factor-κB (NF-κB) transcriptional activity. In skin inflammation mouse models, topically applied DRM02 inhibited the acute response to phorbol ester and induced Th2-type contact hypersensitivity reactivity. Further, DRM02 also decreased cutaneous clinical changes and expression of Th17 immune pathway cytokines in a mouse model of psoriasis evoked by repeated topical imiquimod application. Thus, the overall pharmacological profiling of the PDE4 inhibitor DRM02 has revealed its potential as a topical therapy for inflammatory skin disorders and restoration of skin homeostasis.
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http://dx.doi.org/10.1080/21688370.2020.1765633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549747PMC
July 2020

Spectral Diversification and Trans-Species Allelic Polymorphism during the Land-to-Sea Transition in Snakes.

Curr Biol 2020 Jul 28;30(13):2608-2615.e4. Epub 2020 May 28.

The University of Adelaide, School of Biological Sciences, North Terrace, Adelaide, South Australia 5005, Australia; Department of Life Sciences, The Natural History Museum, Cromwell Road, London SW7 5BD, United Kingdom.

Snakes are descended from highly visual lizards [1] but have limited (probably dichromatic) color vision attributed to a dim-light lifestyle of early snakes [2-4]. The living species of front-fanged elapids, however, are ecologically very diverse, with ∼300 terrestrial species (cobras, taipans, etc.) and ∼60 fully marine sea snakes, plus eight independently marine, amphibious sea kraits [1]. Here, we investigate the evolution of spectral sensitivity in elapids by analyzing their opsin genes (which are responsible for sensitivity to UV and visible light), retinal photoreceptors, and ocular lenses. We found that sea snakes underwent rapid adaptive diversification of their visual pigments when compared with their terrestrial and amphibious relatives. The three opsins present in snakes (SWS1, LWS, and RH1) have evolved under positive selection in elapids, and in sea snakes they have undergone multiple shifts in spectral sensitivity toward the longer wavelengths that dominate below the sea surface. Several relatively distantly related Hydrophis sea snakes are polymorphic for shortwave sensitive visual pigment encoded by alleles of SWS1. This spectral site polymorphism is expected to confer expanded "UV-blue" spectral sensitivity and is estimated to have persisted twice as long as the predicted survival time for selectively neutral nuclear alleles. We suggest that this polymorphism is adaptively maintained across Hydrophis species via balancing selection, similarly to the LWS polymorphism that confers allelic trichromacy in some primates. Diving sea snakes thus appear to share parallel mechanisms of color vision diversification with fruit-eating primates.
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http://dx.doi.org/10.1016/j.cub.2020.04.061DOI Listing
July 2020

Systematic review of prediction models in relapsing remitting multiple sclerosis.

PLoS One 2020 26;15(5):e0233575. Epub 2020 May 26.

Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom.

The natural history of relapsing remitting multiple sclerosis (RRMS) is variable and prediction of individual prognosis challenging. The inability to reliably predict prognosis at diagnosis has important implications for informed decision making especially in relation to disease modifying therapies. We conducted a systematic review in order to collate, describe and assess the methodological quality of published prediction models in RRMS. We searched Medline, Embase and Web of Science. Two reviewers independently screened abstracts and full text for eligibility and assessed risk of bias. Studies reporting development or validation of prediction models for RRMS in adults were included. Data collection was guided by the checklist for critical appraisal and data extraction for systematic reviews (CHARMS) and applicability and methodological quality assessment by the prediction model risk of bias assessment tool (PROBAST). 30 studies were included in the review. Applicability was assessed as high risk of concern in 27 studies. Risk of bias was assessed as high for all studies. The single most frequently included predictor was baseline EDSS (n = 11). T2 Lesion volume or number and brain atrophy were each retained in seven studies. Five studies included external validation and none included impact analysis. Although a number of prediction models for RRMS have been reported, most are at high risk of bias and lack external validation and impact analysis, restricting their application to routine clinical practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250448PMC
August 2020

Directly Transmitted 12.3-Mb Deletion with a Consistent Phenotype in the Variable 11q21q22.3 Region.

Cytogenet Genome Res 2020 22;160(4):185-192. Epub 2020 Apr 22.

A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.
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http://dx.doi.org/10.1159/000507409DOI Listing
July 2020

Association Between Medicare Expenditures and Adverse Events for Patients With Acute Myocardial Infarction, Heart Failure, or Pneumonia in the United States.

JAMA Netw Open 2020 04 1;3(4):e202142. Epub 2020 Apr 1.

General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.

Importance: Studies have shown that adverse events are associated with increasing inpatient care expenditures, but contemporary data on the association between expenditures and adverse events beyond inpatient care are limited.

Objective: To evaluate whether hospital-specific adverse event rates are associated with hospital-specific risk-standardized 30-day episode-of-care Medicare expenditures for fee-for-service patients discharged with acute myocardial infarction (AMI), heart failure (HF), or pneumonia.

Design, Setting, And Participants: This cross-sectional study used the 2011 to 2016 hospital-specific risk-standardized 30-day episode-of-care expenditure data from the Centers for Medicare & Medicaid Services and medical record-abstracted in-hospital adverse event data from the Medicare Patient Safety Monitoring System. The setting was acute care hospitals treating at least 25 Medicare fee-for-service patients for AMI, HF, or pneumonia in the United States. Participants were Medicare fee-for-service patients 65 years or older hospitalized for AMI, HF, or pneumonia included in the Medicare Patient Safety Monitoring System in 2011 to 2016. The dates of analysis were July 16, 2017, to May 21, 2018.

Main Outcomes And Measures: Hospitals' risk-standardized 30-day episode-of-care expenditures and the rate of occurrence of adverse events for which patients were at risk.

Results: The final study sample from 2194 unique hospitals included 44 807 patients (26.1% AMI, 35.6% HF, and 38.3% pneumonia) with a mean (SD) age of 79.4 (8.6) years, and 52.0% were women. The patients represented 84 766 exposures for AMI, 96 917 exposures for HF, and 109 641 exposures for pneumonia. Patient characteristics varied by condition but not by expenditure category. The mean (SD) risk-standardized expenditures were $22 985 ($1579) for AMI, $16 020 ($1416) for HF, and $16 355 ($1995) for pneumonia per hospitalization. The mean risk-standardized rates of occurrence of adverse events for which patients were at risk were 3.5% (95% CI, 3.4%-3.6%) for AMI, 2.5% (95% CI, 2.5%-2.5%) for HF, and 3.0% (95% CI, 2.9%-3.0%) for pneumonia. An increase by 1 percentage point in the rate of occurrence of adverse events was associated with an increase in risk-standardized expenditures of $103 (95% CI, $57-$150) for AMI, $100 (95% CI, $29-$172) for HF, and $152 (95% CI, $73-$232) for pneumonia per discharge.

Conclusions And Relevance: Hospitals with high adverse event rates were more likely to have high 30-day episode-of-care Medicare expenditures for patients discharged with AMI, HF, or pneumonia.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.2142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139276PMC
April 2020

Tracking down the White Plague: The skeletal evidence of tuberculous meningitis in the Robert J. Terry Anatomical Skeletal Collection.

PLoS One 2020 18;15(3):e0230418. Epub 2020 Mar 18.

Institut für Anatomie und Embryologie, Zentrum Anatomie, Universitätsmedizin Göttingen, Göttingen, Germany.

Paleopathological diagnosis of tuberculosis (TB) essentially relies on the identification of macroscopic lesions in the skeleton that can be related to different manifestations of TB. Among these alterations, granular impressions (GIs) on the inner skull surface have been considered as pathognomonic features of tuberculous meningitis (TBM). GIs may be established by pressure atrophy of the tubercles formed on the outermost meningeal layer during later stages of TBM. Although GIs were used as diagnostic criteria for TBM in the paleopathological practice since the late 20th century, their diagnostic value has been questioned. To contribute to strengthening the diagnostic value of GIs, a macroscopic investigation-focusing on the macromorphological characteristics and frequency of GIs-was performed on skeletons of known cause of death from the Terry Collection. The χ2 analysis of our data revealed that GIs were significantly more common in individuals who died of TB than in individuals who died of non-TB causes. Furthermore, GIs were localized on the inner surface of the skull base and of the lower lateral skull vault. The localization pattern and distribution of GIs on the endocranial surface resemble that of the tubercles observed in the affected meninges during the pathogenesis of TBM. Our results strengthen the tuberculous origin of GIs and imply that they can be considered as specific signs of TBM. Therefore, GIs can be used as diagnostic criteria for TBM in the paleopathological practice, and the diagnosis of TBM can be established with a high certainty when GIs are present in ancient human bone remains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080279PMC
June 2020

Comparison of Mendeliome exome capture kits for use in clinical diagnostics.

Sci Rep 2020 02 24;10(1):3235. Epub 2020 Feb 24.

Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

Next generation sequencing has disrupted genetic testing, allowing far more scope in the tests applied. The appropriate sections of the genome to be tested can now be readily selected, from single mutations to whole-genome sequencing. One product offering within this spectrum are focused exomes, targeting ~5,000 genes know to be implicated in human disease. These are designed to offer a flexible platform offering high diagnostic yield with a reduction in sequencing requirement compared to whole exome sequencing. Here, we have undertaken sequencing of control DNA samples and compare two kits, the Illumina TruSight One and the Agilent SureSelect Focused Exome. Characteristics of the kits are comprehensively evaluated. Despite the larger design region of the Agilent kit, we find that the Illumina kit performs better in terms of gene coverage, as well as coverage of clinically relevant loci. We provide exhaustive coverage statistics for each kit to aid the assessment of their suitability and provide read data for control DNA samples to allow for bioinformatic benchmarking by users developing pipelines for these data.
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http://dx.doi.org/10.1038/s41598-020-60215-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039898PMC
February 2020

Quantifying the Relative Thickness of Conductive Ferromagnetic Materials Using Detector Coil-Based Pulsed Eddy Current Sensors.

J Vis Exp 2020 01 16(155). Epub 2020 Jan 16.

Center for Autonomous Systems, University of Technology Sydney.

Thickness quantification of conductive ferromagnetic materials by means of non-destructive evaluation (NDE) is a crucial component of structural health monitoring of infrastructure, especially for assessing the condition of large diameter conductive ferromagnetic pipes found in the energy, water, oil, and gas sectors. Pulsed eddy current (PEC) sensing, especially detector coil-based PEC sensor architecture, has established itself over the years as an effective means for serving this purpose. Approaches for designing PEC sensors as well as processing signals have been presented in previous works. In recent years, the use of the decay rate of the detector coil-based time domain PEC signal for the purpose of thickness quantification has been studied. Such works have established that the decay rate-based method holds generality to the detector coil-based sensor architecture, with a degree of immunity to factors such as sensor shape and size, number of coil turns, and excitation current. Moreover, this method has shown its effectiveness in NDE of large pipes made of grey cast iron. Following such literature, the focus of this work is explicitly PEC sensor detector coil voltage decay rate-based conductive ferromagnetic material thickness quantification. However, the challenge faced by this method is the difficulty of calibration, especially when it comes to applications such as in situ pipe condition assessment since measuring electrical and magnetic properties of certain pipe materials or obtaining calibration samples is difficult in practice. Motivated by that challenge, in contrast to estimating actual thickness as done by some previous works, this work presents a protocol for using the decay rate-based method to quantify relative thickness (i.e., thickness of a particular location with respect to a maximum thickness), without the requirement for calibration.
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http://dx.doi.org/10.3791/59618DOI Listing
January 2020

Diagnosis of pyridoxine-dependent epilepsy in an adult presenting with recurrent status epilepticus.

Epilepsia 2020 01 17;61(1):e1-e6. Epub 2019 Dec 17.

Southampton General Hospital, Southampton, UK.

Pyridoxine-dependent epilepsy (PDE) is a genetic metabolic disease caused by inborn errors affecting vitamin B6 metabolism, which typically presents with neonatal seizures resistant to antiepileptic drugs (AEDs). Treatment with pyridoxine terminates seizures and prevents neurological decline. We describe a case in which the diagnosis was established at the age of 22 years. Birth and development were normal, but there was a history of three isolated tonic-clonic seizures during childhood and adolescence. At the age of 18 years, she developed frequent focal motor seizures, many evolving into tonic-clonic seizures. Electroencephalography identified a focus in the posterior right hemisphere, but magnetic resonance imaging of the brain was normal. Over the next 3 years, she was hospitalized with uncontrolled seizures on six occasions and spent a total of 121 days in intensive care. The seizures proved resistant to 12 different AEDs. Exome sequencing revealed two pathogenic mutations in ALDH7A1. Since starting on pyridoxine 50 mg once daily, she has been seizure-free, all AEDs have been withdrawn, and cognition has improved to premorbid levels. This case illustrates the importance of considering PDE in drug-resistant epilepsy in adults.
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http://dx.doi.org/10.1111/epi.16408DOI Listing
January 2020

Neuromyelitis optica in patients with increased interferon alpha concentrations.

Lancet Neurol 2020 01;19(1):31-33

Anne Rowling Clinic, University of Edinburgh, Edinburgh EH16 4SB, UK; Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK; UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(19)30445-4DOI Listing
January 2020

The future is bright for the next generation of plant scientists.

New Phytol 2020 01;225(1):48-50

UCD School of Biology and Environmental Science, UCD Centre for Plant Science, UCD Earth Institute, University College Dublin, Belfield, Dublin 4, Ireland.

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http://dx.doi.org/10.1111/nph.16313DOI Listing
January 2020

Visual Opsin Diversity in Sharks and Rays.

Mol Biol Evol 2020 03;37(3):811-827

School of Biological Sciences, The University of Western Australia, Crawley, WA, Australia.

The diversity of color vision systems found in extant vertebrates suggests that different evolutionary selection pressures have driven specializations in photoreceptor complement and visual pigment spectral tuning appropriate for an animal's behavior, habitat, and life history. Aquatic vertebrates in particular show high variability in chromatic vision and have become important models for understanding the role of color vision in prey detection, predator avoidance, and social interactions. In this study, we examined the capacity for chromatic vision in elasmobranch fishes, a group that have received relatively little attention to date. We used microspectrophotometry to measure the spectral absorbance of the visual pigments in the outer segments of individual photoreceptors from several ray and shark species, and we sequenced the opsin mRNAs obtained from the retinas of the same species, as well as from additional elasmobranch species. We reveal the phylogenetically widespread occurrence of dichromatic color vision in rays based on two cone opsins, RH2 and LWS. We also confirm that all shark species studied to date appear to be cone monochromats but report that in different species the single cone opsin may be of either the LWS or the RH2 class. From this, we infer that cone monochromacy in sharks has evolved independently on multiple occasions. Together with earlier discoveries in secondarily aquatic marine mammals, this suggests that cone-based color vision may be of little use for large marine predators, such as sharks, pinnipeds, and cetaceans.
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http://dx.doi.org/10.1093/molbev/msz269DOI Listing
March 2020