Duplicate dmbx1 genes regulate progenitor cell cycle and differentiation during zebrafish midbrain and retinal development

Abstract Background The Dmbx1 gene is important for the development of the midbrain and hindbrain, and mouse gene targeting experiments reveal that this gene is required for mediating postnatal and adult feeding behaviours. A single Dmbx1 gene exists in terrestrial vertebrate genomes, while teleost genomes have at least two paralogs. We compared the loss of function of the zebrafish dmbx1a and dmbx1b genes in order to gain insight into the molecular mechanism by which dmbx1 regulates neurogenesis, and to begin to understand why these duplicate genes have been retained in the zebrafish genome. Results Using gene knockdown experiments we examined the function of the dmbx1 gene paralogs in zebrafish, dmbx1a and dmbx1b in regulating neurogenesis in the developing retina and midbrain. Dose-dependent loss of dmbx1a and dmbx1b function causes a significant reduction in growth of the midbrain and retina that is evident between 48-72 hpf. We show that this phenotype is not due to patterning defects or persistent cell death, but rather a deficit in progenitor cell cycle exit and differentiation. Analyses of the morphant retina or anterior hindbrain indicate that paralogous function is partially diverged since loss of dmbx1a is more severe than loss of dmbx1b. Molecular evolutionary analyses of the Dmbx1 genes suggest that while this gene family is conservative in its evolution, there was a dramatic change in selective constraint after the duplication event that gave rise to the dmbx1a and dmbx1b gene families in teleost fish, suggestive of positive selection. Interestingly, in contrast to zebrafish dmbx1a, over expression of the mouse Dmbx1 gene does not functionally compensate for the zebrafish dmbx1a knockdown phenotype, while over expression of the dmbx1b gene only partially compensates for the dmbx1a knockdown phenotype. Conclusion Our data suggest that both zebrafish dmbx1a and dmbx1b genes are retained in the fish genome due to their requirement during midbrain and retinal neurogenesis, although their function is partially diverged. At the cellular level, Dmbx1 regulates cell cycle exit and differentiation of progenitor cells. The unexpected observation of putative post-duplication positive selection of teleost Dmbx1 genes, especially dmbx1a, and the differences in functionality between the mouse and zebrafish genes suggests that the teleost Dmbx1 genes may have evolved a diverged function in the regulation of neurogenesis

Integrated survey of boat-based recreational fishing in inner Shark Bay 2018/19

Inner Shark Bay is a popular recreational fishing destination. As recreational fishing occurs in a World Heritage Area and Marine Park, there is a need for ongoing reliable information on catches. Many boat-based recreational fishers in inner Shark Bay target Pink Snapper (Chrysophrys auratus)

Review of recreational fishing surveys in Western Australia

Recreational fishing has been a popular activity in Western Australia for many years, with an estimated 25% of the population participating in this activity in 2017/18. Recreational fishing surveys have been implemented by the Department of Primary Industries and Regional Development (formally Department of Fisheries) since 1976

Genomic surveillance of 4CMenB vaccine antigenic variants among disease-causing Neisseria meningitidis isolates, United Kingdom, 2010–2016

In September 2015, 4CMenB meningococcal vaccine was introduced into the United Kingdom infant immunization program without phase 3 trial information. Understanding the effect of this program requires enhanced surveillance of invasive meningococcal disease (IMD) Neisseria meningitidis isolates and comparison with prevaccination isolates. Bexsero Antigen Sequence Types (BASTs) were used to analyze whole-genome sequences of 3,073 prevaccine IMD N. meningitidis isolates obtained during 2010−2016. Isolates exhibited 803 BASTs among 31 clonal complexes. Frequencies of antigen peptide variants were factor H binding protein 1, 13.4%; Neisserial heparin-binding antigen 2, 13.8%; Neisseria adhesin A 8, 0.8%; and Porin A-VR2:P1.4,10.9%. In 2015−16, serogroup B isolates showed the highest proportion (35.7%) of exact matches to >1 Bexsero components. Serogroup W isolates showed the highest proportion (93.9%) of putatively cross-reactive variants of Bexsero antigens. Results highlighted the likely role of cross-reactive antigens. BAST surveillance of meningococcal whole-genome sequence data is rapid, scalable, and portable and enables international comparisons of isolates

Assessing the magnitude and uncertainties of the burden of selected diseases attributable to extreme heat and extreme precipitation under a climate change scenario in Michigan for the period 2041–2070

Abstract Background Extreme heat (EH) and extreme precipitation (EP) events are expected to increase with climate change in many parts of the world. Characterizing the potential future morbidity and mortality burden of EH and EP and associated costs, as well as uncertainties in the estimates, can identify areas for public health intervention and inform adaptation strategies. We demonstrate a burden of disease and uncertainty assessment using data from Michigan, USA, and provide approaches for deriving these estimates for locations lacking certain data inputs. Methods Case-crossover analysis adapted from previous Michigan-specific modeling was used to characterize the historical EH-mortality relationship by county poverty rate and age group. Historical EH-associated hospitalization and emergency room visit risks from the literature were adapted to Michigan. In the U.S. Environmental Protection Agency’s BenMAP software, we used a novel approach, with multiple spatially-varying exposures, to estimate all non-accidental mortality and morbidity occurring on EH days (EH days; days where maximum temperature 32.2–35 C or > 35 C) and EP days. We did so for two time periods: the “historical” period (1971–2000), and the “projected” period (2041–2070), by county. Results The rate of all non-accidental mortality associated with EH days increased from 0.46/100,000 persons historically to 2.9/100,000 in the projected period, for 240 EH-attributable deaths annually. EH-associated ED visits increased from 12/100,000 persons to 68/100,000 persons, for 7800 EH-attributable emergency department visits. EP-associated ED visits increased minimally from 1.7 to 1.9/100,000 persons. Mortality and morbidity were highest among those aged 65+ (91% of all deaths). Projected health costs are dominated by EH-associated mortality ($280 million) and EH-associated emergency department visits ($14 million). A variety of sources contribute to a moderate-to-high degree of uncertainty around the point estimates, including uncertainty in the magnitude of climate change, population composition, baseline health rates, and exposure-response estimates. Conclusions The approach applied here showed that health burden due to climate may significantly rise for all Michigan counties by midcentury. The costs to health care and uncertainties in the estimates, given the potential for substantial attributable burden, provide additional information to guide adaptation measures for EH and EP.https://deepblue.lib.umich.edu/bitstream/2027.42/148825/1/12940_2019_Article_483.pd

The application of retinal fundus camera imaging in dementia:A systematic review

INTRODUCTION: The ease of imaging the retinal vasculature, and the evolving evidence suggesting this microvascular bed might reflect the cerebral microvasculature, presents an opportunity to investigate cerebrovascular disease and the contribution of microvascular disease to dementia with fundus camera imaging. METHODS: A systematic review and meta-analysis was carried out to assess the measurement of retinal properties in dementia using fundus imaging. RESULTS: Ten studies assessing retinal properties in dementia were included. Quantitative measurement revealed significant yet inconsistent pathologic changes in vessel caliber, tortuosity, and fractal dimension. Retinopathy was more prevalent in dementia. No association of age-related macular degeneration with dementia was reported. DISCUSSION: Inconsistent findings across studies provide tentative support for the application of fundus camera imaging as a means of identifying changes associated with dementia. The potential of fundus image analysis in differentiating between dementia subtypes should be investigated using larger well-characterized samples. Future work should focus on refining and standardizing methods and measurements

Risk of hospitalisation with fever following MenB vaccination : self-controlled case series analysis

OBJECTIVE: To investigate a possible association between fever admissions and 4 component Meningococcal B (4CMenB). DESIGN: 4CMenB is given at 8 and 16 weeks in the first year of life. Self-controlled case series using linked routinely collected healthcare data, where the risk period was the 3 days immediately following receipt of a vaccine dose. PATIENTS: Children aged under 1 year in Scotland preintroduction and postintroduction of 4CMenB vaccine (pre-September 2014 to August 2015 and post-September 2015 to June 2016). MAIN OUTCOME MEASURES: Hospitalisations for fever attributable to 4CMenB vaccine. RESULTS: The postintroduction model showed an increased risk in the 3 days after dose 1 (relative incidence (RI), 10.78; 95% CI: 8.31 to 14.00) and dose 3 (RI, 9.80; 95% CI: 7.10 to 13.62), with a smaller increased risk after dose 2 (RI, 2.20; 95% CI: 1.27 to 3.82). The magnitude of these effects was greater than in the preintroduction model. The attributable fractions were 90.7%, 54.8% and 89.7%, equating to 162, 14 and 84 vaccine attributable cases per 100 000 doses, respectively.This is equivalent to 102 extra hospitalisations in Scotland annually, based on a birth cohort of 55 100 and extrapolated to 1430 across the UK based on a birth cohort of 777 165. CONCLUSION: There is an increased risk of hospital admission with fever within 3 days of the routine childhood immunisations at 8 and 16 weeks following introduction of 4CMenB vaccine. The results indicate that further understanding of the current use of prophylactic paracetamol is needed. Communication to parents and health professionals may also need to be re-examined, and guidance on the use of prophylactic paracetamol reinforced

New thiophene-based conjugated macrocycles for optoelectronic applications

GC acknowledges the EPSRC for funding (EP/E036244/1). JMS acknowledges the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 for PhD funding. JMS also acknowledges Dr Nor Basid Adiwibawa Prasetya for helpful advice. Dr L. K. Jagadamma acknowledges support from a Marie Skłodowska-Curie Individual Fellowship (European Commission) (MCIF: No. 745776).Thiophene-based semiconductors are amongst the most successful materials in organic electronics. In this contribution, we present the synthesis and characterisation of two thiophene-based macrocycles as well as their evaluation in organic-electronic devices. McT-1 is composed of ten thiophene moieties, whereas in McT-2, four additional electron-deficient benzothiadiazole moieties are incorporated to form a donor–acceptor (D–A) π-system. Red-shifted and broadened absorption spectra as well as more positive redox potentials are observed in McT-2, whereas McT-1 displays a sharper absorption band with a higher extinction coefficient. Macrocycle McT-1 shows emission in the yellow region whereas McT-2 displays emission in the red wavelength region. DFT calculations predict the macrocycles to comprise of mainly the E,E isomers with a near-planar structure, which is further supported by the single crystal X-ray structure for McT-1. Their charge transporting properties are determined by fabricating thin-film OFETs. The photovoltaic properties of McT-1 and McT-2 are also investigated by fabricating bulk heterojunction (BHJ) devices and their potential as photodetectors has been evaluated.Publisher PDFPeer reviewe

The Changing Face of Water: A Dynamic Reflection of Antibiotic Resistance Across Landscapes

Little is known about the role of surface water in the propagation of antibiotic resistance (AR), or the relationship between AR and water quality declines. While healthcare and agricultural sectors are considered the main contributors to AR dissemination, few studies have been conducted in their absence. Using linear models and Bayesian kriging, we evaluate AR among Escherichia coli water isolates collected bimonthly from the Chobe River in Northern Botswana (n = 1997, n = 414 water samples; July 2011–May 2012) in relation to water quality dynamics (E. coli, fecal coliform, and total suspended solids), land use, season, and AR in wildlife and humans within this system. No commercial agricultural or large medical facilities exist within this region. Here, we identify widespread AR in surface water, with land use and season significant predicators of AR levels. Mean AR was significantly higher in the wet season than the dry season (p = 0.003), and highest in the urban landscape (2.15, SD = 0.098) than the protected landscape (1.39, SD = 0.051). In-water E. coli concentrations were significantly positively associated with mean AR in the wet season (p < 0.001) but not in the dry season (p = 0.110), with TSS negatively associated with mean AR across seasons (p = 0.016 and p = 0.029), identifying temporal and spatial relationships between water quality variables and AR. Importantly, when human, water, and wildlife isolates were examined, similar AR profiles were identified (p < 0.001). Our results suggest that direct human inputs are sufficient for extensive dispersal of AR into the environment, with landscape features, season, and water quality variables influencing AR dynamics. Focused and expensive efforts to minimize pollution from agricultural sources, while important, may only provide incremental benefits to the management of AR across complex landscapes. Controlling direct human AR inputs into the environment remains a critical and pressing challenge

Breast-cancer adjuvant therapy with zoledronic acid

Background: Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. Methods: In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. Results: At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths — 243 in the zoledronic acid group and 276 in the control group — were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. Conclusions: These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.