Transcriptional and post-translational regulation of pannexins Boyce, Andrew K.J.; Epp, Anna L.; Nagarajan, Archana ...
Biochimica et biophysica acta. Biomembranes,
January 2018, 2018-Jan, 2018-01-00, 20180101, Volume:
1860, Issue:
1
Journal Article
Peer reviewed
Open access
Pannexins are a 3-membered family of proteins that form large pore ion and metabolite channels in vertebrates. The impact of pannexins on vertebrate biology is intricately tied to where and when they ...are expressed, and how they are modified, once produced. The purpose of this review is therefore to outline our current understanding of transcriptional and post-translational regulation of pannexins. First, we briefly summarize their discovery and characteristics. Next, we describe several aspects of transcriptional regulation, including cell and tissue-specific expression, dynamic expression over development and disease, as well as new insights into the underlying molecular machinery involved. Following this, we delve into the role of post-translational modifications in the regulation of trafficking and channel properties, highlighting important work on glycosylation, phosphorylation, S-nitrosylation and proteolytic cleavage. Embedded throughout, we also highlight important knowledge gaps and avenues of future research. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
•The discovery, topology and oligomerization of pannexin channels•Cell and tissue distribution; dynamic expression during development and disease•Post-translational modifications affecting pannexin trafficking and function
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The neural protein α-synuclein aggregates both in vivo and in vitro to form insoluble fibrils that are involved in Parkinson's disease pathogenesis. We have generated α-synuclein/fluorescent-protein ...fusion constructs overexpressed in muscle cells of the nematode, Caenorhabdtis elegans. Green Fluorescent Protein (GFP) variants, Cerulean (C) or Venus (V), were fused to the C-terminus of human α-synuclein (S); the resultant fusion genes were designated SV and SC, plus a CV fusion as well as S, C and V singly. The aggregation behavior of the purified fusion proteins (expressed in E. coli) will be described elsewhere. These constructs were fused to a C. elegans unc-54 myosin promoter, and integrated transgenic lines generated by microinjection, λ-irradiation, and outcrossing of fluorescent progeny. All transgenic lines expressing α- synuclein showed significant reductions (p <0.05) in lifespan, motility and pharyngeal pumping, as compared to wildtype worms or lines expressing CFP and/or YFP only. We showed that CFP and YFP labels colocalised in granular inclusions throughout the body wall in transgenic lines expressing both SC and SV fusions (SC+SV), whereas SV+C worms displayed YFP-labelled inclusions on a diffuse CFP background. These findings implied that the α-synuclein moieties of these fusion proteins still aggregated together in vivo, whereas CFP or YFP moieties alone did not. This in turn suggested that Foerster Resonanace Energy Transfer (FRET) between CFP and YFP labels in α-synuclein aggregates could allow the extent of aggregation to be quantified. Accordingly, we also showed that net FRET signals increased 2- fold between L4 and adult SC+SV worms.
Lyme borreliosis (LB) is the most prevalent tick-borne disease in Europe and the incidence of LB is increasing owing to an expansion in tick habitats. However, LB surveillance is quite heterogeneous ...across the continent, and for those countries with publicly available data, it is difficult to understand the differences in incidence between countries. The objective of our study was to summarize the publicly available data from surveillance for LB in the form of surveillance reports and/or dashboards and to compare the information available for various countries.
We identified publicly available LB data (online dashboards and surveillance reports) in the European Union, European Economic Area, the United Kingdom, Russia, and Switzerland.
Of the 36 countries studied, 28 had LB surveillance in place; 23 had surveillance reports, and 10 had dashboards. The dashboards, in general, had more granular data compared with the surveillance reports, but the reports covered longer time periods. LB annual cases, incidence, age, and sex-stratified LB data; manifestations; and regional data were available for most of the countries. LB case definitions varied significantly among the countries.
The study highlights large differences in LB surveillance systems, including representativeness, case definitions, type of data available that might inhibit comparison of data between countries and accurate determination of burden of disease, and risk groups within countries. Standardization of case definitions across countries would be a useful first step enabling comparisons between countries and contribute to recognizing the true burden of LB in Europe.
Background
It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or ...Alzheimer's disease (AD).
Methods
We performed a meta‐analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow‐up available. BMD was measured at the hip femoral neck using dual‐energy X‐ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline (“baseline BMD”) and annualized percentage change in BMD prior to baseline (“prior bone loss”) were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education.
Results
The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta‐analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23–0.96; p = 0.038) per increase in g/cm2, or 0.91 (95% CI: 0.84–0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12–1.51; p < 0.001) per percent increase in prior bone loss only in the FHS cohort.
Conclusions
Baseline BMD but not prior bone loss was associated with incident dementia in a meta‐analysis across three studies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Progressive neurodegenerative diseases are among the most frequently occurring aging-associated human pathologies. In a screen for Caenorhabditis elegans mutant animals that lack their normal ...complement of dopaminergic neurons, we identified two strains with progressive loss of dopaminergic neurons during postembryonic life. Through whole-genome sequencing we show that both strains harbor dominant (d), gain-of-function mutations in the Transient Receptor Potential (TRP) mechanosensory channel trp-4, a member of the invertebrate and vertebrate TRPN-type of the TRP family channels. Gain-of-function mutations in TRP channels have not been previously implicated in dopaminergic neuronal degeneration. We show that trp-4(d) induces cell death in dopamine neurons through a defined, calcium-related downstream pathway.
Multiple experimental evolution studies on
Drosophila melanogaster
in the 1980s and 1990s indicated that enhanced competitive ability evolved primarily through increased larval tolerance to ...nitrogenous wastes and increased larval feeding and foraging rate, at the cost of efficiency of food conversion to biomass, and this became the widely accepted view of how adaptation to larval crowding evolves in fruitflies. We recently showed that populations of
D. ananassae
and
D. n. nasuta
subjected to extreme larval crowding evolved greater competitive ability without evolving higher feeding rates, primarily through a combination of reduced larval duration, faster attainment of minimum critical size for pupation, greater efficiency of food conversion to biomass, increased pupation height and, perhaps, greater urea/ammonia tolerance. This was a very different suite of traits than that seen to evolve under similar selection in
D. melanogaster
and was closer to the expectations from the theory of
K
-selection. At that time, we suggested two possible reasons for the differences in the phenotypic correlates of greater competitive ability seen in the studies with
D. melanogaster
and the other two species. First, that
D. ananassae
and
D. n. nasuta
had a very different genetic architecture of traits affecting competitive ability compared to the long-term laboratory populations of
D. melanogaster
used in the earlier studies, either because the populations of the former two species were relatively recently wild-caught, or by virtue of being different species. Second, that the different evolutionary trajectories in
D. ananassae
and
D. n. nasuta
versus
D. melanogaster
were a reflection of differences in the manner in which larval crowding was imposed in the two sets of selection experiments. The
D. melanogaster
studies used a higher absolute density of eggs per unit volume of food, and a substantially larger total volume of food, than the studies on
D. ananassae
and
D. n. nasuta
. Here, we show that long-term laboratory populations of
D. melanogaster
, descended from some of the populations used in the earlier studies, evolve essentially the same set of traits as the
D. ananassae
and
D. n. nasuta
crowding-adapted populations when subjected to a similar larval density at low absolute volumes of food. As in the case of
D. ananassae
and
D. n. nasuta
, and in stark contrast to earlier studies with
D. melanogaster
, these crowding-adapted populations of
D. melanogaster
did not evolve greater larval feeding rates as a correlate of increased competitive ability. The present results clearly suggest that the suite of phenotypes through which the evolution of greater competitive ability is achieved in fruitflies depends critically not just on larval density per unit volume of food, but also on the total amount of food available in the culture vials. We discuss these results in the context of an hypothesis about how larval density and the height of the food column in culture vials might interact to alter the fitness costs and benefits of increased larval feeding rates, thus resulting in different routes to the evolution of greater competitive ability, depending on the details of exactly how the larval crowding was implemented.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In Poland, Lyme borreliosis (LB) has been subject to mandatory public health surveillance since 1996 and, in accordance with EU regulations, Lyme neuroborreliosis has been reported to the European ...Centre for Disease Prevention and Control since 2019. In this study, the incidence, temporal trends, and geographic distribution of LB and its manifestations in Poland are described for the period 2015-2019.
This retrospective incidence study of LB and its manifestations in Poland was based on data sent to the National Institute of Public Health-National Institute of Hygiene-National Research Institute (NIPH-NIH-NRI) by district sanitary epidemiological stations using the electronic Epidemiological Records Registration System and data from the National Database on Hospitalization. Incidence rates were calculated using population data from the Central Statistical Office.
During 2015-2019, Poland reported 94,715 cases of LB with an overall average incidence of 49.3 cases per 100,000 population. Cases increased from 2015 (11,945) to 2016 (20,857) and then remained stable through 2019. Hospitalization due to LB also rose during these years. LB was more common among women (55.7%). Erythema migrans and Lyme arthritis were the most common manifestations of LB. The highest incidence rates occurred among >50-year-olds, with a peak in 65-69-year-olds. The highest number of cases was recorded in the third and fourth quarters of the year (July-December). Incidence rates in the eastern and northeastern regions of the country were higher than the national average.
LB is endemic in all regions of Poland, and many regions reported high incidence rates. Large variations in spatially granular incidence rates highlight the need for targeted prevention strategies.
Abstract
Background
Lyme borreliosis (LB), a tick-borne disease caused by Borrelia burgdorferi sensu lato, has been subject to mandatory public health surveillance since 1996 in Poland. Here, the ...incidence, temporal trends, and geographical distribution of LB and its manifestations in Poland are described for the period 2015-2019.
Methods
This retrospective incidence study of LB and its manifestations in Poland was based on the data sent to the National Institute of Public Health (NIPH-NIH–NRI) by district sanitary-epidemiological stations using the electronic Epidemiological Records Registration System and data from the National Database on Hospitalization. LB and its manifestations were reported in two categories- probable and confirmed (through laboratory tests). Incidence rates were calculated using the population data from the Central Statistical Office of Poland.
Results
In Poland, a total of 94,715 cases of LB with an overall mean incidence of 49.3 cases per 100,000 population were reported between 2015-2019. Cases increased from 2015 (11,945) to 2016 (20,857), and then remained stable through 2019. LB was more common among women (55.7%). The highest incidence rates occurred among >50-year-olds, with a peak in 65-69-year-olds. 48,717 persons with LB were hospitalized in the 5-year period, with higher number of hospitalizations in age groups 55-69 years old. Erythema migrans and Lyme arthritis were the most common manifestations of LB with incidence rates of 36.2 and 15.8 per 100,000 population, respectively. EM accounted for approximately 74% of all manifestations of LB. The highest number of cases were recorded in the 3rd and 4th quarters of the year (July – December). Incidence rates in the East and Northeastern regions (Podlaskie, Lubelskie, and Warmińsko-Mazurskie voivodeships) of the country were higher than the national average. These regions correspond to greater forest cover and/or agricultural areas.
Time trend of LB cases and incidence in Poland, 2015-2019.
Conclusion
LB is endemic in all regions of Poland, and many regions reported high incidence rates. LB is reported year-round in Poland. Thus, large variations in temporal and spatially granular incidence rates highlight the need for targeted prevention strategies, such as vaccines.
Disclosures
Jozica Skufca, Epidemiologist, p95: Paid by Pfizer to perform the study Archana Nagarajan, Ph.D., P95: Paid by Pfizer to perform the study Andreas Pilz, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Andrew Vyse, Ph.D., Pfizer: Stocks/Bonds Elizabeth Begier, M.D., M.P.H., Pfizer: Employee|Pfizer: Stocks/Bonds Mendwas Dzingina, Ph.D., Pfizer: Stocks/Bonds Maxim Blum, Ph.D., P95: Paid by Pfizer to perform the study Margarita Riera, MD, MPH, P95: Paid by Pfizer to perform the study Bradford Gessner, MD, MPH, Pfizer: Stocks/Bonds James Stark, Ph.D., Pfizer: Stocks/Bonds.
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