Multidrug resistance protein 1 (MRP1) (gene symbol ABCC1) is an ATP-binding cassette (ABC) transporter which effluxes xeno- and endobiotic organic anions including estradiol glucuronide and the ...pro-inflammatory leukotriene C4. MRP1 also confers multidrug resistance by reducing intracellular drug accumulation through active efflux. MRP1 has three membrane spanning domains (MSD), and two nucleotide binding domains (NBD). MSD1 and MSD2 are linked to NBD1 and NBD2 by connecting regions (CR) 1 and CR2, respectively. Here we targeted four residues in CR1 (Ser612, Arg615, His622, Glu624) for alanine substitution and unexpectedly, found that cellular levels of three mutants (S612A, R615A, E624A) in transfected HEK cells were substantially lower than wild-type MRP1. Whereas CR1-H622A properly trafficked to the plasma membrane and exhibited organic anion transport activity comparable to wild-type MRP1, the poorly expressing R615A and E624A (and to a lesser extent S612A) mutant proteins were retained intracellularly. Analyses of cryogenic electron microscopic and atomic homology models of MRP1 indicated that Arg615 and Glu624 might participate in bonding interactions with nearby residues to stabilize expression of the transporter. However, this was not supported by double exchange mutations E624K/K406E, R615D/D430R and R615F/F619R which failed to improve MRP1 levels. Nevertheless, these experiments revealed that the highly conserved CR1-Phe619 and distal Lys406 in the first cytoplasmic loop of MSD1 are also essential for expression of MRP1 protein. This study is the first to demonstrate that CR1 contains several highly conserved residues critical for plasma membrane expression of MRP1 but thus far, currently available structures and models do not provide any insights into the underlying mechanism(s). Additional structures with rigorous biochemical validation data are needed to fully understand the bonding interactions critical to stable expression of this clinically important ABC transporter.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cannabis is commonly used among people who drink alcohol, yet evidence on acute effects of co-use is conflicting. Two important variables that may influence the effects of cannabis and alcohol are ...cannabinoid content (i.e., the ratio of cannabidiol CBD and 9-tetrahydrocannabinol THC) as well as the order of use (i.e., cannabis before alcohol vs. alcohol before cannabis). Research is mixed regarding the acute imapct of cannabis on alcohol consumption and intoxication, with some studies suggesting additive effects of alcohol and cannabis, and others demonstrating negligible effects of combining these substances. Further complicating this, high-THC-content cannabis concentrates are increasingly popular on the legal-market, but to our knowledge, no studies have explored concentrate and alcohol co-use. In addition to cannabinoid content, order of use may influence intoxication and other acute effects, but is also understudied. Co-use studies typically administer a fixed dose of alcohol before cannabis, and there is a lack of data on the acute effects of cannabis before alcohol. Thus, there is a need for experimental co-use studies exploring the impact of cannabinoid content (particularly of highly potent cannabis concentrates) and order effects on intoxication. This study uses a federally-compliant mobile laboratory procedure to explore the effects of co-administration of legal-market cannabis concentrates with a moderate alcohol dose (.8g/kg) in a sample of community participants who regularly use alcohol and cannabis. The study will also explore alcohol and cannabis order effects (cannabis before alcohol vs. alcohol before cannabis). Outcomes are objective intoxication (measured using blood cannabinoid level, heart rate, psychomotor performance and breath alcohol level BrAC) and subjective intoxication (assessed via self-report measures). Overall, this study may influence harm-reduction recommendations for individuals who drink alcohol and use cannabis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The measurement of stable isotope values of individual compounds, such as amino acids (AAs), has become a powerful tool in animal ecology and ecophysiology. As with any emerging technique, questions ...remain regarding the capabilities and limitations of this approach, including how metabolism and tissue synthesis impact the isotopic values of individual AAs and subsequent multivariate patterns. We measured carbon isotope (
δ
13
C) values of essential (AA
ESS
) and nonessential (AA
NESS
) AAs in bone collagen, whisker, muscle, and liver from ten southern sea otters (
Enhydra lutris nereis
) that stranded in Monterey Bay, California. Sea otters in this population exhibit high degrees of individual dietary specialization, making this an excellent dataset to explore differences in AA
δ
13
C values among tissues in a wild population. We found the
δ
13
C values of the AA
NESS
glutamic acid, proline, serine, and glycine and the AA
ESS
threonine differed significantly among tissues, indicating possible isotopic discrimination during tissue synthesis. Threonine
δ
13
C values were higher in liver relative to bone collagen and muscle, which may indicate catabolism of threonine for gluconeogenesis, an interpretation further supported by correlations between the
δ
13
C values of threonine and its gluconeogenic products glycine and serine in liver. This intraindividual isotopic variation yielded different ecological interpretations among tissues; for 6/10 of the sea otter individuals analyzed, at least one tissue indicated reliance on a different primary producer source than the other tissues. Our results highlight the importance of gluconeogenesis in a carnivorous marine mammal and indicate that metabolic processes influence AA
ESS
and AA
NESS
δ
13
C values and multivariate AA
δ
13
C patterns.
AbstractObjectiveTo use data from the Global Burden of Disease Study between 1990 and 2017 to report the rates and trends of point prevalence, annual incidence, and years lived with disability for ...neck pain in the general population of 195 countries.DesignSystematic analysis.Data sourceGlobal Burden of Diseases, Injuries, and Risk Factors Study 2017.Main outcome measuresNumbers and age standardised rates per 100 000 population of neck pain point prevalence, annual incidence, and years lived with disability were compared across regions and countries by age, sex, and sociodemographic index. Estimates were reported with uncertainty intervals.ResultsGlobally in 2017 the age standardised rates for point prevalence of neck pain per 100 000 population was 3551.1 (95% uncertainty interval 3139.5 to 3977.9), for incidence of neck pain per 100 000 population was 806.6 (713.7 to 912.5), and for years lived with disability from neck pain per 100 000 population was 352.0 (245.6 to 493.3). These estimates did not change significantly between 1990 and 2017. The global point prevalence of neck pain in 2017 was higher in females compared with males, although this was not significant at the 0.05 level. Prevalence increased with age up to 70-74 years and then decreased. Norway (6151.2 (95% uncertainty interval 5382.3 to 6959.8)), Finland (5750.3 (5058.4 to 6518.3)), and Denmark (5316 (4674 to 6030.1)) had the three highest age standardised point prevalence estimates in 2017. The largest increases in age standardised point prevalence estimates from 1990 to 2017 were in the United Kingdom (14.6% (10.6% to 18.8%)), Sweden (10.4% (6.0% to 15.4%)), and Kuwait (2.6% (2.0% to 3.2%)). In general, positive associations, but with fluctuations, were found between age standardised years lived with disability for neck pain and sociodemographic index at the global level and for all Global Burden of Disease regions, suggesting the burden is higher at higher sociodemographic indices.ConclusionsNeck pain is a serious public health problem in the general population, with the highest burden in Norway, Finland, and Denmark. Increasing population awareness about risk factors and preventive strategies for neck pain is warranted to reduce the future burden of this condition.
Kelp forests are highly productive coastal habitats that serve as biodiversity hotspots and provide valuable ecosystem services. Despite being one the largest marine biomes, kelp forests have been ...drastically understudied relative to other marine systems. Notably, while the role of kelp as habitat‐forming, or ‘foundation species', is well‐documented, a comprehensive understanding of kelp forest food web structure is lacking, particularly regarding the importance of kelp‐derived energy/nutrients to consumers. Here, we provide a biogeographic perspective on the energetic underpinning of kelp forests based on published literature. We targeted studies which used geochemical proxies – stable isotope analysis – to examine the transfer of carbon from kelp to local consumers. These studies (n = 94) were geographically skewed, with > 40% from Northern European Seas and Temperate Northeast Pacific. Quantitative estimates for the percentage of kelp energy (or kelp + macroalgae if sources were pooled) incorporated by local consumers came from 43 publications, which studied 141 species and 35 broader taxonomic groups. We examined these data for trends among functional groups and across upwelling regimes. No patterns are evident at present, perhaps due to the paucity or variability of available data. However, energetic subsides from kelps clearly support a wide range of diverse taxa around the globe. We also characterized biogeographic patterns in δ13C values of kelps and particulate organic matter (POM, a phytoplankton proxy), to evaluate potential limitations of stable isotope analysis in disentangling the relative contributions of pelagic versus benthic resources to coastal food webs. Globally, kelps and POM differed by > 4.5‰, but there was substantial variation among regions and kelp species. Accordingly, we discuss advances in stable isotope techniques which are facilitating more precise analysis of these complex energetic pathways. We end by proposing four main avenues of critical future research that will shed light on the resilience of these communities to global change.
To estimate the global burden of neck pain.
Neck pain was defined as pain in the neck with or without pain referred into one or both upper limbs that lasts for at least 1 day. Systematic reviews were ...performed of the prevalence, incidence, remission, duration and mortality risk of neck pain. Four levels of severity were identified for neck pain with and without arm pain, each with their own disability weights. A Bayesian meta-regression method was used to pool prevalence and derive missing age/sex/region/year values. The disability weights were applied to prevalence values to derive the overall disability of neck pain expressed as years lived with disability (YLDs). YLDs have the same value as disability-adjusted life years as there is no evidence of mortality associated with neck pain.
The global point prevalence of neck pain was 4.9% (95% CI 4.6 to 5.3). Disability-adjusted life years increased from 23.9 million (95% CI 16.5 to 33.1) in 1990 to 33.6 million (95% CI 23.5 to 46.5) in 2010. Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, neck pain ranked 4th highest in terms of disability as measured by YLDs, and 21st in terms of overall burden.
Neck pain is a common condition that causes substantial disability. With aging global populations, further research is urgently needed to better understand the predictors and clinical course of neck pain, as well as the ways in which neck pain can be prevented and better managed.
Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent ...state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.
Gout is the most common cause of inflammatory arthritis in men, but has not previously been included in Global Burden of Disease (GBD) studies. As part of the GBD 2010 Study, the Musculoskeletal ...Disorders and Risk Factors Expert Group estimated the global burden of gout.
The American Rheumatism Association 1977 case definition of primary gout was used in the study. A series of systematic reviews were conducted to gather the age-specific and sex-specific epidemiological data for gout prevalence, incidence, mortality risk and duration. Two main disabling sequelae of gout were identified; acute episode gout and chronic polyarticular gout, and used in the surveys to collect data to derive disability weights. The epidemiological data together with disability weights were then used to calculate years of life lived with disability (YLDs) for gout, for 1990 and 2010. No evidence of cause-specific mortality associated with gout was found. Gout disability-adjusted life years (DALYs), therefore, have the same value as YLDs.
Global prevalence of gout was 0.08% (95% uncertainty interval (UI) 0.07 to 0.08). DALYs increased from 76 000 (95% UI 48 to 112) in 1990 to 114 000 (95% UI 72 to 167) in 2010. Out of all 291 conditions studied in the GBD 2010 Study, gout ranked 138th in terms of disability as measured by YLDs, and 173rd in terms of overall burden (DALYs).
The burden of gout is rising. With increasing ageing populations globally, this evidence is a significant prompt to optimise treatment and management of gout at individual, community and national levels.
Thumbs up: A method of fingerprinting that enables both identification of an individual and simultaneous determination of the chemical makeup of the sweat deposited in the fingerprint has been ...determined. Potential applications of this methodology are enormous as the functionalization of nanoparticles with other antibodies enables the specific detection of numerous antigens within a fingerprint.
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