MicroRNAs Regulate Human Adipocyte Lipolysis: Effects of miR-145 Are Linked to TNF-α

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have multiple effects in various tissues including adipose inflammation, a condition characterized by increased local release of the pro-lipolytic cytokine tumor necrosis factor-alpha (TNF-α). Whether miRNAs regulate adipocyte lipolysis is unknown. We set out to determine whether miRNAs affect adipocyte lipolysis in human fat cells. To this end, eleven miRNAs known to be present in human adipose tissue were over-expressed in human in vitro differentiated adipocytes followed by assessments of TNF-α and glycerol levels in conditioned media after 48 h. Three miRNAs (miR-145, -26a and let-7d) modulated both parameters in parallel. However, while miR-26a and let-7d decreased, miR-145 increased both glycerol release and TNF-α secretion. Further studies were focused therefore on miR-145 since this was the only stimulator of lipolysis and TNF-α secretion. Time-course analysis demonstrated that miR-145 over-expression up-regulated TNF-α expression/secretion followed by increased glycerol release. Increase in TNF-α production by miR-145 was mediated via activation of p65, a member of the NF-κB complex. In addition, miR-145 down-regulated the expression of the protease ADAM17, resulting in an increased fraction of membrane bound TNF-α, which is the more biologically active form of TNF-α. MiR-145 overexpression also increased the phosphorylation of activating serine residues in hormone sensitive lipase and decreased the mRNA expression of phosphodiesterase 3B, effects which are also observed upon TNF-α treatment in human adipocytes. We conclude that miR-145 regulates adipocyte lipolysis via multiple mechanisms involving increased production and processing of TNF-α in fat cells.     

Long-Term Changes in Nutrients and Mussel Stocks Are Related to Numbers of Breeding Eiders Somateria mollissima at a Large Baltic Colony

Background

The Baltic/Wadden Sea eider Somateria mollissima flyway population is decreasing, and this trend is also reflected in the large eider colony at Christiansø situated in the Baltic Sea. This colony showed a 15-fold increase from 1925 until the mid-1990''s, followed by a rapid decline in recent years, although the causes of this trend remain unknown. Most birds from the colony winter in the Wadden Sea, from which environmental data and information on the size of the main diet, the mussel Mytilus edulis stock exists. We hypothesised that changes in nutrients and water temperature in the Wadden Sea had an effect on the ecosystem affecting the size of mussel stocks, the principal food item for eiders, thereby influencing the number of breeding eider in the Christiansø colony.

Methodology/Principal Finding

A positive relationship between the amount of fertilizer used by farmers and the concentration of phosphorus in the Wadden Sea (with a time lag of one year) allowed analysis of the predictions concerning effects of nutrients for the period 1925–2010. There was (1) increasing amounts of fertilizer used in agriculture and this increased the amount of nutrients in the marine environment thereby increasing the mussel stocks in the Wadden Sea. (2) The number of eiders at Christiansø increased when the amount of fertilizer increased. Finally (3) the number of eiders in the colony at Christiansø increased with the amount of mussel stocks in the Wadden Sea.

Conclusions/Significance

The trend in the number of eiders at Christiansø is representative for the entire flyway population, and since nutrient reduction in the marine environment occurs in most parts of Northwest Europe, we hypothesize that this environmental candidate parameter is involved in the overall regulation of the Baltic/Wadden Sea eider population during recent decades.     

Correlation of LMP10 Expression and Clinical Outcome in Human Papillomavirus (HPV) Positive and HPV-Negative Tonsillar and Base of Tongue Cancer

Aim

To examine LMP10 expression and its possible impact on clinical outcome in human papillomavirus (HPV) positive and HPV-negative tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC).

Background

Outcome is better in HPV-positive TSCC and BOTSCC compared to matching HPV-negative tumours, with roughly 80% vs. 40% 5-year disease free survival (DFS) with less aggressive treatment than today’s chemoradiotherapy. Since current treatment often results in harmful side effects, less intensive therapy, with sustained patient survival would be an attractive alternative. However, other markers together with HPV status are necessary to select patients and for this purpose LMP10 expression is investigated here in parallel to HPV status and clinical outcome.

Materials and Methods

From 385 patients diagnosed between 2000 and 2007 at the Karolinska University Hospital, 278 formalin fixed paraffin embedded TSCC and BOTSCC biopsies, with known HPV DNA status, were tested for LMP10 nuclear and cytoplasmic expression (fraction of positive cells and staining intensity). The data was then correlated to clinical outcome.

Results

An absent/low compared to a moderate/high LMP10 nuclear fraction of positive cells was correlated to a better 3-year DFS in the HPV-positive group of patients (log-rank p = 0.005), but not in the HPV-negative group. In the HPV-negative group of patients, in contrast to the HPV-positive group, moderate/high LMP10 cytoplasmic fraction and weak/moderate/high LMP10 cytoplasmic intensity correlated to a better 3-year DFS (p = 0.003 and p = 0.001) and 3-year overall survival (p = 0.001 and 0.009).

Conclusion

LMP10 nuclear expression in the HPV-positive group and LMP10 cytoplasmic expression in the HPV-negative group of patients correlated to better clinical outcome.     

Direct Angiotensin AT2 Receptor Stimulation Using a Novel AT2 Receptor Agonist,Compound 21, Evokes Neuroprotection in Conscious Hypertensive Rats

Background

In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents.

Methods and Results

Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury.

Conclusion

These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development.     

Velocity and Directionality of the Electrohysterographic Signal Propagation

Objective

The initiation of treatment for women with threatening preterm labor requires effective distinction between true and false labor. The electrohysterogram (EHG) has shown great promise in estimating and classifying uterine activity. However, key issues remain unresolved and no clinically usable method has yet been presented using EHG. Recent studies have focused on the propagation velocity of the EHG signals as a potential discriminator between true and false labor. These studies have estimated the propagation velocity of individual spikes of the EHG signals. We therefore focus on estimating the propagation velocity of the entire EHG burst recorded during a contraction in two dimensions.

Study Design

EHG measurements were performed on six women in active labor at term, and a total of 35 contractions were used for the estimation of propagation velocity. The measurements were performed using a 16-channel two-dimensional electrode grid. The estimates were calculated with a maximum-likelihood approach.

Results

The estimated average propagation velocity was 2.18 (±0.68) cm/s. No single preferred direction of propagation was found.

Conclusion

The propagation velocities estimated in this study are similar to those reported in other studies but with a smaller intra- and inter-patient variation. Thus a potential tool has been established for further studies on true and false labor contractions.     

The Dynamics of a Metapopulation: Changes in Life-History Traits in Resident Herring that Co-Occur with Oceanic Herring during Spawning

Different populations of Atlantic herring are regarded as forming a metapopulation, but we know little about the dynamics of the connectivity and degree of interbreeding between the populations. Based on data from three periods between 1962 and 2011, we identified the presence of two components of herring in a small semi-enclosed coastal marine ecosystem based on different somatic growth patterns and mean vertebrae sum (VS). The two components were interpreted as belonging to a resident herring population and the migratory, oceanic Norwegian spring spawning (NSS) herring population, and they co-occurred during spawning. In the 1960s, resident herring characterized by slow growth and low VS co-occurred with rapid growth, high VS oceanic NSS herring. Similar slow-growing resident and rapid-growing NSS herring were found in the 1970–80s, but both populations now had low VS suggesting similar origins. Finally, in the 2000s both populations showed rapid growth. The changes coincided with the NSS herring going from a state of high abundance and oceanic distribution to a collapse in the late 1960s that resulted in a coastal distribution closer to resident herring populations, before full recovery and resumption of the migratory, oceanic pattern in the 1990s. During all three periods, NSS herring were only present in the local system up to an age of about five years, but the synchronous spawning of the populations supports mixed spawning and interbreeding. During the investigation period both longevity, length at age (growth) and length-at-first maturity increased markedly for the resident herring, which then became more similar to the NSS herring. Genetic and/or cultural factors are believed to be the main causes of the observed changes in life history traits, although some effect of changes in environmental factors cannot be excluded. Our study suggests that relationships among populations in a metapopulation can be highly dynamic.     

Strategies for High-Performance Resource-Efficient Compression of Neural Spike Recordings

Brain-machine interfaces (BMIs) based on extracellular recordings with microelectrodes provide means of observing the activities of neurons that orchestrate fundamental brain function, and are therefore powerful tools for exploring the function of the brain. Due to physical restrictions and risks for post-surgical complications, wired BMIs are not suitable for long-term studies in freely behaving animals. Wireless BMIs ideally solve these problems, but they call for low-complexity techniques for data compression that ensure maximum utilization of the wireless link and energy resources, as well as minimum heat dissipation in the surrounding tissues. In this paper, we analyze the performances of various system architectures that involve spike detection, spike alignment and spike compression. Performance is analyzed in terms of spike reconstruction and spike sorting performance after wireless transmission of the compressed spike waveforms. Compression is performed with transform coding, using five different compression bases, one of which we pay special attention to. That basis is a fixed basis derived, by singular value decomposition, from a large assembly of experimentally obtained spike waveforms, and therefore represents a generic basis specially suitable for compressing spike waveforms. Our results show that a compression factor of 99.8%, compared to transmitting the raw acquired data, can be achieved using the fixed generic compression basis without compromising performance in spike reconstruction and spike sorting. Besides illustrating the relative performances of various system architectures and compression bases, our findings show that compression of spikes with a fixed generic compression basis derived from spike data provides better performance than compression with downsampling or the Haar basis, given that no optimization procedures are implemented for compression coefficients, and the performance is similar to that obtained when the optimal SVD based basis is used.     

Hepatitis C Viremia Patterns in Incident Hepatitis C Infection and One Year Later in 150 Prospectively Tested Persons Who Inject Drugs

Objectives

To assess HCV viremia levels just before, during and one year after anti-HCV seroconversion in people who inject drugs (PWID).

Methods

PWID enrolling into a needle exchange program in Malmö, Sweden, 1997–2005 constituted the source population. Sera were obtained at enrolment and at approximately 3–4 monthly intervals afterwards, and were initially tested for anti-HIV, HBsAg/anti-HBc and anti-HCV and thereafter for markers previously negative. Seroconversion to anti-HCV had occurred during the study period in 186 out of 332 seronegative subjects. In these anti-HCV seroconverters, quantitative HCV RNA PCR was retrospectively performed on frozen sera to determine viremia levels in the last anti-HCV negative, the first anti-HCV positive and in one year follow-up samples.

Results

Among 150 subjects seroconverting to anti-HCV with samples available from all three defined time-points, eight different patterns of viremia were observed. Spontaneous clearance at one year was noted in 48 cases (32%) and was associated with female gender (p = 0.03, CI 0.17–1.00). In 13 cases HCV-RNA was not detected in any study sample. Among 61 subjects with pre-seroconversion viremia, viral load was significantly higher in the pre-seroconversion samples compared to subsequent samples. For the whole group, viral load declined to undetectable levels at seroconversion in 28% of cases (but with recurrent viremia in 15%).

Conclusions

Different patterns of HCV RNA kinetics were observed among PWID with documented seroconversion to anti-HCV. The frequently observed absence of detectable HCV RNA in the first anti-HCV positive sample (irrespective of subsequent viremia) demonstrates the importance of repeated sampling and RNA testing for determination of the outcome of acute infection.     

American Exceptionalism: Population Trends and Flight Initiation Distances in Birds from Three Continents

Background

All organisms may be affected by humans'' increasing impact on Earth, but there are many potential drivers of population trends and the relative importance of each remains largely unknown. The causes of spatial patterns in population trends and their relationship with animal responses to human proximity are even less known.

Methodology/Principal Finding

We investigated the relationship between population trends of 193 species of bird in North America, Australia and Europe and flight initiation distance (FID); the distance at which birds take flight when approached by a human. While there is an expected negative relationship between population trend and FID in Australia and Europe, we found the inverse relationship for North American birds; thus FID cannot be used as a universal predictor of vulnerability of birds. However, the analysis of the joint explanatory ability of multiple drivers (farmland breeding habitat, pole-most breeding latitude, migratory habit, FID) effects on population status replicated previously reported strong effects of farmland breeding habitat (an effect apparently driven mostly by European birds), as well as strong effects of FID, body size, migratory habit and continent. Farmland birds are generally declining.

Conclusions/Significance

Flight initiation distance is related to population trends in a way that differs among continents opening new research possibilities concerning the causes of geographic differences in patterns of anti-predator behavior.