Long Inversely Oriented Subunits Form a Complex Monomer of Tribolium brevicornis Satellite DNA

Highly abundant satellite DNA named TBREV is detected and characterized in the beetle Tribolium brevicornis (Insecta: Coleoptera). An outstanding peculiarity of the TBREV satellite monomer is its complex structure based on the two 470-bp-long subunits, inversely oriented within a 1061-bp-long monomer sequence. The proposed evolutionary history demonstrates a clear trend toward increased complexity and length of the TBREV satellite monomer. This tendency has been observed on three levels: first as direct and inverted duplications of short sequence motifs, then by inverse duplication of the 470-bp sequence segment, and, finally, by spread of inversely duplicated elements in a higher-order register and formation of extant monomers. Inversely oriented subunits share a similarity of 82% and have a high capacity to form a thermodynamically stable dyad structure that is, to our knowledge, the longest ever described in any satellite monomer. Analysis of divergences between inversely oriented subunits shows a tendency to a further reduction in similarity between them. Except in its centromeric localization, the TBREV satellite does not show similarity to other known Tribolium satellites, either in nucleotide sequence or in monomer length and complexity. However, TBREV shares common features of other Tribolium satellites that might be under functional constraints: nonconstant rate of evolution along the monomer sequence, short inverted repeats in the vicinity of an A+T tract, nonrandom distribution of A or T 3 tracts, and CENP-B box-like motifs. Although long inverted subunits might reinforce structural characteristics of the satellite monomer, their nucleotide sequence does not seem to be under constraints in order to preserve the dyad structure. Reviewing Editor: Dr. Willie Swanson     

Treatment-seeking practices for malaria in pregnancy among rural women in Mukono district, Uganda

Understanding treatment-seeking practices for malaria in pregnancy is necessary in designing effective programmes to address the high malaria morbidity in pregnancy. This study assessed women's perceptions on malaria in pregnancy, recognition of early signs of pregnancy and of malaria, and the cultural context in which treatment seeking takes place in Mukono District. Focus group discussions (FGD) and key informant interviews were conducted among pregnant women, non-pregnant women, adolescents and men. The results showed that malaria, locally known as omusujja, was perceived as the most common cause of ill health among pregnant women. Although malaria commonly presents with fever, some pregnant women feel hot in the womb with or without signs of fever and this illness, locally known as nabuguma, may lead to progressive weakness and occasionally to miscarriage and few respondents associated it with malaria. Primigravidae, adolescents and men were not considered at risk of omusujja or nabuguma. Similarly anaemia and low birth weight were not associated with malaria; in fact paleness was described as a normal sign of pregnancy. There are cultural and social pressures on married women to get pregnant and this forces them to conceal symptoms like feeling feverishness, backache, nausea, general weakness, loss of appetite and vomiting until they are sure these are due to pregnancy. Most women, however, could not differentiate symptoms of malaria from those of early pregnancy. There is a belief that omusujja is a normal sign of pregnancy and this is coupled with a strong cultural practice of using herbs and clays as a first resort to treat pregnancy ailments including malaria. The cultural beliefs and practices regarding delivery of twin and first births, coupled with the high cost of care, prevent women from delivering and using other services at health units.     

Timing of malaria messages for target audience on radio airwaves

ABSTRACT: BACKGROUND: Due to the limitations of face-to-face communication to teach families how to manage, control and prevent malaria, national and local malaria programmes try to reach people through the radio. However, information regarding the timing of radio messages for the target audiences is lacking. METHODS: Within a large-scale trial (Clinicaltrials.gov: NCT00565071), data regarding the time at which people listen to the radio was collected from 1,628 consenting outpatients (and caregivers for minors) attending six rural government primary level health care centres in Bushenyi and Iganga districts of Uganda from February to July 2011. RESULTS: The majority of households, 1,099 (67.5%) owned a radio. The majority, 1,221 (86.3%), participants had heard about malaria from the radio. Some participants started listening to the radio at about 06.00 East African local time (EAT). The peak hours at which people listen to the radio are 12.00-14.00 and 18.00-23.00 local time. The median time of listening to the radio by men is 20.00 (inter-quartile range (IQR): 18.30-21.00) and women 19.30 (IQR: 13.00-20.30). CONCLUSION: Planners of malaria radio interventions need to broadcast their messages within the two peak EAT of 12.00-14.00 and 18.00-23.00.     

High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy

Notoriously resistant malignant melanoma is one of the most increasing forms of cancer worldwide; there is thus a precarious need for new treatment options. The Wee1 kinase is a major regulator of the G(2)/M checkpoint, and halts the cell cycle by adding a negative phosphorylation on CDK1 (Tyr15). Additionally, Wee1 has a function in safeguarding the genome integrity during DNA synthesis. To assess the role of Wee1 in development and progression of malignant melanoma we examined its expression in a panel of paraffin-embedded patient derived tissue of benign nevi and primary- and metastatic melanomas, as well as in agarose-embedded cultured melanocytes. We found that Wee1 expression increased in the direction of malignancy, and showed a strong, positive correlation with known biomarkers involved in cell cycle regulation: Cyclin A (p<0.0001), Ki67 (p<0.0001), Cyclin D3 (p = 0.001), p21(Cip1/WAF1) (p = 0.003), p53 (p = 0.025). Furthermore, high Wee1 expression was associated with thicker primary tumors (p = 0.001), ulceration (p = 0.005) and poor disease-free survival (p = 0.008). Transfections using siWee1 in metastatic melanoma cell lines; WM239(WTp53), WM45.1(MUTp53) and LOX(WTp53), further support our hypothesis of a tumor promoting role of Wee1 in melanomas. Whereas no effect was observed in LOX cells, transfection with siWee1 led to accumulation of cells in G(1)/S and S phase of the cell cycle in WM239 and WM45.1 cells, respectively. Both latter cell lines displayed DNA damage and induction of apoptosis, in the absence of Wee1, indicating that the effect of silencing Wee1 may not be solely dependent of the p53 status of the cells. Together these results reveal the importance of Wee1 as a prognostic biomarker in melanomas, and indicate a potential role for targeted therapy, alone or in combination with other agents.     

Global assessment of experimental climate warming on tundra vegetation: heterogeneity over space and time

Understanding the sensitivity of tundra vegetation to climate warming is critical to forecasting future biodiversity and vegetation feedbacks to climate. In situ warming experiments accelerate climate change on a small scale to forecast responses of local plant communities. Limitations of this approach include the apparent site-specificity of results and uncertainty about the power of short-term studies to anticipate longer term change. We address these issues with a synthesis of 61 experimental warming studies, of up to 20 years duration, in tundra sites worldwide. The response of plant groups to warming often differed with ambient summer temperature, soil moisture and experimental duration. Shrubs increased with warming only where ambient temperature was high, whereas graminoids increased primarily in the coldest study sites. Linear increases in effect size over time were frequently observed. There was little indication of saturating or accelerating effects, as would be predicted if negative or positive vegetation feedbacks were common. These results indicate that tundra vegetation exhibits strong regional variation in response to warming, and that in vulnerable regions, cumulative effects of long-term warming on tundra vegetation - and associated ecosystem consequences - have the potential to be much greater than we have observed to date.     

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.     

3-Acrylamide-4-aryloxyindoles: Synthesis,biological evaluation and metabolic stability of potent and selective EP3 receptor antagonists

A series of potent and selective EP₃ receptor antagonists are described. Utilizing a pharmacophore model developed for the EP₃ receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.     

Temperature effects on fish production across a natural thermal gradient

Global warming is widely predicted to reduce the biomass production of top predators, or even result in species loss. Several exceptions to this expectation have been identified, however, and it is vital that we understand the underlying mechanisms if we are to improve our ability to predict future trends. Here, we used a natural warming experiment in Iceland and quantitative theoretical predictions to investigate the success of brown trout as top predators across a stream temperature gradient (4–25 °C). Brown trout are at the northern limit of their geographic distribution in this system, with ambient stream temperatures below their optimum for maximal growth, and above it in the warmest streams. A five‐month mark‐recapture study revealed that population abundance, biomass, growth rate, and production of trout all increased with stream temperature. We identified two mechanisms that contributed to these responses: (1) trout became more selective in their diet as stream temperature increased, feeding higher in the food web and increasing in trophic position; and (2) trophic transfer through the food web was more efficient in the warmer streams. We found little evidence to support a third potential mechanism: that external subsidies would play a more important role in the diet of trout with increasing stream temperature. Resource availability was also amplified through the trophic levels with warming, as predicted by metabolic theory in nutrient‐replete systems. These results highlight circumstances in which top predators can thrive in warmer environments and contribute to our knowledge of warming impacts on natural communities and ecosystem functioning.