Point mutations in c-Myc uncouple neoplastic transformation from multiple other phenotypes in rat fibroblasts

Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state.     

Exoskeletal chitin scales isometrically with body size in terrestrial insects

The skeletal system of animals provides the support for a variety of activities and functions. For animals such as mammals, which have endoskeletons, research has shown that skeletal investment (mass) scales with body mass to the 1.1 power. In this study, we ask how exoskeletal investment in insects scales with body mass. We measured the body mass and mass of exoskeletal chitin of 551 adult terrestrial insects of 245 species, with dry masses ranging from 0.0001 to 2.41 g (0.0002–6.13 g wet mass) to assess the allometry of exoskeletal investment. Our results showed that exoskeletal chitin mass scales isometrically with dry body mass across the Insecta as M_chitin = a M, where b = 1.03 ± 0.04, indicating that both large and small terrestrial insects allocate a similar fraction of their body mass to chitin. This isometric chitin‐scaling relationship was also evident at the taxonomic level of order, for all insect orders except Coleoptera. We additionally found that the relative exoskeletal chitin investment, indexed by the coefficient, a, varies with insect life history and phylogeny. Exoskeletal chitin mass tends to be proportionally less and to increase at a lower rate with mass in flying than in nonflying insects (M_{flying insect chitin} = ?0.56 × M; M_{nonflying insect chitin} = ?0.55 × M), and to vary with insect order. Isometric scaling (b = 1) of insect exoskeletal chitin suggests that the exoskeleton in insects scales differently than support structures of most other organisms, which have a positive allometry (b > 1) (e.g., vertebrate endoskeleton, tree secondary tissue). The isometric pattern that we document here additionally suggests that exoskeletal investment may not be the primary limit on insect body size. J. Morphol., 2010. © 2010 Wiley‐Liss, Inc.     

Factors determining species richness of soil seed banks in lowland ancient woodlands

The demise of coppicing in UK ancient woodlands, combined with the planting of non-native, fast-growing conifers in the twentieth century, heightens the potential recharge value of ground flora seed banks. Soil cores from adjoining semi-natural and conifer-containing stands in four lowland ancient woods in central England were removed to establish seed bank species richness. During a fourteen-month germination trial soil from two depths yielded 6554 seedlings from 81 species, ten of which showed a strong affinity for ancient woodland conditions. Juncus effusus accounted for 80% of emergent seeds whilst 23 other species, including Lysimachia nummularia and Potentilla sterilis, were represented by only one individual. Species richness is described by a model that explains 40% of observed variance (P < 0.00001). The model has three significant variables: species richness increases as soil pH rises, and decreases with both depth and increasing time since the most recent planting/disturbance event. No difference was found in the density of seeds from species common to paired semi-natural and conifer-containing stands that were separated only by a woodland ride, suggesting prior management and environmental conditions have a greater influence on seed banks than current stand type. Sørensen similarity index values revealed poor congruence between above-ground vegetation and species in the seed bank. Taking pH measurements in conifer stands identified as younger in terms of planting/disturbance may help locate areas where greater numbers of species (including woodland specialists) are located. Caution is required, however, as these seed banks may also contain non-target, competitive species that may swamp the regeneration of woodland specialists.     

Richard J. Hobbs: how one ecologist has influenced the way we think about restoration ecology

Professor Richard Hobbs has had a profound influence on the development of the discipline of restoration ecology. With more than 300 publications spanning a broad scope of applied ecological sciences, he has collaborated with hundreds of researchers. His sometimes‐provocative insights, balanced by extensive empirical research, will have a lasting impact by encouraging people to think more broadly about the science and practice of ecological restoration. Here, on the eve of his retirement, some of his staff and students, past and present, take a retrospective look at his contributions to restoration ecology both as a scientist and as a mentor.     

Lifeform indicators reveal large‐scale shifts in plankton across the North‐West European shelf

Increasing direct human pressures on the marine environment, coupled with climate‐driven changes, is a concern to marine ecosystems globally. This requires the development and monitoring of ecosystem indicators for effective management and adaptation planning. Plankton lifeforms (broad functional groups) are sensitive indicators of marine environmental change and can provide a simplified view of plankton biodiversity, building an understanding of change in lower trophic levels. Here, we visualize regional‐scale multi‐decadal trends in six key plankton lifeforms as well as their correlative relationships with sea surface temperature (SST). For the first time, we collate trends across multiple disparate surveys, comparing the spatially and temporally extensive Continuous Plankton Recorder (CPR) survey (offshore) with multiple long‐term fixed station‐based time‐series (inshore) from around the UK coastline. These analyses of plankton lifeforms showed profound long‐term changes, which were coherent across large spatial scales. For example, ‘diatom’ and ‘meroplankton’ lifeforms showed strong alignment between surveys and coherent regional‐scale trends, with the 1998–2017 decadal average abundance of meroplankton being 2.3 times that of 1958–1967 for CPR samples in the North Sea. This major, shelf‐wide increase in meroplankton correlated with increasing SSTs, and contrasted with a general decrease in holoplankton (dominated by small copepods), indicating a changing balance of benthic and pelagic fauna. Likewise, inshore‐offshore gradients in dinoflagellate trends, with contemporary increases inshore contrasting with multi‐decadal decreases offshore (approx. 75% lower decadal mean abundance), urgently require the identification of causal mechanisms. Our lifeform approach allows the collation of many different data types and time‐series across the NW European shelf, providing a crucial evidence base for informing ecosystem‐based management, and the development of regional adaptation plans.     

A community survey of coverage and adverse events following country-wide triple-drug mass drug administration for lymphatic filariasis elimination,Samoa 2018

The Global Programme to Eliminate Lymphatic Filariasis has made considerable progress but is experiencing challenges in meeting targets in some countries. Recent World Health Organization guidelines have recommended two rounds of triple-drug therapy with ivermectin, diethylcarbamazine (DEC), and albendazole (IDA), in areas where mass drug administration (MDA) results with two drugs (DEC and albendazole) have been suboptimal, as is the case in Samoa. In August 2018, Samoa was the first country in the world to implement countrywide triple-drug MDA. This paper aims to describe Samoa’s experience with program coverage and adverse events (AEs) in the first round of triple-drug MDA. We conducted a large cross-sectional community survey to assess MDA awareness, reach, compliance, coverage and AEs in September/October 2018, 7–11 weeks after the first round of triple-drug MDA. In our sample of 4420 people aged ≥2 years (2.2% of the population), age-adjusted estimates indicated that 89.0% of the eligible population were offered MDA, 83.9% of the eligible population took MDA (program coverage), and 80.2% of the total population took MDA (epidemiological coverage). Overall, 83.8% (2986/3563) reported that they did not feel unwell at all after taking MDA. Mild AEs (feeling unwell but able to do normal everyday things) were reported by 13.3% (476/3563) and moderate or severe AEs (feeling unwell and being unable to do normal everyday activities such as going to work or school) by 2.9% (103/3563) of participants. This study following the 2018 triple-drug MDA in Samoa demonstrated a high reported program awareness and reach of 90.8% and 89.0%, respectively. Age-adjusted program coverage of 83.9% of the total population showed that MDA was well accepted and well tolerated by the community.     

Need for and Access to Health Care and Medicines: Are There Gender Inequities?

Objective

Differences between women and men in political and economic empowerment, education, and health risks are well-documented. Similar gender inequities in access to care and medicines have been hypothesized but evidence is lacking.

Methods

We analyzed 2002 World Health Survey data for 257,922 adult respondents and 80,932 children less than 5 years old from 53 mostly low and middle-income countries. We constructed indicators of need for, access to, and perceptions of care, and we described the number of countries with equal and statistically different proportions of women and men for each indicator. Using multivariate logistic regression models, we estimated effects of gender on our study outcomes, overall and by household poverty.

Findings

Women reported significantly more need for care for three of six chronic conditions surveyed, and they were more likely to have at least one of the conditions (OR 1.41 [95% CI 1.38, 1.44]). Among those with reported need for care, there were no consistent differences in access to care between women and men overall (e.g., treatment for all reported chronic conditions, OR 1.00 [0.96, 1.04]) or by household poverty. Of concern, access to care for chronic conditions was distressingly low among both men and women in many countries, as was access to preventive services among boys and girls less than 5 years old.

Conclusions

These cross-country results do not suggest a systematic disadvantage of women in access to curative care and medicines for treating selected chronic conditions or acute symptoms, or to preventive services among boys and girls.     

Sonic Hedgehog-Induced Histone Deacetylase Activation Is Required for Cerebellar Granule Precursor Hyperplasia in Medulloblastoma

Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.