Lkb1 Loss Promotes Tumor Progression of BRAFV600E-Induced Lung Adenomas

Aberrant activation of MAP kinase signaling pathway and loss of tumor suppressor LKB1 have been implicated in lung cancer development and progression. Although oncogenic KRAS mutations are frequent, BRAF mutations (BRAF^V600E) are found in 3% of human non-small cell lung cancers. Contrary to KRAS mutant tumors, BRAF^V600E-induced tumors are benign adenomas that fail to progess. Interestingly, loss of tumor supressor LKB1 coexists with KRAS oncogenic mutations and synergizes in tumor formation and progression, however, its cooperation with BRAF^V600E oncogene is unknown. Our results describe a lung cell population in neonates mice where expression of BRAF^V600E leads to lung adenoma development. Importantly, expression of BRAF^V600E concomitant with the loss of only a single-copy of Lkb1, overcomes senencence–like features of BRAF^V600E-mutant adenomas leading malignization to carcinomas. These results posit LKB1 haploinsufficiency as a risk factor for tumor progression of BRAF^V600E mutated lung adenomas in human cancer patients.     

Regulation of stem cell therapies under attack in Europe: for whom the bell tolls

At the time of writing, the Italian Parliament is debating a new law that would make it legal to practice an unproven stem cell treatment in public hospitals. The treatment, offered by a private non‐medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulations. This case raises multiple concerns, most prominently the urgent need to protect patients who are severely ill, exposed to significant risks, and vulnerable to exploitation. The scientific community must consider the context—social, financial, medical, legal—in which stem cell science is currently situated and the need for stringent regulation. Additional concerns are emerging. These emanate from the novel climate, created within science itself, and stem cell science in particular, by the currently prevailing model of ‘translational medicine’. Only rigorous science and rigorous regulation can ensure translation of science into effective therapies rather than into ineffective market products, and mark, at the same time, the sharp distinction between the striving for new therapies and the deceit of patients.     

Spawning, egg development and early ontogenesis in rock cod Patagonotothen ramsayi (Regan, 1913) caught on the Patagonian Shelf and maintained in captivity

Rock cod Patagonotothen ramsayi (Regan, 1913) is one of the most abundant fish of the family Nototheniidae inhabiting the Patagonian Shelf and upper Slope in the southwest Atlantic. Recently, P. ramsayi became an important commercial species around the Falkland Islands with annual catch of 60,000–75,000 t. The present study aimed to reveal previously unknown aspects of reproductive biology of P. ramsayi during the first successful maintenance of adults for more than a year in an aquaculture facility with running seawater. The fish spawned at the end of austral winter. During spawning, males changed their coloration dramatically, occupied artificial shelters on the bottom and showed aggressive territorial behaviour. Egg masses were light-yellow to light-orange irregular spongiform. They were negatively buoyant, but located outside shelters and were ignored by males. Egg diameters varied between 2.1 and 2.3 mm, and the number of eggs per egg mass ranged from 26,800 to 123,400. Embryogenesis lasted 28–32 days. Total lengths of newly hatched larvae ranged from 6.2 to 6.7 mm. The yolk sac feeding period lasted approximately 11 days, during which the larvae showed negative phototaxis. One-month-old larvae attained 8.8–9.0 mm in length. This study confirms that P. ramsayi exhibit the reproductive strategy typical for nototheniid species occupying low-latitude peripheries of their distributional range, characterised by a combination of r-features (small eggs and larvae, high fecundity) and K-features (territorial behaviour and possible nest guarding).     

Elastic properties of the growth-controlling outer cell walls of maize coleoptile epidermis

The effects of tensile stress and temperature on cell wall elasticity have been investigated in the outer cell walls of coleoptile epidermis of 4- and 6-day-old Zea mays L. seedlings. The change in tensile stress from 6 to 40 MPa caused the increase in cell wall elastic modulus from 0.4 to 3 GPa. Lowering the temperature from 30 to 4 °C resulted in instantaneous and reversible cell wall elongation of 0.3–0.5 ‰. At a given temperature and stress level, the wall elastic modulus of 6-day-old seedlings tended to be 30 % higher than that of 4-day-old plants. The relationship between cell wall elasticity and mechanical stress indicated that the stress distribution within the cell wall is highly uneven. The analysis of the effect of temperature on cell wall elastic strain showed that structural differences between crystalline and amorphous load-bearing polymers were not the only cause of the uneven stress distribution. Based on the results obtained by Hejnowicz and Borowska-Wykr?t (Planta 220:465–473, 2005), we suggested that the uneven stress distribution is partially related to the stress gradient between inner and outer layers of the cell wall.     

Types and development pathways of lateral line scales in some teleost species

Voronina, E.P. and Hughes, D.R. 2011. Types and development pathways of lateral line scales in some teleost species. —Acta Zoologica (Stockholm) 00 : 1–13. A comparative study of lateral line scales (lls) in nine teleost species was undertaken to trace their ontogenetic structural changes. Three universal characters were used to describe and classify definitive and developing lls. The four main structural types in teleosts are represented. In adult fish, lls are the same structural type in all parts of lateral line in any one specimen, but number of tubules and their orientation may vary. In juvenile fish, except for one species, the structural type of every lls changes with growth, and this process progresses along the lateral line in the direction of development typical for the species. Definitive structural type of the lls is not determined by common scale type and size, presence or absence of nerve foramen on lls, scale overlapping or time of initiation of scales and trunk canal. Development pathways are proposed in which terminal states correspond to the final development of the most complex lls type in Cyprinus carpio, Carassius carassius, Oncorhynchus mykiss, Diplodus annularis and Mullus barbatus. The intermediate states of these pathways correspond to other types of lls as examples of pedomorphosis in Perca fluviatilis, Sander lucioperca, Symphysodon aequifasciatus and Hippoglossoides platessoides.     

2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.     

Projected marine climate change: effects on copepod oxidative status and reproduction

Zooplankton are an important link between primary producers and fish. Therefore, it is crucial to address their responses when predicting effects of climate change on pelagic ecosystems. For realistic community‐level predictions, several biotic and abiotic climate‐related variables should be examined in combination. We studied the combined effects of ocean acidification and global warming predicted for year 2100 with toxic cyanobacteria on the calanoid copepod, Acartia bifilosa. Acidification together with higher temperature reduced copepod antioxidant capacity. Higher temperature also decreased egg viability, nauplii development, and oxidative status. Exposure to cyanobacteria and its toxin had a negative effect on egg production but, a positive effect on oxidative status and egg viability, giving no net effects on viable egg production. Additionally, nauplii development was enhanced by the presence of cyanobacteria, which partially alleviated the otherwise negative effects of increased temperature and decreased pH on the copepod recruitment. The interactive effects of temperature, acidification, and cyanobacteria on copepods highlight the importance of testing combined effects of climate‐related factors when predicting biological responses.     

An S-Locus Independent Pollen Factor Confers Self-Compatibility in ‘Katy’ Apricot

Loss of pollen-S function in Prunus self-compatible cultivars has been mostly associated with deletions or insertions in the S-haplotype-specific F-box (SFB) genes. However, self-compatible pollen-part mutants defective for non-S-locus factors have also been found, for instance, in the apricot (Prunus armeniaca) cv. ‘Canino’. In the present study, we report the genetic and molecular analysis of another self-compatible apricot cv. termed ‘Katy’. S-genotype of ‘Katy’ was determined as S ₁ S ₂ and S-RNase PCR-typing of selfing and outcrossing populations from ‘Katy’ showed that pollen gametes bearing either the S ₁- or the S ₂-haplotype were able to overcome self-incompatibility (SI) barriers. Sequence analyses showed no SNP or indel affecting the SFB ₁ and SFB ₂ alleles from ‘Katy’ and, moreover, no evidence of pollen-S duplication was found. As a whole, the obtained results are compatible with the hypothesis that the loss-of-function of a S-locus unlinked factor gametophytically expressed in pollen (M’-locus) leads to SI breakdown in ‘Katy’. A mapping strategy based on segregation distortion loci mapped the M’-locus within an interval of 9.4 cM at the distal end of chr.3 corresponding to ∼1.29 Mb in the peach (Prunus persica) genome. Interestingly, pollen-part mutations (PPMs) causing self-compatibility (SC) in the apricot cvs. ‘Canino’ and ‘Katy’ are located within an overlapping region of ∼273 Kb in chr.3. No evidence is yet available to discern if they affect the same gene or not, but molecular markers seem to indicate that both cultivars are genetically unrelated suggesting that every PPM may have arisen independently. Further research will be necessary to reveal the precise nature of ‘Katy’ PPM, but fine-mapping already enables SC marker-assisted selection and paves the way for future positional cloning of the underlying gene.     

Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.