Energy allocation trade-offs as a function of age in fungiid corals

To compete effectively, living organisms must adjust the allocation of available energy resources for growth, survival, maintenance, and reproduction throughout their life histories. Energy demands and allocations change throughout the life history of an organism, and understanding their energy allocation strategies requires determination of the relative age of individuals. As most scleractinian corals are colonial, the relationship between age and mass/size is complicated by colony fragmentation, partial mortality, and asexual reproduction. To overcome these limitations, solitary mushroom corals, Herpolitha limax from Okinawa, Japan and Fungia fungites from Okinawa and the Great Barrier Reef (GBR), Australia, were used to investigate how energy allocation between these fundamental processes varies as a function of age. Measurements of the relative growth, biochemical profiles, fecundity of individuals of different sizes, and the settlement success of their progeny have revealed physiological trade-offs between growth and reproduction, with increasing body mass ultimately leading to senescence. The importance of energy allocation for reproduction led us to examine the reproductive strategies and sex allocation in the two studied species. In the present study, the smallest individuals of both species studied were found to invest most of their energy in relative growth, showing higher lipid and carbohydrate content than the later stages. In medium-sized corals, this pattern was overturned in favour of reproduction, manifesting in terms of both the highest fecundity and settlement success of the resulting brooded larvae. Finally, a phase of apparent senescence was observed in the largest individuals, characterized by a decrease in most of the parameters measured. In addition, complex reproductive plasticity has been revealed in F. fungites in the GBR, with individual females releasing eggs, embryos, planulae, or a combination of these. These data provide the most direct estimates currently available for physiological, age-related trade-offs during the life history of a coral. The unusual reproductive characteristics of the GBR F. fungites indicate previously unknown layers of complexity in the reproductive biology of corals and have implications for their adaptive potential across a wide geographical scale

Augmented antitumor activity of 5‐fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells

Inactivation of the TP53 tumor suppressor gene is essential during cancer development and progression. Mutations of TP53 are often missense and occur in various human cancers. In some fraction of wild‐type (wt) TP53 tumors, p53 is inactivated by upregulated murine double minute homolog 2 (MDM2) and MDM4. We previously reported that simultaneous knockdown of MDM4 and MDM2 using synthetic DNA‐modified siRNAs revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP53 and high MDM4 expression (wtTP53/highMDM4). In the present study, MDM4/MDM2 double knockdown with the siRNAs enhanced 5‐fluorouracil (5‐FU)‐induced p53 activation, arrested the cell cycle at G1 phase, and potentiated the antitumor effect of 5‐FU in wtTP53/highMDM4 human colon (HCT116 and LoVo) and gastric (SNU‐1 and NUGC‐4) cancer cells. Exposure to 5‐FU alone induced MDM2 as well as p21 and PUMA by p53 activation. As p53‐MDM2 forms a negative feedback loop, enhancement of the antitumor effect of 5‐FU by MDM4/MDM2 double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists. Intratumor injection of the MDM4/MDM2 siRNAs suppressed in vivo tumor growth and boosted the antitumor effect of 5‐FU in an athymic mouse xenograft model using HCT116 cells. These results suggest that a combination of MDM4/MDM2 knockdown and conventional cytotoxic drugs could be a promising treatment strategy for wtTP53/highMDM4 gastrointestinal cancers

Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer

BackgroundHuman papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences.MethodsThe entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins.ResultsAmong 52 isolates of HPV52 (CIN1, n = 20; CIN2/3, n = 21; ICC, n = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n = 21; CIN2/3, n = 19; ICC, n = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates.ConclusionsAmong the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome