Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers

The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD—termed 2R-ohnologues—belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42–60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R-ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels

Sea cucumber fishing pattern and the socio-economic characteristics of fisher communities in Sri Lanka

Sea cucumber fishing pattern and the social and economic characteristics of sea cucumber fisher communities in the north, north-west and north-east regions of Sri Lanka were assessed using the data collected from November 2015 to January 2017. A total of 9 sea cucumber species is landed in these areas using three fishing methods; diving (SCUBA and breath-hold), gleaning and surrounding nets. SCUBA diving is the dominant fishing method and SCUBA divers do both day and night fishing reporting the highest catch rates (CPUE ± SD in numbers/person/day) than the other fishers (p < 0.05; ANOVA). Gleaning is entirely carried out by fisherwomen in the northern region whereas 28 surrounding nets are used targeting low-value Stichopus naso. CPUE found to be varied with respect to species, region and fishing method (p < 0.05; ANOVA). Bohadschia vitiensis made the highest percentage contribution (61.3%) to the total sea cucumber landings during the study period. Among all fishers, SCUBA divers reported the highest average net monthly income. Men play a dominant role in sea cucumber fishing (98%), processing (99%) and marketing (100%). Fishermen in the age range of 25–67 yr, having only primary education mainly involved in the sea cucumber industry. The sea cucumber value chain consists of fishers (∼2000), middlemen (12), processors (16) and exporters (7). A significant increase in overall price development from fishers to the exporters was reported for all 9 species (p < 0.05; ANOVA). Fishers received a proportionally higher share of the end-market price mainly for low-value Bohadschia spp. Although fishers receive disproportionately low returns compared to other value chain players, 47.8% of fishers showed high satisfaction towards the prices they received from buyers. However, 83.6% of fishers are not satisfied with existing management measures. Apart from strengthening the existing management measures, this information is important to update the regional and global sea cucumber statistics

Assessing Climate Change Impacts on the Stability of Small Tidal Inlets: Part 2- Data Rich Environments

Climate change (CC) is likely to affect the thousands of bar-built or barrier estuaries (here referred to as Small tidal inlets - STIs) around the world. Any such CC impacts on the stability of STIs, which governs the dynamics of STIs as well as that of the inlet-adjacent coastline, can result in significant socio-economic consequences due to the heavy human utilisation of these systems and their surrounds. This article demonstrates the application of a process based snap-shot modelling approach, using the coastal morphodynamic model Delft3D, to 3 case study sites representing the 3 main STI types; Permanently open, locationally stable inlets (Type 1), Permanently open, alongshore migrating inlets (Type 2) and Seasonally/Intermittently open, locationally stable inlets (Type 3). The 3 case study sites (Negombo lagoon - Type 1, Kalutara lagoon - Type 2, and Maha Oya river - Type 3) are all located along the southwest coast of Sri Lanka. After successful hydrodynamic and morphodynamic model validation at the 3 case study sites, CC impact assessment are undertaken for a high end greenhouse gas emission scenario. Future CC modified wave and riverflow conditions are derived from a regional scale application of spectral wave models (WaveWatch III and SWAN) and catchment scale applications of a hydrologic model (CLSM) respectively, both of which are forced with IPCC Global Climate Model output dynamically downscaled to approximately 50 km resolution over the study area with the stretched grid Conformal Cubic Atmospheric Model CCAM. Results show that while all 3 case study STIs will experience significant CC driven variations in their level of stability, none of them will change Type by the year 2100. Specifically, the level of stability of the Type 1 inlet will decrease from 'Good' to 'Fair to poor' by 2100, while the level of (locational) stability of the Type 2 inlet will also decrease with a doubling of the annual migration distance. Conversely, the stability of the Type 3 inlet will increase, with the time till inlet closure increasing by approximately 75%. The main contributor to the overall CC effect on the stability of all 3 STIs is CC driven variations in wave conditions and resulting changes in longshore sediment transport, not Sea level rise as commonly believed

Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology

Alleviating the Disparities of Resource Allocation for Education in Sri Lanka: Towards a Possible Macro-Economic Growth

The main purpose of this study is the examination of how, an equitable distribution of educational resources would factor in as a contributor to more favorable economic growth of Sri Lanka. If the better facilities, and additional educational resources, offered to urban communities are extended to the rural sector that will increase human productivity, leading in turn, to macro-economic growth and economic development. I have derived and tabulated pertinent statistical data so as to answer the research questions entailed by my inquiry. That has been followed by the conclusions and recommendations sections. Qualitative methods were used to interview rural communities with the aim of analyzing their concerns, anxieties and trepidations from a variety of perspectives involving politics, economics, psychology, sociology and culture. A detailed description of inequitable educational resource distribution among rural communities is included in the document which shows the negative impacts to the macro-economic growth of short-sighted and irrational practices. Thereafter, the study has focused on the lack of leadership characteristics of Sri Lankan political policy makers

Modelling morphological response of large tidal inlet systems to sea level rise; Proefschrift Technische Universiteit Delft.

The research presented in this dissertation qualitatively investigates the morphodynamic response of a large tidal inlet/basin system to future relative sea level rise (RSLR) using the state-of-the-art Delft3D numerical model. Understanding the potential impacts of RSLR on these systems is a prerequisite for the sustainable management due to their rich bio-diversity and the increase in economic activities and local communities in recent decades.The adopted approach used a highly schematised model domain analogous to the Ameland inlet in the Dutch Wadden Sea. Model simulations were undertaken applying tidal and wave boundary forcings with three IPCC projected RSLR scenarios (no RSLR, low RSLR and high RSLR). Predicted inlet evolution indicated a channel/shoal pattern typically observed at the Ameland inlet. RSLR enhances the existing flood-dominance of the system leading to erosion on the ebb-tidal delta and accretion in the basin. Under the no RSLR case, resulting bed evolution of the process-based model (Delft3D) tends to agree with empirical-equilibrium relations of the ASMITA model. Application of the low RSLR scenario resulted in quite stable tidal flat evolution. Model simulations with the high RSLR scenario indicated disappearing the tidal flats over time and turning the system into a lagoon. Applying nourishment hardly compensated the RSLR induced sediment demand of tidal flat evolution