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Wilms tumour (WT), an embryonal kidney cancer, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of foetal kidney with two WT cell lines, filtering our results to remove common cancer‐associated epigenetic changes and to enrich for genes involved in early kidney development. This identified four hypermethylated genes, of which ESRP2 (epithelial splicing regulatory protein 2) was the most promising for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this occurred early in WT development (in nephrogenic rests). ESRP2 expression was reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it inhibited cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA‐seq of the ESRP2‐expressing WT cell lines identified several novel splicing targets. We propose a model in which epigenetic inactivation of ESRP2 disrupts the mesenchymal to epithelial transition in early kidney development to generate WT., ESRP2 regulates alternative splicing events that are critical for the mesenchymal to epithelial transition (MET) that occurs during kidney development. We show that in Wilms tumour, ESRP2 is commonly inactivated by DNA methylation at an early stage of carcinogenesis. We propose that epigenetic inactivation of ESRP2 disrupts the regulation of alternative splicing during MET. Disrupted MET leads in turn to persistence of undifferentiated foetal kidney cells that may progress to a tumour.

The current study is designed to analyze theslope stability of Haditha damwhich is an earth-fill dam constructed on the Euphrates River in the middle-west of Iraq. Finite element modeling was used in the present study to analyze the combined seepage and post-earthquake slope stability of Haditha earth dam. The maximum water level of a steady seepage case was considered to evaluate seepage. - Three different water levels (maximum, normal, and minimum) were applied, and nine different equilibrium slope stability limits were used to analyze the upstream and downstream slopes of the dam with three horizontal maximum accelerations.The input data given to the software are the dam geometry and its material properties with the earthquake records in the year2019.The dam was investigated by considering the water in the reservoir to be at maximum, minimum and normal water levels in its actual design. It was concluded that the dam is on the safe side in terms of stability even though the change in the earthquake's conditions in Iraq.

The Reheating process at the end of inflation is often modeled by an oscillating scalar field which shows a background dust-like behaviour, prompting the analysis of gravitational collapse and black hole formation in this era to be approached by the spherical collapse of standard structure formation. In the scalar field dark matter structure formation process virialized halos halt the direct collapse, resulting in halos with condensed central cores at the de Broglie scale of the dominant scalar field. We show that a similar process can take place during reheating, leading to the formation of primordial black holes (PBHs). We study the formation of PBHs through the gravitational further collapse of structures virialized during reheating, looking at the collapse of either the whole structure, or that of the central core within these configurations. We compute the threshold amplitude for the density contrast to undergo this process, for both free and self-interacting scalar fields. We discuss the relevance of our results for the abundance of PBHs at the lower end of the mass spectrum., 6 pages, 1 figure. Minor updates to accord with the accepted version in Phys. Rev. D

Climate change threatens the security and sustainability of the global food system. In Bangladesh, the fragile food system is strongly being impacted by climate variability and extreme weather events. Estimates indicate that the agricultural sector could lose about USD7.7 billion per annum due to climate change. The average annual rice production could decline by 33% within two decades. However, a few studies investigated the impacts of fluctuating temperature and rainfall, flash floods, drought, and saline water intrusion on the food system and security in an integrated manner. This study examines climate change impacts on food system security and sustainability in Bangladesh. It reviews the country’s food system, the climatic conditions that threaten food security, and impacts climate change on the food systems and the associated vulnerabilities. The study then assesses the existing adaptation initiatives and the extent of their integration among pertinent stakeholders. It concludes that local climate change adaptation strategies and stakeholder collaboration are necessary for reducing climate change impacts on food system security.

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

There is a growing focus on the role of renewable energy (RE) policies such as feed-in tariffs (FITs), renewable portfolio standards (RPSs), subsidies, incentives, and research and development in the global energy policy mix and in promoting environmental sustainability. Although most developed countries have well-formulated RE policies, in developing countries, such policies face many barriers. This study analyzes the policies, drivers, and barriers to RE deployment for fostering environmental sustainability in the Gulf Cooperation Council (GCC) countries. In the GCC region, the need for economic diversification to reduce dependency on single resource, diminishing hydrocarbon reserve, loss of oil export revenue, climate change mitigation pledges, and abundant solar energy resource are the key drivers for diversifying energy sources to include RE. However, the apparent lack of consolidated policy framework for wide-scale RE utilization calls for a well-articulated policy to advance RE development in each member state. Although FIT and RPS approaches could be effective for initial deployment of small-scale RE projects, a competitive tendering and auctioning mechanisms are more suitable for large-scale projects. Whereas, developing effective energy codes could successfully promote RE deployment, the increased share of RE in energy supply would have synergistic impacts on the region. The GHG emissions avoidance expected to be achieved by the GCC countries will vary between 5 and 247 million tons of CO2 equivalent by 2030. The fulfillment of inspirational RE targets for 2030 would contribute in fulfilling climate change mitigation pledges, environmental sustainability, economic growth, and generating new jobs.

Simple Summary Wilms’ tumour (WT) is one of the most common solid paediatric malignancies and arises in the developing kidney. Treatment of most WTs is relatively successful, with the notable exception of tumours with anaplastic histology. Anaplastic WT survival rates can be as low as 30–50%, emphasising the need for a better understanding of their molecular aetiology, in order to facilitate the development of novel therapeutics for poor-prognosis WT. Previous studies have implicated increases in MYCN at the DNA and RNA level in WTs with anaplasia, although the biological functions of MYCN protein have not been reported. In this study, we define the expression pattern of MYCN protein in WTs and also modulate MYCN protein levels in anaplastic WT cell-lines to define the functions of MYCN in WT. We show that MYCN depletion leads to decreased cell growth and identify MYCN-regulated genes and pathways that may represent therapeutic vulnerabilities in poor-prognosis WT. Abstract The MYCN proto-oncogene is deregulated in many cancers, most notably in neuroblastoma, where MYCN gene amplification identifies a clinical subset with very poor prognosis. Gene expression and DNA analyses have also demonstrated overexpression of MYCN mRNA, as well as focal amplifications, copy number gains and presumptive change of function mutations of MYCN in Wilms’ tumours with poorer outcomes, including tumours with diffuse anaplasia. Surprisingly, however, the expression and functions of the MYCN protein in Wilms’ tumours still remain obscure. In this study, we assessed MYCN protein expression in primary Wilms’ tumours using immunohistochemistry of tissue microarrays. We found MYCN protein to be expressed in tumour blastemal cells, and absent in stromal and epithelial components. For functional studies, we used two anaplastic Wilms’ tumour cell-lines, WiT49 and 17.94, to study the biological and transcriptomic effects of MYCN depletion. We found that MYCN knockdown consistently led to growth suppression but not cell death. RNA sequencing identified 561 MYCN-regulated genes shared by WiT49 and 17.94 cell-lines. As expected, numerous cellular processes were downstream of MYCN. MYCN positively regulated the miRNA regulator and known Wilms’ tumour oncogene LIN28B, the genes encoding methylosome proteins PRMT1, PRMT5 and WDR77, and the mitochondrial translocase genes TOMM20 and TIMM50. MYCN repressed genes including the developmental signalling receptor ROBO1 and the stromal marker COL1A1. Importantly, we found that MYCN also repressed the presumptive Wilms’ tumour suppressor gene REST, with MYCN knockdown resulting in increased REST protein and concomitant repression of RE1-Silencing Transcription factor (REST) target genes. Together, our study identifies regulatory axes that interact with MYCN, providing novel pathways for potential targeted therapeutics for poor-prognosis Wilms’ tumour.

The research study provides a comprehensive bibliometric assessment in the field of Software Testing (ST). The dynamic evolution in the field of ST is evident from the publication rate over the last six years. The research study is carried out to provide insight into the field of ST from various research bibliometric aspects. Our methodological approach includes dividing the six-year time frame into the set of two symmetric but different periods (2016–2018) and (2019–2021) comprising a total of 75,098 records. VOSViewer is used to perform analysis with respect to collaboration network of countries and co-word assessment. Bibliometrix (Studio R) analysis tool is used to evaluate research themes/topics. The year 2019 leads the publication rate whereas a decrement in publication frequency is observed for the years 2020 and 2021. Our research study shows the influence of ST in other research domains as depicted in different research areas. Especially the impact of ST in the Electrical and Electronics Domain is quite notable. Most of the research publications are from the USA and China as they are among the most resourceful countries. On the whole, the majority of the publications are from Asian countries. Collaboration networks amongst countries demonstrate the fact that the higher the collaboration network, the greater would be the research output. Co-word analysis presents the relatedness of documents based on the keywords. The topic dendrogram is generated based on the identified research themes. Although English is the leading language, prominent studies are present in other languages also. This research study provides a comprehensive analysis based on 12 informative research questions

Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of whichESRP2(epithelial splicing regulatory protein 2), was the most promising gene for further study.ESRP2was commonly repressed by DNA methylation in WT, and this was shown to occur early in WT development (in nephrogenic rests).ESRP2expression could be reactivated by DNA methyltransferase inhibition in WT cell lines. WhenESRP2was overexpressed in WT cell lines, it acted as an inhibitor of cellular proliferationin vitro,andin vivoit suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. We propose a model in which the mesenchymal to epithelial transition that is essential for early kidney development, can be disrupted in to generate WT, either by genetic abnormalities such asWT1mutations, or by epigenetic defects, such asESRP2methylation.

Three strains of novel bacteria were isolated from oil-contaminated sediment from the Arabian Gulf (Brevibacillus brevis T2C2008, Proteus mirabilis T2A12001, and Rhodococcus quinshengi TA13008). The isolated strains were tested for their degrading efficacy of low and high molecular hydrocarbon (naphthalene and pyrene). The efficacy of the two-hydrocarbon degradation by the isolates bacterial was determined at a temperature of 25 °C and 37 °C and pH of 5.0 and 9.0. In inoculated media at 37 °C, Rhodococcus qinshengi fully metabolized naphthalene and degrade 56% of pyrene. Brevibacillus brevis break down over 80% of naphthalene at room temperatures (25 °C). However, it was found that P. mirabilis and R. qinshengi biodegraded nearly 94% of naphthalene in the incubated media. The capacity for pyrene and naphthalene degradation in varying pH and temperature conditions was shown to be significant in Rhodococcus qinshengi because of its mineralization exceeding 50% across the tested pH and temperature. This implies that the isolated strains are ideal for biodegradation of contaminated sediment with naphthalene and pyrene.

Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a paediatric solid tumour with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with MYCN amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumours is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with MYCN amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638 and UNC0642. The increased efficacy of G9a inhibition in the presence of MYCN-overexpression is also demonstrated in the SHEP-21N isogenic model with tet-regulatable MYCN. Finally, using RNA sequencing, we identify several potential tumour suppressor genes that are reactivated by G9a inhibition in NB, including the CLU, FLCN, AMHR2 and AKR1C1-3. Together, our study underlines the under-appreciated role of G9a in NB, especially in MYCN-amplified tumours.

International audience; To discover epigenetic changes that may underly neuroblastoma pathogenesis, we identified differentially methylated genes in neuroblastoma cells compared to neural crest cells, the presumptive precursors cells for neuroblastoma, by using genome-wide DNA methylation analysis. We previously described genes that were hypermethylated in neuroblastoma; in this paper we report on 67 hypomethylated genes, which were filtered to select genes that showed transcriptional over-expression and an association with poor prognosis in neuroblastoma, highlighting GATA3 for detailed studies. Specific methylation assays confirmed the hypomethylation of GATA3 in neuroblastoma, which correlated with high expression at both the RNA and protein level. Demethylation with azacytidine in cultured sympathetic ganglia cells led to increased GATA3 expression, suggesting a mechanistic link between GATA3 expression and DNA methylation. Neuroblastomas that had completely absent GATA3 methylation and/or very high levels of protein expression, were associated with poor prognosis. Knock-down of GATA3 in neuroblastoma cells lines inhibited cell proliferation and increased apoptosis but had no effect on cellular differentiation. These results identify GATA3 as an epigenetically regulated component of the neuroblastoma transcriptional control network, that is essential for neuroblastoma proliferation. This suggests that the GATA3 transcriptional network is a promising target for novel neuroblastoma therapies. Neuroblastoma (NB) is one of the commonest extra-cranial solid malignancies of childhood, which arises as a result of disordered development of the sympathetic nervous system from neural crest cells 1,2. Neuroblastoma is clinically heterogeneous, with younger patients (18months) mostly have disseminated tumours at diagnosis and poor outcomes 3. The clinical heterogeneity of neuroblastoma is reflected in its molecular pathogenesis, where no single pathway has been identified as being critical for tumour development. Oncogene activations were the first genetic alterations identified in neuroblastoma; initially MYCN amplification was identified in high-risk tumours 4 and later ALK mutations were discovered in inherited neuroblastoma and some sporadic high-risk tumours 5,6. Mutations in tumour suppressor genes such as PHOX2B 7 and NF1 8 have also been reported. Recent genome-wide analyses have identified genomic mutations and other alterations in chromatin remodelling genes such as ATRX, ARID1A and ARID1B, in components of the RAC-RHO pathway 9-11 and in TERT 12,13 , with relapsed tumours demonstrating an increased mutation rate 14,15. Like most childhood cancers, neuroblastomas contain fewer mutations than adult cancers 16,17 , with some tumours apparently containing no detectable driver mutations 9-11. In low-risk neuroblastomas, copy-number changes may drive tumorigenesis 18 , but the lack of driver mutations in many cases, emphasises the need to consider other mechanisms of pathogenesis, such as epigenetic alterations 19 .

Even though the contribution of the aviation sector to the global economy is very notable, it also has an adverse impact on climate change. Improvements have been made in different areas (i.e., technology, sustainable aviation fuel, and design) to mitigate these adverse effects. However, the rate of improvement is small compared to the increase in the demand for air transportation. Hence, greenhouse gas emissions in the aviation sector are steadily increasing and this trend is expected to continue unless adequately addressed. In this context, this study examined the following: (i) the factors that affect the growth of aviation, (ii) trends in greenhouse gas emissions in the sector, (iii) trends in energy demand, (iv) mitigation pathways of emissions, (v) mitigation challenges for the International Civil Aviation Organization, (vi) achievements in mitigating emissions, (vii) barriers against mitigating emissions, and (viii) approaches of overcoming barriers against emissions mitigation. This study finds that continued research and development efforts targeting aircraft fuel burn efficiency are crucial in reducing greenhouse gas emissions. Although biofuels are promising for the reduction of aviation emissions, techniques to reduce NOx emissions could enhance large-scale deployment. Pragmatic market-based mechanisms, such as the Emissions Trading Scheme (ETS) and/or carbon tax must be enforced on a global scale to capitalize on a collective stakeholder effort to curb CO2 emissions. The findings of this study will help in understanding the emissions and energy consumption scenarios, which will provide a comprehensive package of mitigation pathways to overcome future emissions reduction challenges in the aviation sector.

The largest contributor of greenhouse gas (GHG) emission in the United Arab Emirates (UAE) is the energy sector. More than 90% of the total GHG is emitted from this sector. The rapid rise of population, high rate of urbanization, rapid economic growth, and low energy cost increase the demand for energy. The consistently increasing trend of energy consumption and GHG emissions pose a challenge for the country. This study has (i) investigated the major sources of energy consumption and GHG emissions, (ii) analyzed the growth pattern of the source categories, (iii) forecasted the GHG emissions under the business-as-usual and the reformed scenarios, (iv) synthesized widely varied initiatives of the UAE in GHG emission mitigation, (v) highlighted the challenges in deploying renewable energy resources, and (vi) discussed on the possible GHG mitigation approaches. The findings of this study will contribute in preparing national GHG emissions inventory, investigating the dynamics of national GHG emissions with particular reference to the energy sector, developing possible future energy outlook scenarios, and selecting appropriate policy measures to mitigate GHG emissions.

The novel bacterial strains Burkholderia fungorum T3A13001 and Caulobacter sp T2A12002, which were previously isolated from oil-contaminated sites and identified via 16S RNA sequences, were tested for their hydrocarbon degrading efficiency. Media spiked with 100 ppm pyrene were incubated at 25 °C and 37 °C. The bacterial isolates' pyrene-degrading capability was assessed in acidic (pH 5.0) and alkaline (pH 9.0) media. Caulobacter sp degraded 21% and 24% of the pyrene at pH 9.0 and 5.0, respectively; thus, the strain was more active at pH 5.0 than pH 9.0. B. fungorum was active in a wide range of pH values, because it biodegraded 59%–62% of the provided pyrene in acidic and alkaline media. Caulobacter sp degraded 35%–36% of the provided pyrene in cultures at 37 °C and 25 °C. B. fungorum degraded 56% and 59% of the provided pyrene at 37 °C and 25 °C, respectively. Given that B. fungorum biodegraded over the half-life of the initial 100 ppm pyrene in the cultures, the strain may be suitable for bioremediation of high molecular weight PAHs. The study provides important insight into possible PAH biodegradation and bioremediation of hydrocarbon-polluted sites using novel bacterial strains.

The current study is designed to model seepage and slope stability analysis of Haditha dam (Iraq) using finite element method by GEOSTUDIO 2012 software. GEOSTUDIO software is capable to carry out analysis such as, stress-strain, seepage, slope stability, dynamic analysis. SEEP/W and SLOPE/W are sub programs of GEOSTUDIO which can simulate the movement and pore-water pressure distribution within permeable materials like soil and rock. In the present study Haditha dam, which is an earth dam constructed on the Euphrates River in the middle west of Iraq 7 km upstream from Haditha city in Al Anbar governorate with a total length of the barrier 9064 m was chosen as a case study to simulate the seepage and slope stability analysis. The input data given to the software are the geometry of the dam and its material properties. The flow net is generated by SEEP/W software showing phreatic line, equipotential line, and stream line. Also, the seepage influx is computed by the software. The dam at its actual design was investigated by inspected the water in the reservoir to be at maximum, minimum and normal water level. It was concluded that the dolomite core and the presence of asphaltic-concrete diaphragm and the grout curtain have an important effect on decreasing the seepage quantity through the dam body and the factor of safety values of upstream and downstream slopes stability satisfy the minimum limits for all levels of water.

The neural crest, which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of neural crest development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signalling pathways have been characterised, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumourigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the neural crest.In this conceptual analysis, we utilise next generation sequencing data from neuroblastoma cells and tumours to evaluate the possible influences of Wnt signalling on neural crest GRNs and on neuroblastoma cell lineages. We provide evidence that Wnt signalling is a major determinant of regulatory networks that underlie mesenchymal/NCC-like cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signalling in driving proneural differentiation programmes along the adrenergic lineage. We propose that elucidation of Signalling Regulatory Networks can augment and complement GRNs in characterising cell identities, which will in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.

Hypoxia is a hallmark of solid tumours and a key physiological feature distinguishing cancer from normal tissue. However, a major challenge remains in identifying tractable molecular targets that hypoxic cancer cells depend on for survival. Here, we used SILAC‐based proteomics to identify the orphan G protein‐coupled receptor GPRC5A as a novel hypoxia‐induced protein that functions to protect cancer cells from apoptosis during oxygen deprivation. Using genetic approaches in vitro and in vivo, we reveal HIFs as direct activators of GPRC5A transcription. Furthermore, we find that GPRC5A is upregulated in the colonic epithelium of patients with mesenteric ischaemia, and in colorectal cancers high GPRC5A correlates with hypoxia gene signatures and poor clinical outcomes. Mechanistically, we show that GPRC5A enables hypoxic cell survival by activating the Hippo pathway effector YAP and its anti‐apoptotic target gene BCL2L1. Importantly, we show that the apoptosis induced by GPRC5A depletion in hypoxia can be rescued by constitutively active YAP. Our study identifies a novel HIF‐GPRC5A‐YAP axis as a critical mediator of the hypoxia‐induced adaptive response and a potential target for cancer therapy.

In the abstract, the statement “The GHG emissions avoidance expected to be achieved by the GCC countries will vary between 5 and 247 million tons of CO equivalent by 2030.”

The incidence of harmful algal blooms (HABs) in the Arabian Gulf, especially, in 2008 and 2009 has heightened concern regarding monitoring programs. Giovanni is a tool for cheap and rapid assessment of HAB incidences. In order to identify changes in phytoplankton species composition, specifically incidences of HABs, we employed web-based Giovanni coupled with satellite imagery and reported data from literature. In this study, we pinpointed and linked the time of algal bloom occurrence and the region affected in the Arabian Gulf. The data presented graphically and visually using Giovanni emphasized the incidence of HABs in the Arabian Gulf as reported in literature. Giovanni generated high-quality data which is vital to rapid assessment. The deployment of Giovanni as a complementary tool to support comprehensive and robust HAB monitoring in the Arabian Gulf region is indeed recommended.

Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra-and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology.Here we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of β-catenin immunohistochemistry shows high levels of β-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation.

Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers., Highlights • The small molecule inhibitor YK-4-279 can trigger p53-independent apoptosis in neuroblastoma cell lines. • YK-4-279 induces mitotic arrest with multipolar, fragmented and unseparated spindles. • YK-4-279 acts differently from paclitaxel and vincristine. • YK-4-279 can overcome resistance to vincristine and synergize with other inhibitors of mitosis.