A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells.

The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target

Consumers’ salient beliefs regarding foods from edible insects in Kenya: a qualitative study using concepts from the theory of planned behaviour

Population growth, urbanization and climate change, are among the factors that have created uncertainties and pressures on current global food and economic systems. Agricultural intensification can no longer support the increasing demand for food, especially of protein origin. Consequently, pressure is mounting on the supply side (private sector) to develop viable alternative sources of protein’ foods. Insects as food and consumption of foods from edible insects (FEI) are being promoted as one potential solution to the declining access to protein foods. However, one of the challenges facing the private sector is to demonstrate the efficacy of FEI programmes in the face of limited information regarding consumer - psychographic characteristics including their attitudes, values, interests and beliefs. The aim of the study was to explore the salient beliefs underlying consumer attitudes towards FEI consumption in Kenya. To achieve this objective, six focus group discussions (FGDs) were conducted (n= 43), three with only female participants and the other three with a mixed gender. The FGD script was coded using the Theory of Planned Behaviour theoretical framework. The results show that, salient beliefs related to taste, availability, convenience, affordability and other benefits beyond nutrition, are the main determinants of the participants’ intentions to consume FEI. Intentions are also influenced by the perceived feelings regarding the social referents, including family members, peers, religious leaders and health officials; and perceived behavioural control factors such as perceived risks on their food choices, perceived convenience and availability. While designing local programmes to promote FEI consumption, participants support the idea of small groups, but expresses concern about the time of day (evening preferred), length and location of the group session. However, many participants are not receptive to receiving telephone messages, although they are open to the idea of receiving phone calls. The study findings provide unique insights, among them, cultural beliefs that underlies consumer attitudes towards consuming FEI. Additionally, the results suggest possible approaches and practical interventions that can be used to promote FEI consumption in specific regions of Kenya.Key words: Foods from edible insects, theory of planned behaviour, Salient belief

Economics of Insecticide use and Potential for Bt Maize Varieties in the Control of Stalkborer in Kenya.

Maize is the staple food crop and source of income for majority of the Kenyan population and many sub-Saharan African countries. The increasing Kenyan population demands an increase in maize production if intermittent food deficits have to be averted. Since the introduction of improved maize varieties in mid-1960, the start of Green Revolution period, maize yields increased drastically up to 1970s and started declining from 1980s to-date. The key contributory factors are nutrient mining, sub-optimal input use and insect pest damage. Of the insect pests, stalk borer is of economic importance. Currently, KARI and CIMMYT are developing maize varieties that are tolerant to stalk borer damage. In order to evaluate the potential impact of these interventions economics of stalk borer control at farm level was evaluated. Surveys complemented with on-farm trials were executed in six major maize growing zones of Kenya. Farmers were randomly selected and a sample-frame established after which a total of 1854 households were randomly selected using random sampling technique. Each household was interviewed using structured questionnaire. Data on method of stalk borer control and the type insecticides used was collected. Partial budget and economic surplus models were used. The results indicated that very few farmers control stalk borer in maize despite significant stalk borer losses of about 15%. Therefore if Bt maize is introduced in Kenya it is likely to reduce these losses. This will benefit many hungry and poor Kenyans with improved household food supply and on farm incomes, in line with Government policy of food security and poverty eradication.Crop Production/Industries,

p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation

The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-β-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-β1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-β levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-β signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as 'fate determinants' used by HSPCs to modulate their activity

PKM MASYARAKAT PESISIR DENGAN PENCEGAHAN DIABETES MELITUS DAN HIPERURISEMIA DI KAMPUNG BULO KECAMATAN TABUKAN SELATAN KABUPATEN KEPULAUAN SANGIHE PROVINSI SULAWESI UTARA

Diabetes Melitus (DM) adalah suatu kumpulan gejala yang timbul pada seseorang yang disebabkan oleh karena adanya peningkatan kadar gula darah (glukosa) darah akibat kekurangan insulin baik absolut maupun relative. Sedangkan hiperurisemia (asam urat berlebih) adalah kosentrasi asam urat yang larut dalam darah (> 6.8 mg/dl) akibat over produksi asam urat atau ekskresi (pengeluaran) yang berkurang serta kelainan kosentrasi zat dalam serum yang cukup sering ditemukan. Kampung Bulo Kecamatan Tabukan Selatan merupakan salah satu kampung di Kabupaten Kepulauan Sangihe. Kampung ini terletak + 5 mil dari Ibukota Kecamatan dan merupakan sebuah pulau yang harus dilalui dengan perahu motor kira-kira 15-20 menit Karakteristik masyarakat diKampung Bulo Kecamatan Tabukan Selatan sangat berpotensi menimbulkan angka kasus DM dan hiperurisemia menjadi tinggi karena masyarakat Kampung Bulo mengalami perubahan gaya hidup yakni sering mengkonsumsi makanan tinggi purin dan memiliki kebiasaan minum alcohol serta kurangnya pengawasan terhadap peningkatan kadar gula darah dan kadar asam urat berlebih dalam darah. Metode yang digunakan untuk menyekesaikan permasalahan mitra adalah dengan penyuluhan kesehatan dan pemeriksaan kesehatan. Masyarakat yang hadir saat penyuluhan kesehatan berjumlah 48 orang dan yang melakukan pemeriksaan kesehatan berjumlah 41 orang

Placental transfer of the polybrominated diphenyl ethers BDE-47, BDE-99 and BDE-209 in a human placenta perfusion system: an experimental study

<p>Abstract</p> <p>Background</p> <p>Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants in consumer products. PBDEs may affect thyroid hormone homeostasis, which can result in irreversible damage of cognitive performance, motor skills and altered behaviour. Thus, in utero exposure is of very high concern due to critical windows in fetal development.</p> <p>Methods</p> <p>A human ex vivo placenta perfusion system was used to study the kinetics and extent of the placental transfer of BDE-47, BDE-99 and BDE-209 during four-hour perfusions. The PBDEs were added to the maternal circulation and monitored in the maternal and fetal compartments. In addition, the perfused cotyledon, the surrounding placental tissue as well as pre-perfusion placental tissue and umbilical cord plasma were also analysed. The PBDE analysis included Soxhlet extraction, clean-up by adsorption chromatography and GC-MS analysis.</p> <p>Results and Discussion</p> <p>Placental transfer of BDE-47 was faster and more extensive than for BDE-99. The fetal-maternal ratios (FM-ratio) after four hours of perfusion were 0.47 and 0.25 for BDE-47 and BDE-99, respectively, while the indicative permeability coefficient (IPC) measured after 60 minutes of perfusion was 0.26 h^-1and 0.10 h^-1, respectively. The transport of BDE-209 seemed to be limited. These differences between the congeners may be related to the degree of bromination. Significant accumulation was observed for all congeners in the perfused cotyledon as well as in the surrounding placental tissue.</p> <p>Conclusion</p> <p>The transport of BDE-47 and BDE-99 indicates in utero exposure to these congeners. Although the transport of BDE-209 was limited, however, possible metabolic debromination may lead to products which are both more toxic and transportable. Our study demonstrates fetal exposure to PBDEs, which should be included in risk assessment of PBDE exposure of women of child-bearing age.</p

Genetic determinants of cellular addiction to DNA polymerase theta

Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy