Mechanistic characterisation of Activin/Smad and PI3K/mTOR crosstalk during the specification of definitive endoderm from human embryonic stem cells

During the course of development, specification of the three embryonic germ layers, ectoderm, mesoderm and definitive endoderm (DE), is a critical process by which pluripotent cells acquire the temporal and spatial information needed to form specialised tissues. Of these initial germ layers, the DE arises during gastrulation, which latterly gives rise to the liver, pancreas, lung and epithelial lining of the digestive tract. Elucidation of the molecular mechanisms that govern DE specification not only facilitates our understanding of developmental biology but also aids in the differentiation of human pluripotent stem cells to specific cell types for disease modelling and regenerative therapies. DE formation is largely driven by the cooperation of Activin/Nodal and Wnt/β-catenin signalling, however recent evidence has additionally implicated PI3K/Akt signalling in modulating this process. Although it has been previously reported that PI3K activation acts to antagonise the in vitro differentiation of DE, the molecular mechanisms responsible for this effect remains unclear. To address this issue, this study utilises pluripotent human embryonic stem cells (hESCs) as an in vitro model to interrogate the molecular underpinnings of DE formation through a fully defined differentiation protocol. Modulation of PI3K activity was found to reciprocally downregulate the activation of Smad2/3, which was mitigated in the presence of the PI3K inhibitor LY294002 (LY). Suppression of PI3K/Akt signalling prolongs the activation of Smad2/3 in response to Activin, promoting their nuclear accumulation and the enhancement of transcriptional activity, resulting in the upregulation of mesendoderm and DE gene expression. Activation of PI3K negatively impacts the activity of Smad2/3 via phosphorylation of the Smad2/3 linker T220/T179 residue, which is fully independent of Erk and CDK activity. Phosphorylation of this residue induces the recruitment of the E3 ubiquitin ligase Nedd4L to activated Smad2/3, which in turn promotes their ubiquitin-mediated degradation and attrition of activity. Inhibition of mTORC2 activity by both inhibitor supplementation and genetic manipulation, rather than modulation of Akt or mTORC1 activity, recapitulates the LY-mediated reduction of T220/T179 phosphorylation and increases the duration of Smad2/3 transcriptional activity, promoting a more robust mesendoderm and endoderm differentiation. These findings reveal a new and novel connection between the PI3K/mTOR and TGFβ/Activin pathways, which will greatly impact our understanding of both cell fate determination and the preservation of normal cellular functions. Notably, identification of mTORC2 as a key player in the regulation of this differentiation provides new avenues through which hESCs differentiation protocols can be improved for both regenerative and biomedical applications.Open Acces

Axillary accessory breast carcinoma masquerading as axillary abscess: a case report

Accessory breast is a frequently seen developmental breast abnormality, commoner among Asians than Caucasians. This ectopic breast tissue shares many similarities as the normal breast tissue, and although subjected to the same pathological processes, accessory breast carcinoma is rare. As locations of the accessory breast may be variable, detection of pathological lesions through clinical examinations and standard diagnostic tools (i.e., mammogram) can be difficult. Staging and management should be tailored-made according to the location of the accessory breast as well as its known pattern of lymphatic drainage. We report a case of an intra-ductal carcinoma occurring in an axillary accessory breast

Axillary accessory breast carcinoma masquerading as axillary abscess: a case report

Accessory breast is a frequently seen developmental breast abnormality, commoner among Asians than Caucasians. This ectopic breast tissue shares many similarities as the normal breast tissue, and although subjected to the same pathological processes, accessory breast carcinoma is rare. As locations of the accessory breast may be variable, detection of pathological lesions through clinical examinations and standard diagnostic tools (i.e., mammogram) can be difficult. Staging and management should be tailored-made according to the location of the accessory breast as well as its known pattern of lymphatic drainage. We report a case of an intra-ductal carcinoma occurring in an axillary accessory breast

Modelling failure pressure of pipeline composite repair design using finite element analysis incorporating putty’s contribution

A composite repair system which consists of Fibre Reinforced Polymer (FRP) and putty as infill material has been proven effective in repairing pipeline system as it can structurally reinforce the damaged steel pipes and potentially prevent external corrosion. However, previous studies including the design codes are neglecting the contribution of putty as they assume putty is only functioned to fill the corroded section. A recent study has pointed out that putty is not only limited to transfer the load, but it can serve as a load bearing component. Thus, the purpose of this research is to model the contribution of putty in terms of load bearing capacity through finite element analysis (FEA) and mathematical modelling. Two finite elements models were utilized to study the performance of two different material properties of putties used to repair externally corroded pipeline followed by regression analysis. It was found that by incorporating the strength contribution of putty, there are potential to increase the burst pressure by about 5%. The finding of this research is significant as it can serve as a stepping stone towards design optimization of pipeline rehabilitation

Shear Strengthening of Reinforced Concrete Beams Using GFRP

Background: Glass fibre-reinforced polymer (GFRP) is often used as external strengthening material due to its unique benefits. However, the effectiveness of the strengthening configuration, which uses GFRP in different orientations, still has a lot of uncertainties. Objective: This research work aims to study the shear strengthening of reinforced concrete beams using GFRP. Methods: The mechanical properties of the GFRP were investigated, including tensile and flexural tests. Two layers of GFRP were bonded together using epoxy and a hardener of 2:1. The GFRP was then cut according to size for tensile and flexural tests. Five samples were prepared for tensile and flexural tests, respectively. In terms of beam strengthening, a total of four beams were considered for four-point bending tests, whereby two were used as control beams and the remaining two were for strengthening purposes. A 45º strengthening configuration was adopted for the shear strengthening. Results: Results showed that GFRP possessed the highest tensile stress, which was achieved in the range of 208.85 MPa – 319.22 MPa, while the highest flexural stress was achieved in the range of 506.16 MPa – 592.49 MPa. The results showed that shear strengthening at 45º with GFRP achieved an ultimate load of 136.38 kN, which was higher than the control beam's load of 133 kN. This indicates that GFRP managed to regain the beam capacity, which is 2.5% higher than the control beam. Conclusion: This proves that GFRP can be used as an alternative strengthening material other than carbon fibre-reinforced polymer (CFRP)

Efficacy of low residue enteral formula versus clear liquid diet during bowel preparation for colonoscopy: a randomised controlled pilot trial

Objectives: Conventional bowel preparation for colonoscopy confines patient to clear liquid diet the day before and such non-nutritive dietary regimen often caused discomfort and hunger. The purpose of this study is to determine the feasibility of feeding patient with low-residue, lactose-free semi-elemental enteral formula (PEPTAMEN®) compare to conventional clear liquid diet during bowel preparation before colonoscopy. Methods: This was a randomised, endoscopist-blinded study. Patients were randomised into two groups, those receiving oral PEPTAMEN® and mechanical bowel preparation (A) and those receiving clear liquid while undergoing mechanical bowel preparation (B). Documentation was made with regard to the type of bowel cleansing agents used, completeness of the colonoscopy, cleanliness quality score, and hunger score. Results: A total of 97 patients were included in the study, A=48 and B=49. Eight patients, who were not compliant to the bowel-cleansing agent or had an incomplete colonoscopic examination, were excluded from the study. In terms of the overall cleanliness score, no statistical significant difference was seen (p=0.25) between the two groups, A (fair or poor 37.5%, good or excellent 62.5%) and B (fair or poor 49%, good or excellent 51%) whereas the hunger score showed a significant difference (p=0.016), A (no hunger 41.7%, slight hunger 12.5%, hungry 12.5%) and B (no hunger 24.5%, slight hunger 38.8%, hungry 36.7%). Conclusions: These data suggest that the addition of oral PEPTAMEN® as part of the bowel preparation regimen did not significantly alter the luminal cleanliness score during colonoscopy while alleviating hunger

Sex recognition by odour and variation in the uropygial gland secretion in starlings

1. Although a growing body of evidence supports that olfaction based on chemical compounds emitted by birds may play a role in individual recognition, the possible role of chemical cues in sexual selection of birds has been only preliminarily studied.2. We investigated for the first time whether a passerine bird, the spotless starling Sturnus unicolor, was able to discriminate the sex of conspecifics by using olfactory cues and whether the size and secretion composition of the uropygial gland convey information on sex, age and reproductive status in this species.3. We performed a blind choice experiment during mating, and we found that starlings were able to discriminate the sex of conspecifics by using chemical cues alone. Both male and female starlings preferred male scents. Furthermore, the analysis of the chemical composition of the uropygial gland secretion by using gas chromatography–mass spectrometry (GC–MS) revealed differences between sexes, ages and reproductive status.4. In conclusion, our study reveals for first time that a passerine species can discriminate the sex of conspecifics by relying on chemical cues and suggests that the uropygial gland secretion may potentially function as a chemical signal used in mate choice and/or intrasexual competition in this species.This research was funded by the Spanish Ministry of Education and Science ⁄ FEDER (CGL2008-00718) and PIE 200930I029 to J. M. Avilés and D. Parejo.The study was conducted under licence of the Junta de Andalucía GC–MS analyses were performed by Dr. Rafael Núñez at the Scientific Instrumentation Service (EEZ, CSIC) (Granada, Spain).Peer reviewe

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology

The Yuan-Tseh Lee Array for Microwave Background Anisotropy

The Yuan-Tseh Lee Array for Microwave Background Anisotropy (AMiBA) is the first interferometer dedicated to studying the cosmic microwave background (CMB) radiation at 3mm wavelength. The choice of 3mm was made to minimize the contributions from foreground synchrotron radiation and Galactic dust emission. The initial configuration of seven 0.6m telescopes mounted on a 6-m hexapod platform was dedicated in October 2006 on Mauna Loa, Hawaii. Scientific operations began with the detection of a number of clusters of galaxies via the thermal Sunyaev-Zel'dovich effect. We compare our data with Subaru weak lensing data in order to study the structure of dark matter. We also compare our data with X-ray data in order to derive the Hubble constant.Comment: accepted for publication in ApJ (13 pages, 7 figures); a version with high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/pho_highreso.pd