Endomembrane PtdIns(3,4,5)P3 activates the PI3K–Akt pathway

PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)- trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex - they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P3, we show that PtdIns(3,4,5)P3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P3- dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention

Design and evaluation of a cassava milling machine

Abstract onlyCassava is one of the most important crops being produced in Region VI, specifically in the province of Capiz. It is commonly used as food for people and as feed for livestock animals. Basically, matured cassava is harvested and processed by chipping and sold in the market in powdered form. However, for medium-scale processors, converting cassava to powder form is a common problem. In order to address the need of medium-scale processors for a machine that will powder cassava, the Appropriate Technology Center, Department of Agricultural Engineering, College of Agriculture, Central Philippine University, Iloilo City, in collaboration with SUNLIT International, Inc., Jaro, Iloilo City, designed and developed a cassava milling machine. This machine was fabricated and its performance was evaluated in the months of June to August, 2002. The cassava milling machine consists of the following: a feeding hopper where dried, chipped cassava is fed; a milling cylinder where chipped cassava were being powdered through the impact action of fixed hammers; a discharge hopper where powdered cassava is collected; a suction blower which moves the powdered cassava vi pneumatically to the collector; and a cyclone separator for separating powdered cassava from the air for bagging. Performance evaluation revealed that the throughput capacity of the milling machine has an average of 327.5 kg/hr for the first pass and 640 kg/hr for the second pass. The machine has a capacity per hammer of 16.4 and 32.0 kg/hr-hammer, for the first and second pass, respectively. Similarly, it has a specific capacity of 1056.4 and 2064.5 kg/hr-m2 for the first and the second pass, respectively. The fuel consumption rate of the 7.5-Hp gasoline engine used to drive the machine ranged from 1.6 to 1.9 liters/hour. The machine can be operated by one person only. The cassava milling machine can be fabricated using commonly available tools and equipment. It requires an investment cost of P43,000.00 per unit, including the engine. It has a total operating cost of P512.73 per day. At a milling capacity of 1 ton per day, the cost of operating the machine is P0.51 per kg. At 2 tons per day capacity, the operating cost is P0.26 per kg. Cost return analysis showed that for the local and the export markets, the payback periods are 41 and 183 days, respectively. Benefit cost ratio is 2.79 for the local market while 12.54 for the export market. The return on investment is 199.53 and 897.12 percent for the local and the export market, respectively.Includes bibliographical reference

Molecular Recognition of Glycan-Bearing Glycomacromolecules Presented at Membrane Surfaces by Lectins: An NMR View

Lectin–glycan interactions are at the heart of a multitude of biological events. Glycans are usually presented in a multivalent manner on the cell surface as part of the so-called glycocalyx, where they interact with other entities. This multivalent presentation allows us to overcome the typical low affinities found for individual glycan–lectin interactions. Indeed, the presentation of glycans may drastically impact their binding by lectins, highly affecting the corresponding binding affinity and even selectivity. In this context, we herein present the study of the interaction of a variety of homo- and heteromultivalent lactose-functionalized glycomacromolecules and their lipid conjugates with two human galectins. We have employed as ligands the glycomacromolecules, as well as liposomes decorated with those structures, to evaluate their interactions in a cell-mimicking environment. Key details of the interaction have been unravelled by NMR experiments, both from the ligand and receptor perspectives, complemented by cryo-electron microscopy methods and molecular dynamics simulations.M.H. and L.H. thank the DFG for support through the ViroCarb research consortium (HA5950/5-2) and the CeMSA@HHU (Center for Molecular and Structural Analytics @ Heinrich-Heine University) for recording the mass spectrometric and the NMR-spectroscopic data for the structural conformation of the glycomacromolecules and their lipid conjugates. The CIC bioGUNE EM platform is also thanked for infrastructural support during cryo-EM data collection. The group in Spain thank the European Research Council (RECGLYCANMR, Advanced grant no. 788143), MCIN/AEI/10.13039/501100011033 for grants PDI2021-1237810B-C21, PID2021-126130OB-I00, CEX2021-001136-S, and CIBERES, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spain, for generous funding

One-step nucleic acid amplification (Osna) of sentinel lymph node in early-stage endometrial cancer: Spanish multicenter study (endo-osna)

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 µm intervals and examined by hematoxylin–eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/µL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

One-Step Nucleic Acid Amplification (OSNA) of Sentinel Lymph Node in Early-Stage Endometrial Cancer : Spanish Multicenter Study (ENDO-OSNA)

One-step nucleic acid amplification (OSNA) is an automated molecular diagnostic assay used to detect metastases by analyzing the levels of cytokeratin 19 mRNA in whole lymph nodes. It has been validated as an accurate and reliable tool for staging in several types of cancers and is included in the National Institute for Health and Care Excellence guidelines for the management of breast cancer. ENDO-OSNA is a large, observational, multicenter study designed to evaluate the efficacy of OSNA for the detection of sentinel lymph node (SLN) metastasis in patients with early-stage endometrial cancer. We found that the OSNA assay shows higher sensitivity, specificity, and diagnostic accuracy in the detection of SLN metastasis, including low-volume metastasis, compared to standard pathological ultrastaging. Moreover, OSNA could aid in the identification of patients with intermediate or high-risk endometrial cancer, and lead to treatment decisions that could improve their prognosis. The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study, and 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1 mm portion of each lymph node was subjected to semi-serial sectioning at 200 μm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analyzed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μL), the sensitivity of the OSNA assay was 92%, specificity was 82%, diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis

‘Proclaim Liberty Throughout All the Land unto All the Inhabitants Thereof!’:Reading Leviticus 25:10 Through the Centuries

This paper follows the text of Leviticus 25:10 in the Hebrew Bible and in selected works of the exegetical tradition of both Rabbinic Judaism and Western Christianity, in order to provide a lens through which to assess the use of a biblical text which was instrumental during the early modern period in formulating ideas about the republic and from thence to the modern liberal state. The main argument of the paper is that over time the meaning of the text shifted depending on the context in which it was read, ranging from the socio-economic to the salvific to the political. Further, all the authors cited here approached the text as an authoritative normative text, and did not look at the text as a textual artefact. While the move to re-introduce Jewish Sources into the debate in political theory is welcomed, it is argued that the results would be improved by balanced reading strategies and interaction with critical academic biblical scholarship

Relationships, love and sexuality: what the Filipino teens think and feel

<p>Abstract</p> <p>Background</p> <p>In order to achieve a change among teens' sexual behavior, an important step is to improve our knowledge about their opinions concerning relationships, love and sexuality.</p> <p>Methods</p> <p>A questionnaire including topics on relationships, love and sexuality was distributed to a target population of 4,000 Filipino students from third year high school to third year college. Participants were obtained through multi-stage sampling of clusters of universities and schools. This paper concentrates on teens aged 13 to 18.</p> <p>Results</p> <p>Students reported that they obtained information about love and sexuality mainly from friends. However, they valued parents' opinion more than friends'. They revealed few conversations with their parents on these topics. A majority of them would like to have more information, mainly about emotion-related topics. Almost half of respondents were not aware that condoms are not 100% effective in preventing STIs or pregnancies. More girls, compared to boys, were sensitive and opposed to several types of sexism. After adjusting for sex, age and institution, the belief of 100% condom effectiveness and the approval of pornography and sexism were associated with being sexually experienced.</p> <p>Conclusion</p> <p>There is room for further encouraging parents to talk more with their children about sexuality, specially aspects related to feelings and emotions in order to help them make better sexual choices. Indeed, teens wish to better communicate with their parents on these issues. Condoms are regarded as safer than what they really are by almost half of the participants of this study, and such incorrect knowledge seems to be associated with sexual initiation.</p

Candidiasis, Bacterial Vaginosis, Trichomoniasis and Other Vaginal Conditions Affecting the Vulva

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