Primary metabolic pathways to high-energy molecules in yeasts

A cell is the basic unit of life, where metabolism takes place. The three main purposes of metabolism are the conversion of fuel (food) to energy for cellular processes, conversion of nutrients to cellular building blocks, and also the generation of wastes and sometimes the recycle of valuable elements from those wastes. Metabolites, the (small) molecules circulating around in all cells, are not only the passive participants in metabolic reactions but also essential parts of metabolic pathway regulations. Commonly, due to experimental limitations, we extract metabolites and measure their concentrations as an average value of the same metabolite in different compartments. Similar to the Heisenberg’s uncertainty principle, now we have a accuracy dilemma in quantitative metabolomics: we “cannot” measure the immediate steady-state value of metabolites if we extract a certain cellular organelle for the spatial information of metabolite distributions. However, if we define our biological focus clearly and utilize the power of mathematics and chemistry (mostly linear algebra and isotopic labeling), we can resolve this dilemma in many compartmentalized reactions. The work described here demonstrates the power of stable isotopic tracing in deciphering unique metabolic phenomenon in different yeast chassis strains, covering major primary metabolic pathways (glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, and folate cycle). Moreover, scientific discoveries from this work will provide a base to unlock biomanufacturing potentials in these synthetic biology platforms. As NADPH production is the cellular powerhouse for biosynthesis and carbon economy is the hottest development of human society in 21th century, this work carefully explores the intrisic metabolic features on up-scaling NADPH supply and maximizing the carbon efficiency in yeasts with great industrialization potentials, namely, Saccharomyces cerevisae, Rhodosporidium toruloides, and Yarrowia Lipolytica

Do street-level scene perceptions affect housing prices in Chinese megacities? An analysis using open access datasets and deep learning.

Many studies have explored the relationship between housing prices and environmental characteristics using the hedonic price model (HPM). However, few studies have deeply examined the impact of scene perception near residential units on housing prices. This article used house purchasing records from FANG.com and open access geolocation data (including massive street view pictures, point of interest (POI) data and road network data) and proposed a framework named "open-access-dataset-based hedonic price modeling (OADB-HPM)" for comprehensive analysis in Beijing and Shanghai, China. A state-of-the-art deep learning framework and massive Baidu street view panoramas were employed to visualize and quantify three major scene perception characteristics (greenery, sky and building view indexes, abbreviated GVI, SVI and BVI, respectively) at the street level. Then, the newly introduced scene perception characteristics were combined with other traditional characteristics in the HPM to calculate marginal prices, and the results for Beijing and Shanghai were explored and compared. The empirical results showed that the greenery and sky perceptual elements at the property level can significantly increase the housing price in Beijing (RMB 39,377 and 6011, respectively) and Shanghai (RMB 21,689 and 2763, respectively), indicating an objectively higher willingness by buyers to pay for houses that provide the ability to perceive natural elements in the surrounding environment. This study developed quantification tools to help decision makers and planners understand and analyze the interaction between residents and urban scene components

A Low-Power Stable Wideband Current Source for Acupuncture Point Skin Impedance Measurements

A low-power stable wideband current source for acupuncture point skin impedance measurements has been designed employing a differential architecture and negative feedback. The circuits extend bandwidth to 1 MHz, reducing harmonic distortion to 0.24% at 1 MHz. The output impedance is 37 MΩ at 100 kHz and 11 MΩ at 1 MHz. The stability of the output current of the current source when connected to different loads is below 0.1% at frequencies up to 500 kHz and increases to 0.74% at 1 MHz. The circuit was manufactured in a 0.13-μm CMOS technology and measured results are presented. The area of the current source is 0.09 mm2 and its consumption is 1.2 mW. It is intended for low-power acupuncture point skin impedance measurements

Chemerin: A Functional Adipokine in Reproductive Health and Diseases

As a multifaceted adipokine, chemerin has been found to perform functions vital for immunity, adiposity, and metabolism through its three known receptors (chemokine-like receptor 1, CMKLR1; G-protein-coupled receptor 1, GPR1; C-C motif chemokine receptor-like 2, CCRL2). Chemerin and the cognate receptors are also expressed in the hypothalamus, pituitary gland, testis, ovary, and placenta. Accumulating studies suggest that chemerin participates in normal reproduction and underlies the pathological mechanisms of certain reproductive system diseases, including polycystic ovary syndrome (PCOS), preeclampsia, and breast cancer. Herein, we present a comprehensive review of the roles of the chemerin system in multiple reproductive processes and human reproductive diseases, with a brief discussion and perspectives on future clinical applications

An analytical model for rapid prediction and compensation of springback for chain-die forming of an AHSS U-channel

Chain-die forming is an emerging technique for manufacturing AHSS component as an alternative to roll forming. The pronounced springback of AHSS due to their high strength is a key factor in chain-die blocks design. In this paper, a modified Chaboche hardening model that assumes a Hollomon–Voce combined equation and incorporates variation of elastic modulus is established to better describe hardening behaviors of AHSS. An analytical method for rapid prediction of springback of a U-channel is developed and then combined with an optimization algorithm to minimize springback. The springback compensation is validated by a chain-die forming experiment of a QP1180 U-channel by using the optimal die blocks. The proposed analytical modeling method provides a fast and effective tool for die block design of U-channel chain-die forming

Table1_Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression.XLSX

Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.</p

Placental trophoblast-specific overexpression of chemerin induces preeclampsia-like symptoms

Maternal circulating levels of the adipokine chemerin are elevated in preeclampsia, but its origin and contribution to preeclampsia remain unknown. We therefore studied (1) placental chemerin expression and release in human pregnancy, and (2) the consequences of chemerin overexpression via lentivirus-mediated trophoblast-specific gene manipulation in both mice and immortalized human trophoblasts. Placental chemerin expression and release were increased in women with preeclampsia, and their circulating chemerin levels correlated positively with the soluble Fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, a well-known biomarker of preeclampsia severity. Placental trophoblast chemerin overexpression in mice induced a preeclampsia-like syndrome, involving hypertension, proteinuria, and endotheliosis, combined with diminished trophoblast invasion, a disorganized labyrinth layer, and up-regulation of sFlt-1 and the inflammation markers nuclear factor-κB (NFκB), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. It also led to embryo resorption, while maternal serum chemerin levels correlated negatively with fetal weight in mice. Chemerin overexpression in human trophoblasts up-regulated sFlt-1, reduced vascular endothelial factor-A, and inhibited migration and invasion, as well as tube formation during co-culture with human umbilical vein endothelial cells (HUVECs). The chemokine-like receptor 1 (CMKLR1) antagonist α-NETA prevented the latter phenomenon, although it did not reverse the chemerin-induced down-regulation of the phosphoinositide 3-kinase/Akt pathway. In conclusion, up-regulation of placental chemerin synthesis disturbs normal placental development via its CMKLR1 receptor, thereby contributing to fetal growth restriction/resorption and the development of preeclampsia. Chemerin might be a novel biomarker of preeclampsia, and inhibition of the chemerin/CMKLR1 pathway is a promising novel therapeutic strategy to treat preeclampsia

Targeted delivery of doxorubicin by CSA-binding nanoparticles for choriocarcinoma treatment

<p>Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles <i>in vitro</i>. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis <i>in vivo</i>. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.</p