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Abstract Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia.

Abstract Engrailed‐1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain‐ and loss‐of‐function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

Acute myeloid leukemia (AML) therapy involves compounds that are cytotoxic to both normal and cancer cells, and relapsed AML is resistant to subsequent chemotherapy. Thus, agents are needed that selectively kill AML cells with minimal toxicity. Here, we report that AML is dependent on DDX5 and that inhibiting DDX5 expression slows AML cell proliferation in vitro and AML progression in vivo but is not toxic to cells from normal bone marrow. Inhibition of DDX5 expression in AML cells induces apoptosis via induction of reactive oxygen species (ROS). This apoptotic response can be blocked either by BCL2 overexpression or treatment with the ROS scavenger N-acetyl-L-cysteine. Combining DDX5 knockdown with a BCL2 family inhibitor cooperates to induce cell death in AML cells. By inhibiting DDX5 expression in vivo, we show that DDX5 is dispensable for normal hematopoiesis and tissue homeostasis. These results validate DDX5 as a potential target for blocking AML.

The reverse osmosis (RO) technology is currently the leading desalination method. However, until recently, application of RO technology on a large scale has been primarily limited by membrane fouling. The mechanism of fouling is complex, which is not well understood in full-scale plants. Although many studies about modeling and prediction of fouling have been done, in most cases, the experimental data set of lab or pilot scale systems, which may not show fouling characteristics well in full-scale systems were used. In this study, both artificial neural network (ANN) model and tree model (TM) was evaluated to analyze long-term performance of full scale reverse osmosis desalination plant. The results of application of the ANN and TM indicated high correlation coefficients between the measured and simulated output variables. However, it is not easy to use ANN for the full scale plant operation because the final model is not expressed as a form of mathematical functions. TM has advantages over ANN because the model can be obtained as forms of simple function and it showed reasonably high R². Therefore, TM is shown to be more adequate than ANN for developing models in which the full-scale RO plant data is considered as an input. [ABSTRACT FROM AUTHOR]

The occurrence of natural disasters such as floods, droughts, and earthquakes may cause water supply to stop working, which may also lead to social disasters and economic damages. Therefore, it is essential to prepare an emergency response management system to prepare disasters in water treatment infrastructures. In this study, a decision support system (DSS) responding to an emergency was proposed to systematically address possible problems in water treatment plants affected by various disasters. The DSS consists of several modules in the stages for planning, disaster sensing, and response and each module was developed based on a different approach depending on its function and purpose. The paper illustrates each module in detail and discusses the application in the proposed situation. [ABSTRACT FROM AUTHOR]

This study focused on the comparison of inside-out or outside-in membrane distillation (MD) modules under the conditions where fouling due to scale formation occurs. Experiments were carried out using a laboratory-scale direct contact MD setup. Synthetic feed water containing NaCl of 200,000 mg/L and CaSO4 of 2,000 mg/L was used for accelerated fouling tests. In-house MD mini modules were fabricated and operated either in the inside-out or outside-in modes. Results showed that the initial flux of the inside-out MD module was slightly higher than the outside-in MD module under no fouling conditions. The temperature difference was maintained at 40°C (feed inlet: 60°C; distillate: 20°C). The flow rate of the feed was the same as that of the distillate, which was 0.4 L/min. The average flux values of the inside-out and outside-in modes were, approximately, 1.56 and 1.42 kg/m²h, respectively. However, a more rapid decline of flux due to scale formation occurred in the inside-out MD modules compared with the outside-in MD modules under the same operating condition. The blocking coefficient was initially very low and suddenly increased after the volume of concentration factor (VCF) of 1.35 in the case of the inside-out mode. The blocking coefficient started to increase after the VCF of 1.75 in the case of the outside-in mode. Different mechanisms for scale formation in the inside-out and outside-in modes were suggested to elucidate the results of fouling tests, which were also supported by the scanning electron microscope analysis. [ABSTRACT FROM AUTHOR]

Although membrane distillation (MD) has great promise for desalination of saline water sources, it is crucial to improve its thermal efficiency to reduce the operating cost. Accordingly, this study intended to examine the thermal energy efficiency of MD modules in a pilot scale system. Two different modules of hollow fiber membranes were compared in direct contact MD mode. One of them was made of polypropylene with the effective membrane area of 2.6 m2 and the other was made of polyvinylidene fluoride with the effective membrane area of 7.6 m2. The influence of operation parameters, including the temperatures of feed and distillate, feed flow rate, and distillate flow rate on the flux, recovery, and performance ratio (PR), was investigated. Results showed that the two MD membranes showed different flux and PR values even under similar conditions. Moreover, both flow rate and temperature difference between feed and distillate significantly affect the PR values. These results suggest that the operating conditions for MD should be determined by considering the module properties. [ABSTRACT FROM AUTHOR]

A major obstacle to further incorporation of microfiltration (MF) membrane processes in water treatment plants is trans-membrane pressure (TMP) increase due to membrane fouling. Modelling and simulation of changes in TMP may be useful to describe fouling through the identification of the most relevant operating conditions. In this study, M5P model tree was applied to predict the fouling of the pilot scale MF system for drinking water. A 500 m³/d MF pilot plant was operated for 1 year to analyze the performance of MF process under various operating conditions. The effects of operating parameters on membrane performance were evaluated based on the comparison of TMP as a function of operating time. The M5P model tree used five input variables including turbidity (NTU), temperature (°C), total organic carbon (mg/L), total operating period (d) and operating period after clean in place (d). The results of application of the M5P model tree indicated high correlation coefficients between the measured and predicted output variables. Therefore, it appears that the M5P model tree is applicable in the long-term prediction of the membrane performance in the pilot-scale MF systems. [ABSTRACT FROM AUTHOR]

This paper investigated the feasibility and limitation of statistical models to predict membrane fouling in a pilot-scale system. Operation data from an MF pilot plant with the capacity of 440 m³/d were used for the application of these models. Water quality parameters including feed water turbidity, algae concentration, total organic carbon, dissolved organic carbon, and UV254 absorbance were correlated with transmembrane pressure, total resistance, and the rate of resistance change. Model fit equations were derived from multiple linear regression, artificial neural network, genetic programming, and support vector machine. The performances of models were compared in terms of accuracy and prediction capability. [ABSTRACT FROM AUTHOR]

Thermal effluents discharged from thermal power plants are problematic because of their adverse impact on receiving environments. Accordingly, it is necessary to develop technologies to mitigate the effect of thermal effluents on the aquatic environment. In this study, membrane distillation (MD) was applied to treat thermal effluents for the first time. Because MD can be operated by utilizing temperature difference between feed and product, it may produce freshwater from thermal effluents and reduce their temperature by transferring latent heat. To examine its feasibility, experiments were carried out in a semi-pilot direct contact MD equipment under various operating conditions. Based on real thermal effluent conditions, synthetic feed solutions were prepared. A series of experiments were conducted to measure flux, performance ratio, and temperature of the feed using a semi-pilot hollow fiber MD system during the treatment of the synthetic thermal effluents by MD. Results showed that MD hold potential to reduce the volume and temperature of the thermal effluents, thereby mitigating their possible impact. [ABSTRACT FROM AUTHOR]

Although many studies have been done on membrane distillation (MD) for seawater desalination and wastewater treatment, relatively few works have been done in pilot- or full-scale plants. Accordingly, this study intended to investigate the performance of a vacuum MD system at pilot scale. Factors affecting MD flux were examined, including feed temperature, feed flow rate, and applied vacuum. Results showed that the MD flux was almost linearly proportional to feed temperature and flow rate. Moreover, the flux was also sensitive to the applied vacuum. Based on the analysis, the minimum feed temperature and vacuum to operate the MD pilot plant were determined to be 56°C and 0.28 bar, respectively. The flux and energy utilization ratio were analyzed as a function of feed temperature and flow rate, indicating that the feed temperature should be over 69°C to obtain flux over 4 kg/m2 h and the feed flow rate should be over 5.6 m³ /h to achieve energy utilization ratio above 0.65. [ABSTRACT FROM AUTHOR]

Although membrane distillation (MD) holds promise as an emerging desalination technology, relatively few studies were carried out to analyze energy efficiency of MD modules. Accordingly, this study intended to establish an energy balance for a 1 m² hollow fiber MD module. Experiments were carried out under a semi-pilot direct contact MD equipment. The feed and distillate temperatures were adjusted from 50°C to 60°C and from 25°C to 35°C, respectively. The feed and distillate flow rates ranged from 0.6 to 1.2 m³ /h. A performance ratio was evaluated from a thermal energy balance in each operation condition. Results showed that the feed flow rate and temperature difference greatly affect water flux (productivity) and performance ratio (energy efficiency). The conductive heat loss through the membrane was found to be substantial, which decreased with a reduction in the temperature difference. The performance ratio was proportional to the single pass water recovery of the MD module, suggesting that the sufficient feed flow rate is required for efficient operation of MD. [ABSTRACT FROM AUTHOR]

Programmable memory built-in self-test (PMBIST) is an attractive approach for testing embedded memory. However, the main difficulties of the previous works are the large area overhead and low flexibility. To overcome these problems, a new flexible PMBIST (FPMBIST) architecture that can test both single-port memory and dual-port memory using various test algorithms is proposed. In the FPMBIST, a new instruction set is developed to minimize the FPMBIST area overhead and to maximize the flexibility. In addition, FPMBIST includes a diagnostic scheme that can improve the yield by supporting three types of diagnostic methods for repair and diagnosis. The experiment results show that the proposed FPMBIST has small area overhead despite the fact that it supports various test algorithms, thus having high flexibility. [ABSTRACT FROM AUTHOR]

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both an increased level and the sustained translation of HIF1α mRNA. Sustained glycogen synthase kinase 3β inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1 abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2-/- cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2-/- cells to serum deprivation-induced apoptosis. [ABSTRACT FROM AUTHOR]

With the rapid increase occurring in both the capacity and density of memory products, test and repair issues have become highly challenging. Memory repair is an effective and essential methodology for improving memory yield. An SoC utilizes builtin redundancy analysis (BIRA) with built-in self-test for improving memory yield and reliability. This letter proposes a new heuristic algorithm and new hardware architecture for the BIRA scheme. Experimental results indicate that the proposed algorithm shows near-optimal repair efficiency in combination with low area and time overheads. [ABSTRACT FROM AUTHOR]

Peroxisome proliferators-activated receptor-γ (PPARγ), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPARγ mutations have features of the metabolic syndrome (severe insulin resistance, dyslipidemia, and hypertension). We created a knock-in mouse model containing a potent dominant negative PPARγ L466A mutation, shown previously to inhibit wild-type PPARγ action in vitro. Homozygous PPARγ L466A knock-in mice die in utero. Heterozygous PPARγ L466A knock-in (PPARKI) mice exhibit hypoplastic adipocytes, hypoadiponectinemia, increased serum-free fatty acids, and hepatic steatosis. When subjected to high fat diet feeding, PPARKI mice gain significantly less weight than controls. Hyperinsulinemic-euglycemic clamp studies in PPARKI mice revealed insulin resistance and reduced glucose uptake into skeletal muscle. Female PPARKI mice exhibit hypertension independent of diet. The PPARKI mouse provides a novel model for studying the relationship between impaired PPARγ function and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

We sought to elucidate the role of AKT in folliclestimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-α, microtubuleassociated protein 2D, and the PKA type IIβ regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSHstimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated upregulation of reporter activities for LHR, inhibin-α, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1α interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers. [ABSTRACT FROM AUTHOR]