An Empirical Study of the Impact of Free Cash Flow on Overinvestment: Based on the data of China's listed real estate companies from 2010 to 2018

Modern corporate structures have led to a gradual separation of ownership and control of the firm, which has led to an increase in agency problems. Free cash flow and over-investment caused by agency problems have begun to receive attention from researchers in recent years. Based on the 2010-2018 data of listed real estate companies in China, this research adopts a quantitative research approach to verify the link between free cash flow and over-investment and finds a positive correlation between free cash flow and over-investment. Firms with more free cash flow face more severe overinvestment. However, overinvestment due to free cash flow is also influenced by several factors, such as managerial overconfidence, type of ownership, equity concentration, institutional ownership, and managerial ownership. A discussion of these factors reveals that state-owned enterprise (SOEs) are more subject to political control and that increased equity concentration is not an effective deterrent to free cash flow over-investment. The virtual absence of major owners in SOEs leads to multiple levels of principal-agent relationships and weak supervision of regulators. Overinvestment in non-state holding companies is more sensitive to free cash flow than in state-owned companies because private firms are freer and thus overinvestment is more severe. In the case of non-state-owned holding companies, equity concentration can unify the interests of the majority shareholders and the company, thus providing an incentive for the majority shareholders to take on the responsibility of supervising management. Also, the appropriate use of institutional and managerial shareholdings can, for all enterprises, discourage over-investment to some extent

Combinatorial approach to identify electronically cloaked hollow nanoparticles

The possibility of designing core-shell nanoparticles that are “invisible” to the conduction electrons has been demonstrated recently. A total scattering cross section smaller than 0.01% of the physical cross section was demonstrated by artificially adjusting the parameters of the barrier and the well in a core-shell geometry. In this paper, we aim to extend the developed concept and find realistic material combinations that satisfy the cloaking criteria. We report designs of hollow nanoparticles that could be used to realize the cloaking concept in III–V semiconductor host matrices. Such particles could be used in advanced materials design to enhance and tune the electrical and the thermoelectric properties of a given host matrix. This paper may also contribute to defect engineering by coating defect sites with a proper cloaking layer.United States. Dept. of Energy. Office of Basic Energy Sciences (Award DE-FG02-09ER46577

DAAM1 Is a Formin Required for Centrosome Re-Orientation during Cell Migration

BACKGROUND: Disheveled-associated activator of morphogenesis 1 (DAAM1) is a formin acting downstream of Wnt signaling that is important for planar cell polarity. It has been shown to promote proper cell polarization during embryonic development in both Xenopus and Drosophila. Importantly, DAAM1 binds to Disheveled (Dvl) and thus functions downstream of the Frizzled receptors. Little is known of how DAAM1 is localized and functions in mammalian cells. We investigate here how DAAM1 affects migration and polarization of cultured cells and conclude that it plays a key role in centrosome polarity. METHODOLOGY/PRINCIPAL FINDINGS: Using a specific antibody to DAAM1, we find that the protein localizes to the acto-myosin system and co-localizes with ventral myosin IIB-containing actin stress fibers. These fibers are particularly evident in the sub-nuclear region. An N-terminal region of DAAM1 is responsible for this targeting and the DAAM1(1-440) protein can interact with myosin IIB fibers independently of either F-actin or RhoA binding. We also demonstrate that DAAM1 depletion inhibits Golgi reorientation in wound healing assays. Wound-edge cells exhibit multiple protrusions characteristic of unpolarized cell migration. Finally, in U2OS cells lines stably expressing DAAM1, we observe an enhanced myosin IIB stress fiber network which opposes cell migration. CONCLUSIONS/SIGNIFICANCE: This work highlights the importance of DAAM1 in processes underlying cell polarity and suggests that it acts in part by affecting the function of acto-myosin IIB system. It also emphasizes the importance of the N-terminal half of DAAM1. DAAM1 depletion strongly blocks centrosomal re-polarization, supporting the concept that DAAM1 signaling cooperates with the established Cdc42 associated polarity complex. These findings are also consistent with the observation that ablation of myosin IIB but not myosin IIA results in polarity defects downstream of Wnt signaling. The structure-function analysis of DAAM1 in cultured cells parallels more complex morphological events in the developing embryo

Combinatorial approach to identify electronically cloaked hollow nanoparticles

The possibility of designing core-shell nanoparticles that are “invisible” to the conduction electrons has been demonstrated recently. A total scattering cross section smaller than 0.01% of the physical cross section was demonstrated by artificially adjusting the parameters of the barrier and the well in a core-shell geometry. In this paper, we aim to extend the developed concept and find realistic material combinations that satisfy the cloaking criteria. We report designs of hollow nanoparticles that could be used to realize the cloaking concept in III–V semiconductor host matrices. Such particles could be used in advanced materials design to enhance and tune the electrical and the thermoelectric properties of a given host matrix. This paper may also contribute to defect engineering by coating defect sites with a proper cloaking layer.United States. Dept. of Energy. Office of Basic Energy Sciences (Award DE-FG02-09ER46577

Simplified, Enhanced Protein Purification Using an Inducible, Autoprocessing Enzyme Tag

We introduce a new method for purifying recombinant proteins expressed in bacteria using a highly specific, inducible, self-cleaving protease tag. This tag is comprised of the Vibrio cholerae MARTX toxin cysteine protease domain (CPD), an autoprocessing enzyme that cleaves exclusively after a leucine residue within the target protein-CPD junction. Importantly, V. cholerae CPD is specifically activated by inositol hexakisphosphate (InsP6), a eukaryotic-specific small molecule that is absent from the bacterial cytosol. As a result, when His6-tagged CPD is fused to the C-terminus of target proteins and expressed in Escherichia coli, the full-length fusion protein can be purified from bacterial lysates using metal ion affinity chromatography. Subsequent addition of InsP6 to the immobilized fusion protein induces CPD-mediated cleavage at the target protein-CPD junction, releasing untagged target protein into the supernatant. This method condenses affinity chromatography and fusion tag cleavage into a single step, obviating the need for exogenous protease addition to remove the fusion tag(s) and increasing the efficiency of tag separation. Furthermore, in addition to being timesaving, versatile, and inexpensive, our results indicate that the CPD purification system can enhance the expression, integrity, and solubility of intractable proteins from diverse organisms

Plasma Clusterin and the CLU Gene rs11136000 Variant Are Associated with Mild Cognitive Impairment in Type 2 Diabetic Patients

Objective: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. Methods: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study. Demographic parameters were collected and neuropsychological tests were conducted. Plasma clusterin and CLU rs11136000 genotype were examined.Results: Plasma clusterin was significantly higher in MCI patients than in control group (p=0.007). In subjects with MCI, plasma clusterin level was negatively correlated with Montreal cognitive assessment and auditory verbal learning test_delayed recall scores (p=0.027 and p=0.020, respectively). After adjustment for age, educational attainment, and gender, carriers of rs11136000 TT genotype demonstrated reduced risk for MCI compared with the CC genotype carriers (OR=0.158, χ2=4.113, p=0.043). Multivariable regression model showed that educational attainment, duration of diabetes, HDL-c, and plasma clusterin levels are associated with MCI in T2DM patients.Conclusions: Plasma clusterin was associated with MCI and may reflect a protective response in T2DM patients. TT genotype exhibited a reduced risk of MCI compared to CC genotype. Further investigations should be conducted to determine the role of clusterin in cognitive decline

PO-062 Acute exercise intervention combined with metformin’s influences on glucose homeostasis in T2D mice

Objective Type 2 diabetes mellitus is a common chronic diseases prevailing in the world and the amount of diabetic and pre-diabetic patients is increasing gradually. Exercise combined with hypoglycemic drug is the first recommended therapy to treat type 2 diabetes. Metformin was found from galegine in 1957 and has been used now as the first cheap and effective hypoglycemic guanidines. Our study aims to explore the effects of different ways of acute exercise intervention combined with high dose of metformin on glucose homeostasis and its relative molecular mechanisms in type 2 diabetic mice. Methods Adopt 4-week high fat diet (HFD, 45% fat content) and one-time STZ (Streptozocin, 100mg/kg) intraperitoneal injection to build type 2 diabetic mice. There are 84 mice in total, 24 mice were divided into three groups: normal control (NC) group, normal acute resistance training (NCR) group and normal acute endurance training (NCE) group, N=8 each group, they were fed normal chow. The rest 60 mice were fed HFD as T2D modeling group. 48 mice were developing type 2 diabetes and they were divided into 6 groups: diabetic control (DC) group, diabetic acute resistance training (DCR) group, diabetic acute endurance training (DCE) group, high dose of metformin control (HMC) group, high dose of metformin combined with acute resistance training (HMR) group and high dose of metformin combined with acute endurance training (HME) group, N=8 each group. Acute resistance training is climbing 1 meter ladder from down to up, 5 times a group, 3 groups in total, monitoring the glucose change with extracting mouse tail vein blood during each group, using ACCU-CHEK monitor. Acute endurance training is running at the speed of 18 m/min on the platform for 50 minutes and blood glucose change was monitored every 10 minutes by extracting mouse tail vein blood. HMC, HMR and HME group mice were intraperitoneally injected high dose of metformin (200mg/kg) one hour before the acute exercise intervention. Comparatively, NC, NCR, NCE, DC, DCR, DCE group mice were intraperitoneally injected 0.9% saline one hour before the acute exercise intervention. ELISA, RT-PCR and Western Blot were used to evaluate relative serum indicators, mRNA and protein expression of regulating blood glucose homeostasis. Results 1) 4-week high fat diet and one time 100mg/kg Streptozocin intraperitoneal injection induces mice to develop type 2 diabetes. The fasting blood glucose, IPGTT, ITT, glucose AUC and insulin AUC of T2D group mice are significantly higher than NC group. 2) Compared with DCR group, the blood glucose value and fluctuation of HMR group mice are both significantly decreased, but the blood glucose value of DCR and HMR group mice are significantly higher than NCR group. In the same way, the blood glucose value and fluctuation of HME group mice is lower than DCE group and the whole blood glucose level of both group are higher than NCE group. Acute resistance training and acute endurance training combined with high dose of metformin have not affected the weight of type 2 diabetic mice. Hence compared with HMC group, the eWAT (epididymal white adipose tissue) of HMR and HME group mice is significantly declined. 3) Compared with NC group, the indicators of serum glucose, GSP (glycosylated serum protein), serum TG and serum T-CHO of DC group are notably increased, further reflect that the success model of type 2 diabetic mice. Compared with HMC group, the indicators of serum glucose, GSP, serum TG and serum T-CHO of HMR group mice are notably decreased, in the mean time, the indicators of serum glucose and serum TG of HME group mice are significantly declined. Interestingly, the serum insulin of HME group mice is notably lower than HMR group. 4) Compared with DC group, the indicators of mRNA expression about hepatic gluconeogenesis key rate-limiting enzymes PEPCK and G6pase of HMC group are significantly declined, but mRNA expression of regulating hepatic glucose homeostasis GLUT2 of HMC group is notably raised. Compared with HMC group, G6Pase mRNA expression of HMR and HME group is significantly escalated and Fbp mRNA expression of both groups are significantly declined. Compared with HMC, the indicators of mRNA expression about regulating hepatic glucose homeostasis GLUT2 and Gck of HMR and HME group mice show opposite trend, the former is down and the latter is up. Compared with HMC group, PEPCK mRNA expression of HMR group mice is notably escalated. Compared with HMR group, PEPCK and G6Pase mRNA expression of HME group mice are notably raised. 5) In the liver, there is a signaling pathway of AMPKα-PGC-1α-CREB to regulate glucose homeostasis and hepatic gluconeogenesis. Our study find that compared with HMC group, AMPKα2, PGC-1α and CREB mRNA expression of HMR and HME group mice are notably increased and only AMPKα1 mRNA expression of HMR group mice is significantly increased. Conclusions 1) Acute resistance training and acute endurance training combined with high dose of metformin can effectively reduce glucose fluctuation during exercise in type 2 diabetic mice, therefore these two way can both improve glucose homeostasis during acute exercise intervention in type 2 diabetic mice. 2) Acute resistance training and acute endurance training combined with high dose of metformin can improve serum glucose and lipid metabolism in type 2 diabetic mice, but acute resistance training combined with high dose of metformin are better to improve serum lipid metabolism. 3) Acute exercise intervention combined with high dose of metformin can comparatively increase hepatic gluconeogenesis key rate-limiting enzymes PEPCK and G6Pase and regulating hepatic glucose transport Gck mRNA expression. In the opposite, these two ways inhibit the other hepatic gluconeogenesis key rate-limiting enzyme Fbp and regulating hepatic glucose transport GLUT2 mRNA expression. 4) Compared with acute endurance training combined with high dose of metformin, acute resistance training combined with high dose of metformin can better improve glucose homeostasis and hepatic gluconeogenesis in type 2 diabetic mice via the signaling pathway of AMPKα-PGC-1α-CREB

Caloric restriction delays age-related muscle atrophy by inhibiting 11β−HSD1 to promote the differentiation of muscle stem cells

IntroductionCalorie restriction (CR) is an important direction for the delay of sarcopenia in elderly individuals. However, the specific mechanisms of CR against aging are still unclear.MethodsIn this study, we used a CR model of elderly mice with muscle-specific 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) knockout mice and 11β-HSD1 overexpression mice to confirm that CR can delay muscle aging by inhibiting 11β-HSD1 which can transform inactive GC(cortisone) into active GC(cortisol). The ability of self-proliferation and differentiation into muscle fibers of these mouse muscle stem cells (MuSCs) was observed in vitro. Additionally, the mitochondrial function and mitochondrial ATP production capacity of MuSCs were measured by mitochondrial oxygen consumption.ResultsIt was found that the 11β-HSD1 expression level was increased in age-related muscle atrophy. Overexpression of 11β-HSD1 led to muscle atrophy in young mice, and 11β-HSD1 knockout rescued age-related muscle atrophy. Moreover, CR in aged mice reduced the local effective concentration of glucocorticoid (GC) through 11β-HSD1, thereby promoting the mitochondrial function and differentiation ability of MuSCs.ConclusionsTogether, our findings highlight promising sarcopenia protection with 40% CR in older ages. Furthermore, we speculated that targeting an 11β-HSD1-dependent metabolic pathway may represent a novel strategy for developing therapeutics against age-related muscle atrophy

Oral delivery of il-27 recombinant bacteria attenuates immune colitis in mice

BACKGROUND & AIMS: Treatment of inflammatory bowel disease (IBD) would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine IL27, which is actively synthesized in situ by the food-grade bacterium Lactococcuslactis (LL-IL-27), and tested its ability to reduce colitis in mice. METHODS: The 2 genes encoding mouse IL27 were synthesized with optimal codon usage for L lactis and joined with a linker; a signal sequence was added to allow for secretion of the product. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(−/−) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed. RESULTS: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced numbers of CD4(+) and IL17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice following administration of dextran sodium sulfate. CONCLUSIONS: L lactis engineered to express IL27 (LL-IL-27) reduces colitis in mice, by increasing production of IL10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for IBD