Lfc subcellular localization and activity is controlled by αv-class integrin.

Fibronectin (FN)-binding integrins control a variety of cellular responses through Rho GTPases. The FN-binding integrins, αvß3 and α5ß1, are known to induce different effects on cell morphology and motility. Here, we report that FN-bound αvß3 integrin, but not FN-bound α5ß1 integrin, triggers the dissociation of the RhoA GEF Lfc (also known as GEF-H1 and ARHGEF2 in humans) from microtubules (MTs), leading to the activation of RhoA, formation of stress fibres and maturation of focal adhesions (FAs). Conversely, loss of Lfc expression decreases RhoA activity, stress fibre formation and FA size, suggesting that Lfc is the major GEF downstream of FN-bound αvß3 that controls RhoA activity. Mechanistically, FN-engaged αvß3 integrin activates a kinase cascade involving MARK2 and MARK3, which in turn leads to phosphorylation of several phospho-sites on Lfc. In particular, S151 was identified as the main site involved in the regulation of Lfc localization and activity. Our findings indicate that activation of Lfc and RhoA is orchestrated in FN-adherent cells in an integrin-specific manner.

Nonclinical pharmacokinetics, pharmacodynamics and safety assessment of a FLT3L-Fc molecule for cancer immunotherapy.

FLT3L-Fc is a cytokine-Fc fusion agonizing receptor-type tyrosine-protein kinase FLT3 (fms-related tyrosine kinase 3; CD135). FLT3 is expressed on dendritic cells (DCs) as well as myeloid and lymphoid progenitors. Nonclinical pharmacokinetics, pharmacodynamics and safety of FLT3L-Fc were investigated in rats and cynomolgus monkeys. FLT3L-Fc induced robust pharmacodynamic responses, evidenced by marked expansion of peripheral blood cDC1s, cDC2s, and pDCs (up to 301-fold in rats and 378-fold in monkeys), peaking at 8-10 days after the first dose. FLT3L-Fc was well tolerated with no adverse findings at doses up to 10 mg/kg administered intravenously twice three weeks apart. In both species, major clinical pathology findings consisted of expansion of white blood cell (WBC) populations including lymphocytes, monocytes, neutrophils, basophils, and large unstained cells, which were pronounced after the first dose. The WBC findings were associated microscopically with histiocytic and mononuclear cell infiltrates in multiple organs. Tissue immunohistochemistry in monkeys showed that the leukocyte infiltrates consisted of hematopoietic progenitor cells and histiocytes with a reactive morphology and were associated with a slight stimulation of regional T and B cell populations. Additional FLT3L-Fc-associated changes included decreases in red blood cell (RBC) mass, increases in RBC distribution width, variable changes in reticulocytes, and transient alterations in platelet counts (rats only). The RBC and WBC findings were associated microscopically with increased hematopoietic cellularity of the bone marrow in both species and increased splenic megakaryocytic extramedullary hematopoiesis in rats. The totality of nonclinical safety data support the clinical development of FLT3L-Fc.

Targeted dendrimers for antagonizing the migration and viability of NALM-6 lymphoblastic leukemia cells.

Acute lymphoblastic leukemia (ALL) or white blood cell cancer is one of the major causes that kills many children worldwide. Although various therapeutic agents are available for ALL treatment, the new drug discovery and drug delivery system are needed to improve their effectiveness, to reduce the toxicity and side-effect, and to enhance their selectivity to target cancer cells. CXCR4 is a protein expressed on the surface of various types of cancer cell including ALL. In this work, the CXCR4-targeted PAMAM dendrimer was constructed by conjugating G5 PAMAM with a CXCR4 antagonist, LFC131. The results revealed that the LFC131-conjugated G5 PAMAM selectively targeted CXCR4 expressing leukemic precursor B cells (NALM-6) and the migration of NALM-6 cells induced by SDF-1α was inhibited at non-cytotoxic concentration. Further research based on this findings may contribute to potential anti-metastatic drugs for lymphoblastic leukemia.

Resilient Adaptive Event-Triggered Load Frequency Control of Network-Based Power Systems against Deception Attacks.

This paper investigates the problem of networked load frequency control (LFC) of power systems (PSs) against deception attacks. To lighten the load of the communication network, a new adaptive event-triggered scheme (ETS) is developed on the premise of maintaining a certain control performance of LFC systems. Compared with the existing ETSs, the proposed adaptive ETS can adjust the number of triggering packets, along with the state changes in the presence of deception attacks, which can reduce the average data-releasing rate. In addition, sufficient conditions can be derived, providing a trade-off between the limited network communication resources and the desired control performance of PSs. Finally, an application case is presented for the PSs to demonstrate the advantages of the proposed approach.

Design, synthesis, bioevaluation of LFC- and PA-tethered anthraquinone analogues of mitoxantrone.

The clinical application of mitoxantrone (MTZ), a DNA-intercalating topoisomerase II (topo II) poison, has been largely limited by the risk of secondary tumor and severe myelosuppression. To develop more effective antineoplastic agents with less toxicity, a spectrum of anthraquinone analogues of MTZ were herein designed and synthesized based on the concept of 'enhancing protein backbone-binding', by rationally introducing hydrophobic long fatty acid chain (LFC) and hydrophilic polyamine (PA) components, which are reported to function as effective tumor-targeting tethers. The SAR exploration implicated that in our synthesized molecules, the introduction of both lipophilic LFC and hydrophilic PA fragment is plausibly beneficial to the anti-proliferative potency, with a certain degree of selectivity between the hematopoietic and solid malignant cells, which still need to be further accurately confirmed. Meanwhile, many compounds, the LFC-tethered 5d2 and PA-bridged 8c in particular, provided satisfactory topo IIα inhibition by acting as DNA non-intercalators, largely attributable to their strong adaptability to three binding regions (pocket I, II and III) and also the generated H-bonding interactions between inhibitors and key residues of topo IIα. In brief, 5d2 and 8c might be promising hits for further exploitation of more potent topo IIα inhibitors.

A method for generating virus-free cassava plants to combat viral disease epidemics in Africa.

Here, we report a method to clean cassava plants from viral infections that cause cassava mosaic and brown streak diseases in Africa. Infected plants of resistant or tolerant varieties from Malawi, Mozambique, Kenya, Tanzania and Uganda were cleaned in the UK using a combination of tissue culture, chemotherapy and thermotherapy. In the first cycle of our virus-indexing procedure, we successfully cleaned 27 of the 31 varieties (87%), and after an additional three cleaning cycles, all plants were virus-free. Virus-free tissue-cultured plants were shipped back to Africa for distribution to farmers. This first cross-boundary effort provides important lessons for mitigating the two-major cassava viral diseases.

Rotenone inhibits axonogenesis via an Lfc/RhoA/ROCK pathway in cultured hippocampal neurons.

Rotenone, a broad-spectrum insecticide, piscicide and pesticide, produces a complete and selective suppression of axonogenesis in cultured hippocampal neurons. This effect is associated with an inhibition of actin dynamics through activation of Ras homology member A (RhoA) activity. However, the upstream signaling mechanisms involved in rotenone-induced RhoA activation were unknown. We hypothesized that rotenone might inhibit axon growth by the activation of RhoA/ROCK pathway because of the changes in microtubule (MT) dynamics and the concomitant release of Lfc, a MT-associated Guanine Nucleotide Exchange Factor (GEF) for RhoA. In this study, we demonstrate that rotenone decreases MT stability in morphologically unpolarized neurons. Taxol (3 nM), a drug that stabilizes MT, attenuates the inhibitory effect of rotenone (0.1 µM) on axon formation. Radiometric Forster Resonance Energy Transfer, revealed that this effect is associated with inhibition of rotenone-induced RhoA and ROCK activation. Interestingly, silencing of Lfc, but not of the RhoA GEF ArhGEF1, prevents the inhibitory effect of rotenone on axon formation. Our results suggest that rotenone-induced MT de-stabilization releases Lfc from MT thereby promoting RhoA and ROCK activities and the consequent inhibition of axon growth. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

GEF-H1 functions in apical constriction and cell intercalations and is essential for vertebrate neural tube closure.

Rho family GTPases regulate many morphogenetic processes during vertebrate development including neural tube closure. Here we report a function for GEF-H1/Lfc/ArhGEF2, a RhoA-specific guanine nucleotide exchange factor that functions in neurulation in Xenopus embryos. Morpholino-mediated depletion of GEF-H1 resulted in severe neural tube defects, which were rescued by GEF-H1 RNA. Lineage tracing of GEF-H1 morphants at different developmental stages revealed abnormal cell intercalation and apical constriction, suggesting that GEF-H1 regulates these cell behaviors. Molecular marker analysis documented defects in myosin II light chain (MLC) phosphorylation, Rab11 and F-actin accumulation in GEF-H1-depleted cells. In gain-of-function studies, overexpressed GEF-H1 induced Rho-associated kinase-dependent ectopic apical constriction - marked by apical accumulation of phosphorylated MLC, γ-tubulin and F-actin in superficial ectoderm - and stimulated apical protrusive activity of deep ectoderm cells. Taken together, our observations newly identify functions of GEF-H1 in morphogenetic movements that lead to neural tube closure.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients.

BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

2DOF-PID-TD: A new hybrid control approach of load frequency control in an interconnected thermal-hydro power system.

The Load Frequency Control (LFC) scheme, with its primary aim being the maintenance of uniform frequency, has been a heavily researched topic for decades. Achieving a consistent frequency necessitates a delicate balance between load demand and power generation. Researchers strive to find an optimal solution within the LFC domain-one that can effectively withstand drastic load fluctuations. Despite a plethora of efforts, the LFC dilemma remains unresolved, complicated by factors such as dwindling demand-supply and the rapid integration of renewables. Furthermore, the lack of innovation in controller structure design exacerbates the complexity of solving modern LFC problems. Consequently, a robust control approach capable of handling uncertainties while simultaneously regulating system frequency becomes crucial. In light of this, we propose a novel hybrid control architecture called 2DOF-PID-TD. This architecture combines Two Degrees Of Freedom Proportional-Integral-Derivative (2DOF-PID) and Tilt-Derivative (TD) controllers. To optimize the proposed controller, we employ a metaheuristic called the Artificial Gorilla Troops Optimizer (AGTO), which mimics the social behavior and intelligence of gorilla troops. The proposed approach is analyzed in a realistic multi-area multi-source hydro-thermal system, accounting for nonlinearities, random load perturbations, and system parametric uncertainties. Experimental results, when compared with current state-of-the-art optimization algorithms and traditional controller structures, demonstrate the prowess of our approach in terms of precision, robustness, and resilience.

LFC study: Protocol for a longitudinal follow-up cohort study on ageing and mental health in community-dwelling older adults in Singapore.

The rapid pace of population ageing worldwide has prompted the need to better understand the ageing process. The current study, titled the Longitudinal Follow-up of the CHI (LFC) study, was a 3-year follow-up study of an earlier study titled the Community Health and Intergenerational (CHI) study. The LFC study looked to examine longitudinal changes in their cognitive functioning and psychosocial outcomes across the 3-year period. Additionally, the current study built upon the earlier CHI study by collecting neuroimaging data and exploring the long-term effects of non-pharmacological interventions, which were not examined in the prior study. A total of 653 community-dwelling participants from the baseline CHI study cohort were invited to take part in the LFC study, where they underwent a battery of neuropsychological assessments, psychosocial questionnaires, a Magnetic Resonance Imaging scan and a voice recording segment. The current study would holistically track longitudinal changes in cognitive functioning and psychosocial outcomes in the ageing population in Singapore. Unique associations between linguistics and neuroimaging data alongside cognitive and psychosocial outcomes would be explored. This study also serves to guide the development of new interventions for older adults and assist in improving the well-being of the local and global ageing population.

Antifungal Activity of Camelus-Derived LFA-LFC Chimeric Peptide Gelatin Film and Effect on Oral Bacterial Biofilm.

The objective of this study was to construct lactoferrin (LFA-LFC) chimeric peptide gelatin drug-loaded fiber film by tissue engineering strategy, and study its bacteriostatic effect on oral pathogens (especially Candida albicans) and its effect on biofilm. First of all, LFA-LFC chitosan nanoparticles were prepared firstly, and then fluconazole gelatin (LF/GH/F) film loaded with LFA-LFC was prepared by electrospinning. Scanning electron microscope (SEM), mechanical strength, drug release, cytotoxicity, and real-time PCR were used to test the properties of the synthesized materials. SEM showed that there was the reticular structure for fiber film before and after cross-linking. LF/GH/F film had no obvious cytotoxicity, with good biocompatibility and drug release; real-time PCR and antibacterial test showed that the LF/GH/F film had good antibacterial activity. LF/GH/F film has a good inhibitory effect on oral pathogens, and its mechanism is related to biofilm. The antibacterial experiments of nanofiber membrane in vitro and the effect of bacterial biofilm were carried out. The effect of LF/GH/F on oral microbial flora structure was studied by fluorescence quantitative pest techniques.

Design of event trigger based multirate sliding mode load frequency controller for interconnected power system.

This paper proposes an event triggered (ET) multi-rate output feedback sliding mode control technique for load frequency control (LFC) in multi-area interconnected power systems. Uncertainties and disturbances are commonly found in LFC problem. The designed controller attains quasi sliding mode in discrete time (DT) for linear time invariant (LTI) interconnected power executing system with limited matched variability. Event-triggered control is used to minimalize the control updates resulting in reduced utilization of resources. The ET rule is designed using Lyapunov stability analysis. The efficacy of the presented controller in the presence of generation rate constraint (GRC) and governor dead band (GDB) is authenticated through simulation results. A comparative study of the proposed controller and the reported ET control scheme for power executing system is also presented for a peer-reported two-area power executing system.

Quantification of reagent mixing in liquid flow cells for Liquid Phase-TEM.

Liquid-Phase Transmission Electron Microscopy (LP-TEM) offers the opportunity to study nanoscale dynamics of phenomena related to materials and life science in a native liquid environment and in real time. Until now, the opportunity to control/induce such dynamics by changing the chemical environment in the liquid flow cell (LFC) has rarely been exploited due to an incomplete understanding of hydrodynamic properties of LP-TEM flow systems. This manuscript introduces a method for hydrodynamic characterization of LP-TEM flow systems based on monitoring transmitted intensity while flowing a strongly electron scattering contrast agent solution. Key characteristic temporal indicators of solution replacement for various channel geometries were experimentally measured. A numerical physical model of solute transport based on realistic flow channel geometries was successfully implemented and validated against experiments. The model confirmed the impact of flow channel geometry on the importance of convective and diffusive solute transport, deduced by experiment, and could further extend understanding of hydrodynamics in LP-TEM flow systems. We emphasize that our approach can be applied to hydrodynamic characterization of any customized LP-TEM flow system. We foresee the implemented predictive model driving the future design of application-specific LP-TEM flow systems and, when combined with existing chemical reaction models, to a flourishing of the planning and interpretation of experimental observations.

Load frequency control for multi-area power systems: A new type-2 fuzzy approach based on Levenberg-Marquardt algorithm.

In this study, a new fuzzy approach is proposed for load frequency control (LFC) of a multi-area power system. The main control system is constructed by use of interval type-2 fuzzy inference systems (IT2FIS) and fractional-order calculus. In designing the controller, there is no need for the system dynamics, therefore the system Jacobian is obtained by a multilayer perceptron neural network (MLP-NN). Uncertainties are modeled by IT2FIS, and for training fuzzy parameters, Levenberg-Marquardt algorithm (LMA) is used, which is faster and more robust than gradient descent algorithm (GDA). The system stability is studied by Matignon's stability method under time-varying disturbances. A comparison between the proposed controller with type-1 fuzzy controller on the New England 39-bus test system is also carried out. The simulations demonstrate the superiority of the designed controller.

300 mm Large Area Wire Grid Polarizers with 50 nm Half-Pitch by ArF Immersion Lithography.

The large area wire grid polarizers (LA-WGPs) with 50 nm half-pitch were fabricated using ArF immersion lithography overcoming the limit of the shot field size. To realize the 50 nm line and space patterns on a 300 mm wafer, a zero-distance stitching process that connects the shot fields is suggested. To compensate for mutual interference between the shot fields which is called the local flare effect (LFE), the shot field arrangement is changed with optical proximity correction (OPC). Using a master wafer produced by the suggested method, 300 mm large-area WGPs were fabricated by the nano-imprint process. The WGPs have more than 80% transmittance in the visible light region, and the possibility of performance improvement can be confirmed depending on the number and method of the etch process.

Design of fractional order PID controller for load frequency control system with communication delay.

This work explores a frequency-domain approach to design a fractional order proportional-integral-derivative (FO-PID) controller cascaded with a first-order filter for the load frequency control (LFC) system with communication delay. The proposed method is based on suitable reference model development in the direct synthesis (DS) approach, followed by frequency response matching technique. The reference model is developed for robust control-loop performance using the stability-margin and time-domain specifications. The values of the fractional orders of the integral and derivative terms are obtained according to the dynamics of the nominal system. The proposed controllers have been designed for some LFC systems taken from the literature that have different dynamics with reheat, non-reheat and hydraulic turbines and performances with non-linearity like generation rate constraint (GRC), generation dead band (GDB) along with noise have been compared favorably with that of some controllers prevalent in the literature. The proposed controllers have been shown to work efficaciously for the decentralized multi-area IEEE 39-bus New England test system along with variable communication delay. To show the efficacy of the proposed controllers the load-disturbance responses along with the frequency and time domain performance indices have been evaluated for comparison.

Investigation of SiO2 Etch Characteristics by C6F6/Ar/O2 Plasmas Generated Using Inductively Coupled Plasma and Capacitively Coupled Plasma.

The etching properties of C6F6/Ar/O2 in both an inductively coupled plasma (ICP) system and a capacitively coupled plasma (CCP) system were evaluated to investigate the effects of high C/F ratio of perfluorocarbon (PFC) gas on the etch characteristics of SiO2. When the SiO2 masked with ACL was etched with C6F6, for the CCP system, even though the etch selectivity was very high (20 ~ infinite), due to the heavy-ion bombardment possibly caused by the less dissociated high-mass ions from C6F6, tapered SiO2 etch profiles were observed. In the case of the ICP system, due to the higher dissociation of C6F6 and O2 compared to the CCP system, the etching of SiO2 required a much lower ratio of O2/C6F6 (~1.0) while showing a higher maximum SiO2 etch rate (~400 nm/min) and a lower etch selectivity (~6.5) compared with the CCP system. For the ICP etching, even though the etch selectivity was much lower than that by the CCP etching, due to less heavy-mass-ion bombardment in addition to an adequate fluorocarbon layer formation on the substrate caused by heavily dissociated species, highly anisotropic SiO2 etch profiles could be obtained at the optimized condition of the O2/C6F6 ratio (~1.0).

Dataset of 1H-nuclear magnetic resonance and mass spectra of surface modified Poly(amidoamine) dendrimers with LFC131 peptide.

In the present article, we describe the spectroscopic data of poly(amido)amine dendrimers generation 5.0 (G5 PAMAM) conjugated with LFC131 peptide at different specified reaction points. The raw data regarding the 1H NMR and mass spectra of G5 PAMAM dendrimers with and without LFC131 peptide conjugation and with or without FITC labelled are presented for comparison.

Fast frequency recovery-oriented distributed optimal load frequency control: An active disturbance rejection control approach.

With high penetration of renewable energy sources in nested multiple-microgrids, conventional solutions for the integration of load frequency control and economic dispatch may degrade frequency control performance and decrease operational economy. In this paper, a fast frequency recovery-oriented distributed optimal control strategy is proposed to deal with these problems. Firstly, a partial primal-dual gradient algorithm is dynamically integrated with an active disturbance rejection control algorithm (instead of conventional Proportional-Integral (PI) controller) to realize the fast frequency recovery and enhance anti-disturbance capability. As a result, frequent adjustments of resources can be avoided and this is crucial in extending the life cycles of batteries. Then, based on the above integration, the distributed optimal control law is derived, which is independent of load measurement and fully distributed, to coordinate the microgrids to share their power economically during the frequency regulation process. This can also relieve the communication and computation burden of the system. Finally, a set of numerical simulations is presented and the effectiveness of the proposed distributed optimal control is verified by the obtained results, which include a comparison with the conventional distributed PI-based optimal control strategy.