AP2M1 Supports TGF-β Signals to Promote Collagen Expression by Inhibiting Caveolin Expression

The extracellular matrix (ECM) is important for normal development and disease states, including inflammation and fibrosis. To understand the complex regulation of ECM, we performed a suppressor screening using Caenorhabditis elegans expressing the mutant ROL-6 collagen protein. One cuticle mutant has a mutation in dpy-23 that encodes the μ2 adaptin (AP2M1) of clathrin-associated protein complex II (AP-2). The subsequent suppressor screening for dpy-23 revealed the lon-2 mutation. LON-2 functions to regulate body size through negative regulation of the tumor growth factor-beta (TGF-β) signaling pathway responsible for ECM production. RNA-seq analysis showed a dominant change in the expression of collagen genes and cuticle components. We noted an increase in the cav-1 gene encoding caveolin-1, which functions in clathrin-independent endocytosis. By knockdown of cav-1, the reduced TGF-β signal was significantly restored in the dpy-23 mutant. In conclusion, the dpy-23 mutation upregulated cav-1 expression in the hypodermis, and increased CAV-1 resulted in a decrease of TβRI. Finally, the reduction of collagen expression including rol-6 by the reduced TGF-β signal influenced the cuticle formation of the dpy-23 mutant. These findings could help us to understand the complex process of ECM regulation in organism development and disease conditions.     

Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95

Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by ¹H,¹⁵N HSQC NMR to bind in the small hydrophobic P⁰ pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.     

Effect of post heat-treatment on the microstructure and high-temperature oxidation behavior of precipitation hardened IN738LC superalloy fabricated by selective laser melting

The present study investigated the effect of as-built and post heat-treated microstructures of IN738LC alloy fabricated via selective laser melting process on high temperature oxidation behavior.The as-built microstructure showed fine cell and columnar structure due to high cooling rate.Ti element segrega-tion was observed in inter-cell/inter-columnar area.After post heat-treatment,the initially-observed cell structure disappeared,instead bimodal Ni3(Al,Ti)particles formed.High temperature(1273 K and 1373 K)oxidation test results showed parabolic oxidation curves regardless of temperature and initial microstructure.The as-built IN738LC fabricated via the selective laser melting process displayed oxida-tion resistance similar to or slightly better than that of IN738LC fabricated via wrought or cast process.Heat-treated SLM IN738LC,although had similar oxidation weight-gain values to those of the SLM as-built material at 1273 K,showed relatively better oxidation resistance at 1373 K.Bimodal Ni3(Al,Ti)precipitate formed in the post heat treatment changed the local chemical composition,thereby led to changes in alumina former/chromia former location and fraction on the alloy surface.It was concluded that in heat-treated IN738LC increased alumina former fraction was found,and this resulted in excellent oxidation resistance and relatively low weight-gain.     

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

The low overall survival rate of patients with pancreatic cancer has driven research to seek a new therapeutic protocol. Radiotherapy (RT) is frequently an option in the neoadjuvant or palliative settings for pancreatic cancer treatment. This study explored the effect of RT protocols on the tumor microenvironment (TME) and their consequent impact on anti-programmed cell death ligand-1 (PD-L1) therapy. Using a murine orthotopic pancreatic tumor model, UN-KC-6141, RT-disturbed TME was examined by immunohistochemical staining. The results showed that ablative RT is more effective than fractionated RT at recruiting T cells. On the other hand, fractionated RT induces more myeloid-derived suppressor cell infiltration than ablative RT. The RT-disturbed TME presents a higher perfusion rate per vessel. The increase in vessel perfusion is associated with a higher amount of anti-PD-L1 antibody being delivered to the tumor. Animal survival is increased by anti-PD-L1 therapy after ablative RT, with 67% of treated animals surviving more than 30 days after tumor inoculation compared to a median survival time of 16.5 days for the control group. Splenocytes isolated from surviving animals were specifically cytotoxic for UN-KC-6141 cells. We conclude that the ablative RT-induced TME is more suited than conventional RT-induced TME to combination therapy with immune checkpoint blockade.     

On the Catalytic Activity of Sn Monomers and Dimers at Graphene Edges and the Synchronized Edge Dependence of Diffusing Atoms in Sn Dimers

In this study, in situ transmission electron microscopy is performed to study the interaction between single (monomer) and paired (dimer) Sn atoms at graphene edges. The results reveal that a single Sn atom can catalyze both the growth and etching of graphene by the addition and removal of C atoms respectively. Additionally, the frequencies of the energetically favorable configurations of an Sn atom at a graphene edge, calculated using density functional theory calculations, are compared with experimental observations and are found to be in good agreement. The remarkable dynamic processes of binary atoms (dimers) are also investigated and is the first such study to the best of the knowledge. Dimer diffusion along the graphene edges depends on the graphene edge termination. Atom pairs (dimers) involving an armchair configuration tend to diffuse with a synchronized shuffling (step-wise shift) action, while dimer diffusion at zigzag edge terminations show a strong propensity to collapse the dimer with each atom diffusing in opposite directions (monomer formation). Moreover, the data reveals the role of C feedstock availability on the choice a single Sn atom makes in terms of graphene growth or etching. This study advances the understanding single atom catalytic activity at graphene edges.     

Enriched multi-agent middleware for building rule-based distributed security solutions for IoT environments

The Journal of Supercomputing - The increasing number of connected devices and the complexity of Internet of Things (IoT) ecosystems are demanding new architectures for managing and securing these...     

Mimic Drug Dosage Modulation for Neuroplasticity Based on Charge-Trap Layered Electronics

The human brain is often likened to an incredibly complex and intricate computer, rather than electrical devices, consisting of billions of neuronal cells connected by synapses. Different brain circuits are responsible for coordinating and performing specific functions. The reward pathway of the synaptic plasticity in the brain is strongly related to the features of both drug addiction and relief. In the current study, a synaptic device based on layered hafnium disulfide (HfS₂) is developed for the first time, to emulate the behavioral mechanisms of drug dosage modulation for neuroplasticity. A strong gate-dependent persistent photocurrent is observed, arising from the modulation of substrate-trapping events. By controlling the polarity of gate voltage, the basic functions of biological synapses are realized under a range of light spiking conditions. Furthermore, under the control of detrapping/trapping events at the HfS₂/SiO₂ interface, positive/negative correlations of the A_n/A₁ index, which significantly reflected the weight change of synaptic plasticity, are realized under the same stimulation conditions for the emulation of the drug-related addition/relief behaviors in the brain. The findings provide a new advance for mimicking human brain plasticity.     

Microstructure induced ultra-high energy storage density coupled with rapid discharge properties in lead-free Ba0.9Ca0.1Ti0.9Zr0.1O3–SrNb2O6 ceramics

Novel lead-free (1-x)Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃-xSrNb₂O₆ ceramics were synthesized via a two-step high energy ball milling process. The evolution of microstructural properties, phase transformation, and energy storage characteristics was comprehensively investigated to assess the applicability of material in multi-layered ceramic capacitors. The substitution of SrNb₂O₆ (SNO) in Ba_0·9Ca_0·1Ti_0·9Zr_0·1O₃ (BTCZ) has resulted in substantial improvement in materials density along with a small increase in the grain size of the synthesized ceramic. A thorough microstructural investigation indicates an excellent dispersibility and compatibility between BTCZ and SNO phases. With an increase in SNO substitution, a transition from typical ferroelectric to relaxor ferroelectric has been observed, which has led to a significantly slimmer ferroelectric loop along with frequency dispersive dielectric properties. The optimized composition (i.e., x = 0.10) exhibits an ultra-high recoverable energy density of 2.68 J/cm³ along with a moderately high energy efficiency of 83.4%. Further, SNO substituted samples have also shown an enhancement in breakdown strength. The improvement in energy storage performance and breakdown strength of SNO substituted BTCZ composites are mainly attributed to relatively homogeneous grain morphology, optimum grain size, microstructural density, and improved grain boundary interface.     

Strain mediated enhancement in magnetoelectric properties of sonochemically synthesized piezoelectric and piezomagnetic composites

Materials with magneto-electric (ME) properties are of great importance because of their demand in electronic industries. Three dimensional nano-particles of the ME-composites having the general formula (1-x)CoCr_0.3Fe_1.7O₄(CCFO)+(x)BaTiO₃(BTO) (x = 0.0, 0.2, 0.4, 0.6, 0.8 and 1.0) were obtained by comprising the piezoelectric-BTO and piezomagnetic-CCFO phases. The individual phases of CCFO and BTO were synthesized separately by ultrasonic irradiation assisted sonochemical and sol-gel routs. X-ray diffraction patterns (XRD) confirmed the well-crystalline nature of both the phases. BTO and CCFO phases were under tensile strain as confirmed by the variation in lattice constants with varying proportion of BTO and CCFO. An energy-dispersive X-ray spectroscopy spectrum confirmed the phase purity of the samples and stoichiometric concentration of elements. Magnetic properties were investigated by M ? H loop measurements and dielectric properties by using RF impedance analyzer. Dielectric constant increased with the increasing percentage of BTO. The maximum value of ME coefficient (24.7 mV/cm?Oe) is observed for the 60%CCFO+40%BTO sample. The obtained results were discussed in the light of grain size, strain and the basic properties of the individual phases. The prepared materials can be applicable in electronic devices where high magneto-electric coefficient is desirable.     

Effect of CdO addition on photon,electron, and neutron attenuation properties of boro-tellurite glasses

This research article aims to study the effect of CdO addition on the radiation shielding characteristics of boro-tellurite glasses in the composition of 50B₂O₃ - (50-x) TeO2- xCdO, where x = 0, 10, 20, 30, 40 and 50 mol%. These glasses were exposed to gamma radiation and the transmitted gamma photons were evaluated for energies varying from 15 keV to 15 MeV using Geant4 simulation toolkit. The number of transmitted photons was then used to characterize the gamma shielding for the studied glasses in terms of linear/mass attenuation coefficients, MFP, Z_eff, and HVL. The simulation outcomes were theoretically confirmed by using Phy-X software. The beta (electron) shielding characterization of the involved glasses was also investigated by determining the projectile range and stopping power using ESTAR software. Additionally, the fast neutron shielding characterization of the glasses was achieved by evaluating removal cross-section (Σ_R). The results reveal that the CdO has a small influence on the shielding performance of the boro-tellurite glasses against gamma, beta, and neutron radiations. The shielding performance of the boro-tellurite glasses was compared with that of common shielding materials in terms of MFP. It can be concluded that the boro-tellurite glasses regardless of the concentration of CdO content have promising shielding performance to be used for radiation applications.