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Multiaxial low cycle fatigue tests under non‐proportional stress (NPSS) controlled mode were performed on commercial pure titanium (CP‐Ti). Strain responses of axial and torsional channels under highly applied stress amplitudes show an initial hardening phenomenon. Non‐proportional hardening coefficient of CP‐Ti is independent of the controlled mode. The critical plane of CP‐Ti under NPSS controlled mode is aligned with the maximum principal stress plane proved by optical microscopy observation. Optimized FSM model and KBM‐PM model with mean axial and torsional strain are established. These models are further integrated into equations related to multiaxial stress ratio with high accuracy of life prediction for CP‐Ti under NPSS controlled mode. Highlights: Non‐proportional hardening coefficient of CP‐Ti is independent of the controlled mode.The critical plane of CP‐Ti is aligned with the maximum principal stress plane.Energy and optimized critical plane model with mean strain are established. [ABSTRACT FROM AUTHOR]

Considering T‐stress components under compression, the crack initiation characteristics of HT200 and PMMA under uniaxial compression have been investigated by theoretical analysis and experimental study for central cracked plate (CCP) and compact tension shear (CTS) specimens with I‐II mixed mode crack. Crack initiation angles of CCP and CTS specimens under compressive load were theoretical predicted according to modified maximum tangential stress (MMTS) criterion and modified maximum shear stress (MMSS) criterion. The influence of material parameters and specimen geometrical configurations on crack initiation characteristics was illustrated through experiments. It demonstrates that the modified fracture criterion considering T‐stress components is more consistent with experiments. Crack initiation angle is related to material properties. Limit load PL is controlled by KII under compression for CCP specimen, and PL of PMMA is less than that of HT200. The closure effect on CTS specimens is less significant than that on CCP specimens. Highlights: Crack initiation angle of closed crack is related to material properties.Limit load PL is controlled by KII under compression for CCP specimens.The closure effect on CTS specimens is less significant than that on CCP specimens. [ABSTRACT FROM AUTHOR]

In‐plane biaxial fatigue tests of commercial pure titanium (CP‐Ti) were performed to investigate the effects of load ratio and phase shift on fatigue and ratcheting behavior. The results show that with the decrease of load ratio or the increase of phase shift, biaxial ratcheting strain effect is more significant, leading to the deterioration of fatigue resistance. Analysis of the crack morphology and fracture characteristic reveals that the crack propagation path becomes complex and the fracture morphology changes due to the enhanced non‐proportional hardening effect. Finally, current multiaxial life prediction models are evaluated to compare the applicability in the biaxial fatigue life prediction. Highlights: Effects of load ratio and phase shift on biaxial ratcheting behavior are discussed.Biaxial fatigue life is more sensitive to the variation of the phase shift.The crack morphology and fracture characteristics are analyzed.The applicability of different multiaxial life prediction models is evaluated. [ABSTRACT FROM AUTHOR]

Summary: Aim: Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T‐cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model. Methods: Experimental autoimmune encephalomyelitis (EAE) rat model was established. The neuroprotective effect of ImK was assessed by immunohistochemistry and transmission electron microscopy (TEM). In addition, the antiinflammatory effect of ImK by suppressing T‐cell activation was assessed by flow cytometry and ELISA in vitro. Results: Our results demonstrated that ImK administration ameliorated EAE clinical severity. Moreover, ImK increased oligodendrocytes survival, preserved axons, and myelin integrity and reduced the infiltration of activated T cells into the CNS. This protective effect of the peptide may be related to its suppression of autoantigen‐specific T‐cell activation via calcium influx inhibition. Conclusion: ImK prevents neurological damage by suppressing T‐cell activation, suggesting the applicability of this peptide in MS therapy. [ABSTRACT FROM AUTHOR]

Abstract: Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8+ T lymphocytes and inhibit CD4+ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma. [ABSTRACT FROM AUTHOR]

Purpose Cerebral hypoxia is a major cause of neonatal seizures, and can lead to epilepsy. Pathologic anatomic and physiologic changes in the dentate gyrus have been associated with epileptogenesis in many experimental models, as this region is widely believed to gate the propagation of limbic seizures. However, the consequences of hypoxia-induced seizures for the immature dentate gyrus have not been extensively examined. Methods Seizures were induced by global hypoxia (5-7% O2 for 15 min) in rat pups on postnatal day 10. Whole-cell voltage-clamp recordings were used to examine A-type potassium currents ( IA) in dentate granule cells in hippocampal slices obtained 1-17 days after hypoxia treatment. Key Findings Seizure-inducing hypoxia resulted in decreased maximum IA amplitude in dentate granule cells recorded within the first week but not at later times after hypoxia treatment. The decreased IA amplitude was not associated with changes in the voltage-dependence of activation or inactivation removal, or in sensitivity to inhibition by 4-aminopyridine (4- AP). However, consistent with the role of IA in shaping firing patterns, we observed in the hypoxia group a significantly decreased latency to first spike with depolarizing current injection from hyperpolarized potentials. These differences were not associated with changes in resting membrane potential or input resistance, and were eliminated by application of 10 m 4- AP. Significance Given the role of IA to slow action potential firing, decreased IA could contribute to long-term hippocampal pathology after neonatal seizure-inducing hypoxia by increasing dentate granule cell excitability during a critical window of activity-dependent hippocampal maturation. [ABSTRACT FROM AUTHOR]

From a cDNA library of Chinese scorpion Buthus martensii Karsch, full-length cDNAs of 351 nucleotides encoding precursors (named BmKIM) that contain signal peptides of 21 amino acid residues, a mature toxin of 61 residues with four disulfide bridges, and an extra Gly-Lys-Lys tail, were isolated. The genomic sequence of BmKIM was cloned and sequenced; it consisted of two exons disrupted by an intron of 1622 bp, the largest known in scorpion toxin genomes, inserted in the region encoding the signal peptide. The cDNA was expressed in Escherichia coli . The recombinant BmKIM was toxic to both mammal and insects. This is the first report that a toxin with such high sequence homology with an insect-specific depressant toxin group exhibits toxicity to mammals. Using whole cell patch-clamp recording, it was discovered that the recombinant BmKIM inhibited thesodium current in rat dorsal root ganglion neurons andventricular myocytes and protected against aconitine- induced cardiac arrhythmia. [ABSTRACT FROM AUTHOR]