Impairments in endogenous AMPA receptor dynamics correlates with learning deficits in Alzheimer's disease model mice.

AMPA receptors (AMPARs) play a critical role in synaptic plasticity and learning and memory, and dysfunction or dysregulation of AMPARs could lead to various neurological and psychiatric disorders, such as Alzheimer's disease (AD). However, the dynamics and/or longitudinal changes of AMPARs in vivo during AD pathogenesis remain elusive. Here, employing 5xFAD SEP-GluA1 KI mice, we investigated endogenous AMPA receptor dynamics in a whisker deflection-associated Go/No-go learning paradigm. We found a significant increase in synaptosomal AMPA receptor subunits GluA1 in WT mice after learning, while no such changes were detected in 7-mo-old 5xFAD mice. Daily training led to an increase in endogenous spine surface GluA1 in Control mice, while this increase was absent in 5xFAD-KI mice which correlates with its learning defects in Go/No-go paradigm. Furthermore, we demonstrated that the onset of abnormal AMPAR dynamics corresponds temporally with microglia and astrocyte overactivation. Our results have shown that impairments in endogenous AMPA receptor dynamics play an important role in learning deficits in 5xFAD mice and AD pathogenesis.

Pathological hemodynamic changes and leukocyte transmigration disrupt the blood-spinal cord barrier after spinal cord injury.

BACKGROUND: Blood-spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. METHODS: A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. RESULTS: Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. CONCLUSIONS: Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.

Pressure-induced novel ZrN4 semiconductor materials with high dielectric constants: a first-principles study.

In addition to Zr3N4 and ZrN2 compounds, zirconium nitrides with a rich family of phases always exhibit metal phases. By employing an evolutionary algorithm approach and first-principles calculations, we predicted seven novel semiconductor phases for the ZrN4 system at 0-150 GPa. Through calculating phonon dispersions, we identified four dynamically stable semiconductor structures under ambient pressure, namely, α-P1̄, ß-P1̄, γ-P1̄, and ß-P1 (with bandgaps of 1.03 eV, 1.10 eV, 2.33 eV, and 1.49 eV calculated using the HSE06 hybrid density functional, respectively). The calculated work functions and dielectric functions show that the four dynamically stable semiconductor structures are all high dielectric constant (high-k) materials, among which the ß-P1̄ phase has the largest static dielectric constant (3.9 times that of SiO2). Furthermore, we explored band structures using the HSE06 functional and density of states (DOS) and the response of bandgaps to pressure using the PBE functional for the four new semiconductor configurations. The results show that the bandgap responses of the four structures exhibit significant differences when hydrostatic pressure is applied from 0 to 150 GPa.

Selective P-C(sp3 ) Bond Cleavage and Radical Alkynylation of α-Phosphorus Alcohols by Photoredox Catalysis.

Herein the first P-C(sp3 ) bond cleavage and radical alkynylation of α-phosphorus alcohols to construct phosphonoalkynes is reported. The phosphorus radical is generated upon P-C bond cleavage reaction via the alkoxyl radical through photoredox catalysis with cyclic iodine(III) reagents. Various arylphosphinoyl-, alkylphosphinoyl-, phosphonate-, and phosphonic amide alcohols serve as radical phosphorus precursors to construct phosphonoalkynes for the first time.

Asymmetric Construction of Six-Membered Rings by Cyclization of Allenes with Dinuclear Gold Catalysis.

A simple and efficient method for the synthesis of 1,4-dihydroarenes by gold-catalyzed 6-endo cyclization of benzylic allenes has been developed. Furthermore, asymmetric hydroarylation of enantioenriched allenes has been realized to offer a practical and convergent approach to aromatic ring-fused six-membered cycles containing a chiral stereocenter such as 1,4-dihydronaphthalenes, 1,4-dihydrodibenzo[b,d]thiophenes, and 4,7-dihydrobenzo[b]thiophenes by applying dinuclear [(dppm)Au2 Cl2 ] [dppm=methylenebis(diphenylphosphane)] combined with AgOTf as the catalyst to ensure the high efficiency of chirality transfer. ESI-MS has been applied to characterize some of the key reactive dinuclear gold intermediates successfully.

The neurovascular unit in healthy and injured spinal cord.

The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood-central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.

5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) for acneform rash induced by erlotinib: A case report.

Erlotinib is an anticancer drug approved for the treatment of non-small cell lung cancer. It inhibits growth and proliferation of tumor cells by targeting epidermal growth factor receptor (EGFR). Dermatological toxicities are common side effects associated with EGFR inhibition. Here we describe a patient with acneform rash following oral medication of erlotinib, presented as facial erythema, papules and pustules. Two sessions of 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with a 2-week interval were performed. No significant side effects or scarring were observed. The patient showed no recurrence within 6 months. Thus, we conclude that ALA-PDT is an effective treatment for skin lesions induced by erlotinib, especially for patients with need to sustain medication.

Moderate systemic therapeutic hypothermia is insufficient to protect blood-spinal cord barrier in spinal cord injury.

Blood-spinal cord barrier (BSCB) disruption is a pivotal event in spinal cord injury (SCI) that aggravates secondary injury but has no specific treatment. Previous reports have shown that systemic therapeutic hypothermia (TH) can protect the blood-brain barrier after brain injury. To verify whether a similar effect exists on the BSCB after SCI, moderate systemic TH at 32°C was induced for 4 h on the mice with contusion-SCI. In vivo two-photon microscopy was utilized to dynamically monitor the BSCB leakage 1 h after SCI, combined with immunohistochemistry to detect BSCB leakage at 1 and 4 h after SCI. The BSCB leakage was not different between the normothermia (NT) and TH groups at both the in vivo and postmortem levels. The expression of endothelial tight junctions was not significantly different between the NT and TH groups 4 h after SCI, as detected by capillary western blotting. The structural damage of the BSCB was examined with immunofluorescence, but the occurrence of junctional gaps was not changed by TH 4 h after SCI. Our results have shown that moderate systemic TH induced for 4 h does not have a protective effect on the disrupted BSCB in early SCI. This treatment method has a low value and is not recommended for BSCB disruption therapy in early SCI.

[Levels of TNF-α, IL-6 and IL-10 in bronchoalveolar lavage fluid in children with Mycoplasma pneumoniae pneumonia].

OBJECTIVE: To study the levels and roles of cytokines TNF-α, IL-6 and IL-10 in bronchoalveolar lavage fluid (BALF) in children with Mycoplasma pneumoniae pneumonia (MPP). METHODS: The levels of TNF-α, IL-6 and IL-10 in BALF were measured using ELISA in children with MPP at acute stage (n=45) and at remission stage (n=30). Twenty children without lung lesions severed as the control group. RESULTS: The TNF-α, IL-6 and IL-10 levels in BALF were higher in children with MPP at acute stage than those in the control group (P<0.05). The levels of TNF-α and IL-6 in BALF at remission stage were reduced to the levels similar to the control group and were significantly lower than those at the acute stage in children with MPP. However, the levels of IL-10 in BALF remained at higher levels at remission stage in children with MPP. CONCLUSIONS: The levels of TNF-α, IL-6 and IL-10 in BALF increase in children with MPP at acute stage, suggesting that the cytokines may be involved in the pathogenesis of MPP.

Terminal Trifluoromethylation of Ketones via Selective C-C Cleavage of Cycloalkanols Enabled by Hypervalent Iodine Reagents.

We report the first terminal trifluoromethylation at aryl and alkyl ketones' γ, δ, ε, or more remote sites via the selective C-C bond cleavage of cycloalkanols. The noncovalent interactions between alcohols and hypervalent iodines(III) reagents were disclosed to activate both alcohols and the Togni I reagent in the dual photoredox/copper catalysis for the transformation. This reaction was scalable to the gram-scale synthesis, applicable to the structurally complex steroid trifluoromethylation, and extendable to the pentafluoroethylation.

Safinamide prevents lipopolysaccharide (LPS)-induced inflammation in macrophages by suppressing TLR4/NF-κB signaling.

Inflammation is a basal host defense response that eliminates the causes and consequences of infection and tissue injury. Macrophages are the primary immune cells involved in the inflammatory response. When activated by LPS, macrophages release various pro-inflammatory cytokines, chemokines, inflammatory mediators, and MMPs. However, unbridled inflammation causes further damage to tissues. Safinamide is a selective and reversible monoamine oxidase B (MAOB) inhibitor that has been used for the treatment of Parkinson's disease. In this study, we aimed to investigate whether safinamide has effects on LPS-treated macrophages. Our results show that safinamide inhibited the expression of pro-inflammatory cytokines such as IL-1α, TNF-α, and IL-6. Furthermore, safinamide suppressed the production of CXCL1 and CCL2, thereby preventing leukocyte migration. In addition, safinamide reduced iNOS-derived NO, COX-2-derived PGE2, MMP-2, and MMP-9. Importantly, the functions of safinamide mentioned above were found to be dependent on its inhibitory effect on the TLR4/NF-κB signaling pathway. Our data indicates that safinamide may exert a protective effect against inflammatory response.

Microstructure and Mechanical Properties of Al/Steel Butt Joint by Hybrid CMT Welding with External Axial Magnetic Field.

The 6061 aluminum alloy and 304 stainless steel were welded by hybrid cold metal transfer (CMT) welding with external axial magnetic field. The effects of magnetic intensity and frequency on joint microstructure and mechanical properties were studied. It was found that the magnetic field can promote the spreading of aluminum weld metal on the steel surface and thus increase the bonding area of Al/steel butt joint. The welding process stability improved, while the wetting behavior worsened with the introduction of alternating frequencies. The thickness of the intermetallic compound (IMC) layer at Al/steel interface was reduced to 3 µm with the coil current of 2 A. The application of the magnetic field promoted the aggregation of Si atoms at the interface and inhibited the formation of brittle (Al, Si)13Fe4 phase. The fracture paths were transformed from (Al, Si)13Fe4 layer to Al8Fe2Si layer with the application of the magnetic field. The maximum tensile strength reached 130.2 MPa, an increase of 61.6% in comparison to the normal CMT process.

Acyl Radical Smiles Rearrangement To Construct Hydroxybenzophenones by Photoredox Catalysis.

The first visible-light-induced acyl radical Smiles rearrangement to transform biaryl ethers to hydroxybenzophenones under mild and metal-free conditions is reported. Using the dual catalysis of hypervalent iodine(III) reagents and organophotocatalysts, ketoacids readily generate acyl radicals and undergo 1,5- ipso addition. This method can construct electron-deficient and electron-rich hydroxybenzophenones with excellent chemoselectivity and on gram scale. The performance of the reaction in neutral aqueous conditions holds potential for future biomolecule applications.

Weld Formation Mechanism and Microstructural Evolution of TC4/304 Stainless Steel Joint with Cu-Based Filler Wire and Preheating.

Ti-Fe intermetallic compounds were effectively suppressed with Cu-based filler wire and weld formation was greatly improved with the preheating of substrates when joining TC4 titanium alloy and 304 stainless steel. A Ti/Cu transition zone consisting of complex TiCu, Ti2Cu3, TiFe, and TiFe2 phases was formed between Cu-weld/TC4 interface, while Cu-weld/304ss interface was mainly composed of α-Fe and ε-Cu solid solution. At lower heat input, the undercut defect in back surface had potential to cause crack initiation and joint fracture. Though increasing heat input would improve weld morphology, the formation of thick interfacial reaction layer and weld cracking led to low weld quality and joint strength. The preheating of substrates had an obvious effect on wetting ability of liquid filler metal and could achieve a better weld quality at lower heat input. The back formation of weld was improved to decrease the occurrence of weld defects. The highest tensile strength of 365 MPa occurred at welding heat input of 0.483 kJ/cm, increasing by 47% compared to the joint without preheating. The interfacial reaction mechanism was discussed to reveal the relationship between microstructural characteristics and fracture behavior of Ti/steel welded joints with Cu-based filler wire.

PtCl4-catalyzed skeleton rearrangement-cyclization of tertiary indolyl-3-alkynols.

An unexpected PtCl4-catalyzed cyclization reaction of tertiary indol-2-yl-3-alkynols occurred smoothly in toluene to form various poly-substituted carbazole derivatives efficiently. A possible mechanism involving the formation of a spiro-tricyclic intermediate via indole C-2 attack, highly selective ring expansion and then 1,2-migration has been proposed for the formation of carbazoles.