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Abstract Parkinson’s disease (PD) is an irreversible and progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Growing evidence indicates that endoplasmic reticulum stress is a hallmark of PD; however, its exact contribution to the disease process remains poorly understood. Here, we used molecular biology methods and RNA-Seq analysis to explored an unexpected role of spliced X-Box binding protein 1 (XBP1s) in the nervous system. In this study, we determined that the IRE1α/XBP1 pathway is activated in MPP+-treated neurons. Furthermore, XBP1s was identified as a substrate of CDK5 and that the phosphorylation of XBP1s at the Ser61 residue enhances its nuclear migration, whereas mutation of the residue to alanine substantially reduces its nuclear translocation and activity. Importantly, phosphorylated XBP1s acts as a nuclear transcription factor for multiple target genes, including metabolic-related genes, FosB, and non-coding RNAs. Our findings confirm that the IRE1α/XBP1 pathway is activated in PD, and reveal a novel role of XBP1s in the pathogenesis of PD. This pathway may be a new therapeutic strategy for PD.

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aβ1 − 42-induced cognitive impairment, significantly prevented the effects of Aβ1 − 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Novel scaffolds are expected to treat Alzheimer’s disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1–K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ1 − 42-induced cognitive impairment, and significantly prevented the effects of Aβ1 − 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

Purpose: Auditory nerve injury is one of the most common nerve injury complications of skull base fractures. However, there is currently a lack of auxiliary examination methods for its direct diagnosis. The purpose of this study was to find a more efficient and accurate means of diagnosis for auditory nerve injury. Methods: Through retrospectively analyzing the results of brainstem auditory evoked potential (BAEP) and high-resolution CT (HRCT) in 37 patients with hearing impairment following trauma from January 1, 2018 to July 31, 2020, the role of the two inspection methods in the diagnosis of auditory nerve injury was studied. Inclusion criteria were patient had a clear history of trauma and unilateral hearing impairment after trauma; while exclusion criteria were: (1) severe patient with a Glasgow coma scale score ≤5 because these patients were classified as severe head injury and admitted to the intensive care unit, (2) patient in the subacute stage admitted 72 h after trauma, and (3) patient with prior hearing impairment before trauma. According to Goodman's classification of hearing impairment, the patients were divided into low/medium/severe injury groups. In addition, patients were divided into HRCT-positive and negative groups for further investigation with their BAEP results. The positive rates of BEAP for each group were observed, and the results were analyzed by Chi-square test (p

The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases (PM) and primary tumors in resectable CRC. The clinical data of 410 patients with PM after CRC surgery and 33 paraffin-embedded tissue samples from January 2012 to July 2019 in our hospital were collected retrospectively. Next, 450-panel gene detection technologies based on next-generation sequencing (NGS) were used to analyze the changes in the gene map and the overall variation in cancer-related genes in PM and primary tumors. After quality control, 19 samples were included in the final gene analysis. The results showed that APC (89.5%), TP53 (89.5%), and KRAS (53%) were the most common mutations in PM and primary tumors, but the gene amplification variation was enriched in primary tumors (4.6% vs. 11.4%). KRAS G12D was the most common site variation of the KRAS gene in both PM and primary tumors of CRC. There was no hotspot mutation in the TP53 locus in CRC, and the TP53 mutation in the PM was consistent with that in the primary lesion. The microsatellite instability (MSI) levels of 10 patients were MSS. The mean tumor mutation burden (TMB) of the primary tumor (5.3 muts·Mb−1) was slightly higher than that of metastasis (5.0 muts·Mb−1). In our institution, the genetic characteristics of resectable PM from CRC may be highly consistent with those of the primary tumor.

To understand that 18β-Glycyrrhetic acid 3-O-mono-β-D-glucuronide (GAMG) showed better pharmacological activity and drug-like properties than 18β-Glycyrrhizin (GL); a rapid and sensitive HPLC-MS/MS method was established for the simultaneous determination of GAMG and its metabolite 18β-Glycyrrhetinic acid (GA) in rat plasma and tissues after oral administration of GAMG or GL. This analytical method was validated by linearity, LLOQ, specificity, recovery rate, matrix effect, etc. After oral administration, GAMG exhibited excellent Cmax (2377.57 ng/mL), Tmax (5 min) and AUC0-T (6625.54 mg/L*h), which was much higher than the Cmax (346.03 ng/mL), Tmax (2.00 h) and AUC0-T (459.32 mg/L*h) of GL. Moreover, GAMG had wider and higher tissue distribution in the kidney, spleen, live, lung, brain, etc. These results indicated that oral GAMG can be rapidly and efficiently absorbed and be widely distributed in tissues to exert stronger and multiple pharmacological activities. This provided a physiological basis for guiding the pharmacodynamic study and clinical applications of GAMG.

Purpose Microvascular endothelial integrity is important for maintaining the blood-brain barrier (BBB). However, subarachnoid hemorrhage (SAH) disrupts this integrity, making the BBB dysfunctional—an important pathophysiological change after SAH. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) regulate microvascular permeability by balancing each other’s expression. Methods This study investigated the dynamics of Ang-1 and Ang-2 expression after SAH and the protective effect of Ang-1 on BBB functioning using an endovascular puncture model of rat SAH. The Ang-1 and Ang-2 expression in brain tissue was determined by immunohistochemistry. In addition, Western blotting was used to estimate Ang-1 and Ang-2 concentration and to compare them at 6–72 hours post-SAH cortex and hippocampus. Evans blue viability assay was used to evaluate BBB permeability, and neurological testing was implemented to evaluate neurological impairment during SAH. Results It was found that following SAH, Ang-1 expression decreases and Ang-2 expression increases in the cortex, hippocampus, and microvessels. The Ang-1/Ang-2 ratio decreased as quickly as 6 hours after SAH and reached its lowest 1 day after SAH. Finally, it was found that exogenous Ang-1 reduces SAH-associated BBB leakage and improves neurological function in post-SAH rats. Conclusions Our findings suggest that the equilibrium between Ang-1 and Ang-2 is broken in a period shortly after SAH, and the treatment of exogenous Ang-1 injection alleviates neurological dysfunctions through decreasing BBB destruction.

The ZnO-based nanogenerators (NGs) with a precisely controlled interlayer of AlN are fabricated based on atomic layer deposition technique, which was proved to possess an enhanced output signal. The microstructure and composition profiles of the prepared ZnO/AlN stack layer are well characterized first. It was found that the piezoelectric performance of ZnO/AlN stacked nanofilm NGs depends strongly on the thickness of AlN. The maximum piezoelectric open circuit output voltage of 4.0 V and output power of 2.42 µW have been achieved with an optimum 2.3 nm thick AlN interlayer. The piezoelectric output of the NGs also relates with the value and the frequency of the compressive force. The inherent mechanism for the improvement of piezoelectric performance in the stacked structure is well discussed. The findings are expected to provide a simple, inexpensive, and effective approach for enhancing the performance of ZnO-based NGs.

Purpose: Loose endothelial cells and the destruction of the blood–brain barrier (BBB) are one of the pathophysiological mechanisms of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Tie-2 receptor phosphorylation is important for maintaining integrity of microvascular endothelial cells and BBB. This study aimed to explore the role and changes of Tie-2 receptor phosphorylation levels in EBI after SAH. Methods: This study used an endovascular puncture model of rat to simulate the occurrence and development of aneurysmal subarachnoid hemorrhage. The location of Tie-2 receptor in brain tissues was determined by immunofluorescence. Immunofluorescence and western blot was carried out to observe the expression of Claudin-5 and Occludin in cortex and hippocampus. We chose to observe the Tie-2 receptor phosphorylation level in hippocampus according western blot. Evans blue viability assay was used to evaluate BBB permeability. Results: The results suggested that Tie-2 receptor mainly expressed around the vascular endothelial cells in brain. Following SAH, the Tie-2 receptor phosphorylation level and expression of tight junction protein (claudin-5 and occluding) decreased. Both of these downtrends were reversed by exogenous Angiopoietin-1 (Ang-1). Finally, injection of exogenous Ang-1 reduced SAH-associated BBB leakage. Conclusions: Our study indicated that Tie-2 receptor phosphorylation in microvascular endothelial cells was involved in pathophysiological process after SAH, and the decline of Tie-2 receptor phosphorylation might increase blood–brain barrier permeability by decreasing the tight junction protein expression.

Seventeen novel 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate and -carboxamide derivatives were synthesized and evaluated for their growth inhibition in seven human solid tumor and a human leukemia HL-60 cell lines. Compound IVa showed more activity than the other compounds and the positive control temozolomide. In the presence of 40 mg/mL of IVa, the survival rate of all tested tumor cells was less than 10%. Esters displayed more potent antitumour activity than amides and temozolomide against HL-60 cells. These compounds also exhibited considerably enhanced water-solubility.

Biological nitrogen fixation is a complex process requiring multiple genes working in concert. To date, the Klebsiella pneumoniae nif gene cluster, divided into seven operons, is one of the most studied systems. Its nitrogen fixation capacity is subject to complex cascade regulation and physiological limitations. In this report, the entire K. pneumoniae nif gene cluster was reassembled as operon-based BioBrick parts in Escherichia coli. It provided ~100% activity of native K. pneumoniae system. Based on the expression levels of these BioBrick parts, a T7 RNA polymerase-LacI expression system was used to replace the σ(54)-dependent promoters located upstream of nif operons. Expression patterns of nif operons were critical for the maximum activity of the recombinant system. By mimicking these expression levels with variable-strength T7-dependent promoters, ~42% of the nitrogenase activity of the σ(54)-dependent nif system was achieved in E. coli. When the newly constructed T7-dependent nif system was challenged with different genetic and physiological conditions, it bypassed the original complex regulatory circuits, with minor physiological limitations. Therefore, we have successfully replaced the nif regulatory elements with a simple expression system that may provide the first step for further research of introducing nif genes into eukaryotic organelles, which has considerable potentials in agro-biotechnology.

In the structure of the title compound, C12H11N3O3·H2O, the dihedral angle formed by the benzene and isoxazole rings is 2.03 (8)°. The molecular conformation is stabilized by an intramolecular O—H...N hydrogen bond. In the crystal structure, molecules are linked into a three-dimesional network by intermolecular N—H...O, O—H...N and O—H...O hydrogen bonds, and by π–π stacking interactions involving adjacent benzene and isoxazole rings [centroid–centroid separation = 3.663 (2) Å].

Although deep neural networks perform well in many areas,research shows that deep neural networks are vulnerable to attacks from adversarial examples.There are many algorithms for attacking neural networks,but the attack speed of most attack algorithms is slow.Therefore,the rapid generation of adversarial examples has gradually become the focus of research in the area of adversarial examples.AdvGAN is an algorithm that uses the network to attack another network,which can generate adversarial samples extremely faster than other methods.However,when carrying out a targeted attack,AdvGAN needs to train a network for each target,so the efficiency of the attack is low.In this article,we propose a multi-target attack network(MTA) based on the generative adversarial network,which can complete multi-target attacks and quickly generate adversarial examples by training only once.Experiments show that MTA has a higher success rate for targeted attacks on the CIFAR10 and MNIST datasets than AdvGAN.We have also done adversarial sample transfer experiments and attack experiments under defense.The results show that the transferability of the adversarial examples generated by MTA is stronger than other multi-target attack algorithms,and our MTA method also has a higher attack success rate under defense.