A novel approach to treating post-stroke depression: administration of Botulinum Toxin A via local facial injection.

Background: Post-stroke depression (PSD) is a frequent complication following a stroke, characterized by prolonged feelings of sadness and loss of interest, which can significantly impede stroke rehabilitation, increase disability, and raise mortality rates. Traditional antidepressants often have significant side effects and poor patient adherence, necessitating the exploration of more suitable treatments for PSD. Previous researchers and our research team have discovered that Botulinum Toxin A (BoNT-A) exhibits antidepressant effects. Therefore, our objective was to assess the efficacy and side effects of BoNT-A treatment in patients with PSD. Methods: A total of 71 stroke patients meeting the inclusion criteria were allocated to the two group. 2 cases were excluded due to severe neurological dysfunction that prevented cooperation and 4 cases were lost follow-up. Ultimately, number of participants in the BoNT-A group (n = 32) and Sertraline group (n = 33). Treatment efficacy was evaluated 1, 2, 4, 8 and 12 weeks post-treatment. Results: There were no significant differences in baseline characteristics between the two groups (p > 0.05). Both groups exhibited comparable treatment efficacy, with fewer side effects observed in the BoNT-A group compared to the Sertraline group. BoNT-A therapy demonstrated significant effects as early as the first week (p < 0.05), and by the 12th week, there was a notable decrease in neuropsychological scores, significantly lower than the baseline level. The analysis revealed significant differences in measurements of the Hamilton Depression Scale (HAMD) (F(770) = 12.547, p = 0.000), Hamilton Anxiety Scale (HAMA) (F(951) = 10.422, p = 0.000), Self-Rating Depression Scale (SDS) (F(1385) = 10.607, p = 0.000), and Self-Rating Anxiety Scale (SAS) (F(1482) = 11.491, p = 0.000). Conclusion: BoNT-A treatment effectively reduces depression symptoms in patients with PSD on a continuous basis.

Correlation between bone mineral density and type 2 diabetes mellitus in elderly men and postmenopausal women.

The relationship between bone mineral density and type 2 diabetes is still controversial. The aim of this study is to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in elderly men and postmenopausal women. The participants in this study included 692 postmenopausal women and older men aged ≥ 50 years, who were divided into the T2DM group and non-T2DM control group according to whether or not they had T2DM. The data of participants in the two groups were collected from the inpatient medical record system and physical examination center systems, respectively, of the Tertiary Class A Hospital. All data analysis is performed in SPSS Software. Compared with all T2DM group, the BMD and T scores of lumbar spines 1-4 (L1-L4), left femoral neck (LFN) and all left hip joints (LHJ) in the non-T2DM group were significantly lower than those in the T2DM group (P < 0.05), and the probability of major osteoporotic fracture in the next 10 years (PMOF) was significantly higher than that in T2DM group (P < 0.001). However, with the prolongation of the course of T2DM, the BMD significantly decreased, while fracture risk and the prevalence of osteoporosis significantly increased (P < 0.05). We also found that the BMD of L1-4, LFN and LHJ were negatively correlated with homeostatic model assessment-insulin resistance (HOMA-IR) (P = 0.028, P = 0.01 and P = 0.047, respectively). The results also showed that the BMD of LHJ was positively correlated with indirect bilirubin (IBIL) (P = 0.018). Although the BMD was lower in the non-T2DM group than in the T2DM group, the prolongation of the course of T2DM associated with the lower BMD. And the higher prevalence of osteoporosis and fracture risk significantly associated with the prolongation of the course of T2DM. In addition, BMD was significantly associated with insulin resistance (IR) and bilirubin levels in T2DM patients.Registration number: China Clinical Trials Registry: MR-51-23-051741; https://www.medicalresearch.org.cn/search/research/researchView?id=c0e5f868-eca9-4c68-af58-d73460c34028 .

Enhancement of endothelial function and attenuation of portal vein injury using mesenchymal stem cells carrying miRNA-25-3p.

The aims of this study were to determine whether human umbilical cord mesenchymal stem cells (hucMSCs) modified by miRNA-25-3p (miR-25-3p) overexpression could promote venous endothelial cell proliferation and attenuate portal endothelial cell injury. HucMSCs and human umbilical vein endothelial cells (HUVEC) were isolated and cultured from human umbilical cord and characterized. Lentiviral vectors expressing miRNA-25-3p were transfected into hucMSCs and confirmed by PCR. We verified the effect of miR-25-3p-modified hucMSCs on HUVEC by cell co-culture and cell supernatant experiments. Subsequently, exosomes of miR-25-3p-modified hucMSCs were isolated from cell culture supernatants and characterized by WB, NTA and TEM. We verified the effects of miR-25-3p-modified exosomes derived from hucMSCs on HUVEC proliferation, migration, and angiogenesis by in vitro cellular function experiments. Meanwhile, we further examined the downstream target genes and signaling pathways potentially affected by miR-25-3p-modified hucMSC-derived exosomes in HUVEC. Finally, we established a rat portal vein venous thrombosis model by injecting CM-DiR-labeled hucMSCs intravenously into rats and examining the homing of cells in the portal vein by fluorescence microscopy. Histological and immunohistochemical experiments were used to examine the effects of miRNA-25-3p-modified hucMSCs on the proliferation and damage of portal vein endothelial cells. Primary hucMSCs and HUVECs were successfully isolated, cultured and characterized. Primary hucMSCs were modified with a lentiviral vector carrying miR-25-3p at MOI 80. Co-culture and cell supernatant intervention experiments showed that overexpression of miRNA-25-3p in hucMSCs enhanced HUVEC proliferation, migration and tube formation in vitro. We successfully isolated and characterized exosomes of miR-25-3p-modified hucMSCs, and exosome intervention experiments demonstrated that miR-25-3p-modified exosomes derived from hucMSCs similarly enhanced the proliferation, migration, and angiogenesis of HUVECs. Subsequent PCR and WB analyses indicated PTEN/KLF4/AKT/ERK1/2 as potential pathways of action. Analysis in a rat portal vein thrombosis model showed that miR-25-3p-modified hucMSCs could homing to damaged portal veins. Subsequent histological and immunohistochemical examinations demonstrated that intervention with miR-25-3p overexpression-modified hucMSCs significantly reduced damage and attenuated thrombosis in rat portal veins. The above findings indicate suggest that hucMSCs based on miR-25-3p modification may be a promising therapeutic approach for use in venous thrombotic diseases.

Downregulation of DIP2B as a prognostic marker inhibited cancer proliferation and migration and was associated with immune infiltration in lung adenocarcinoma via CCND1 and MMP2.

Background: DIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD). Methods: DIP2B expression and the relationship between survival time of cancer patients and DIP2B expression were analyzed. The relationship between DIP2B expression and survival time in LUAD patients was evaluated by a meta-analysis. Cox and survival analyses were used to evaluate the prognostic factors and construct a prognostic nomogram. The mechanisms and effects of DIP2B and the relationship between DIP2B expression and the immune microenvironment were investigated using bioinformatics, CCK-8, western blotting, and transwell experiments. Results: DIP2B was overexpressed in LUAD tissues. DIP2B overexpression was associated with shorter prognosis and was an unfavorable risk factor for prognosis in LUAD patients. DIP2B co-expressed genes were involved in cell division, DNA repair, cell cycle, and others. Inhibition of DIP2B expression could downregulate the proliferation, migration, and invasion of LUAD A549 and H1299 cells, which was related to the decrease in CCND1 and MMP2 protein expression. BRCA1 overexpression was associated with short prognosis, and the nomogram formed by DIP2B and BRCA1 was associated with a poor prognosis in LUAD patients. DIP2B expression correlated with immune cells (such as CD8 T cells, Tcm, and iDCs) and cell markers. Conclusion: DIP2B is a potential biomarker of poor prognosis and the immune microenvironment in LUAD. Inhibition of DIP2B expression downregulated cancer cell proliferation, migration, and invasion, which might be related to the decrease in CCND1 and MMP2 protein expression. DIP2B-related nomograms might be useful tools for predicting the prognosis of LUAD patients.

The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present).

INTRODUCTION: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates. AREA COVERED: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present. EXPERT OPINION: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense.

Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (ß) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-ß and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-ß and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-ß- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.

The Role of Phosphorus on Alkaline Hydrogen Oxidation Electrocatalysis for Ruthenium Phosphides.

Transition metal/p-block compounds are regarded as the most essential materials for electrochemical energy converting systems involving various electrocatalysis. Understanding the role of p-block element on the interaction of key intermediates and interfacial water molecule orientation at the polarized catalyst-electrolyte interface during the electrocatalysis is important for rational designing advanced p-block modified metal electrocatalysts. Herein, taking a sequence of ruthenium phosphides (including Ru2P, RuP and RuP2) as model catalysts, we establish a volcanic-relation between P-proportion and alkaline hydrogen oxidation reaction (HOR) activity. The dominant role of P for regulating hydroxyl binding energy is validated by active sites poisoning experiments, pH-dependent infection-point behavior, in situ surface enhanced absorption spectroscopy, and density functional theory calculations, in which P could tailor the d-band structure of Ru, optimize the hydroxyl adsorption sites across the Ru-P moieties, thereby leading to improved proportion of strongly hydrogen-bonded water and facilitated proton-coupled electron transfer process, which are responsible for the enhanced alkaline HOR performance.

Establishment and characterization of the PDAC-X3 cell line: a novel Chinese-origin pancreatic ductal adenocarcinoma cell line.

In this study, a novel pancreatic cancer cell line, termed pancreatic ductal adenocarcinoma (PDAC)-X3 cell line, was successfully derived from the primary tumor. Comprehensive analyses of its malignant phenotype, molecular properties, specific biomarkers, and histological features confirmed that PDAC-X3 cells serve as a valuable model for investigating the underlying mechanisms driving pancreatic carcinogenesis and advancing potential therapeutic strategies. The newly established cell line was continuously cultured for over 12 months and was stably passaged through more than 50 generations. Morphologically, PDAC-X3 cells displayed characteristics typical of epithelial tumors. The population doubling time for PDAC-X3 cells was determined to be 50 h. Karyotype analysis revealed that 75% of PDAC-X3 cells presented as hypotriploid, while 25% were sub-tetraploid, with representative karyotypes being 53 and XY der (1) inv (9) der (22). In suspension culture, PDAC-X3 cells efficiently formed organoids. Upon inoculation into BALB/C nude mice, these cells initiated the development of xenograft tumors, achieving a tumor formation rate of 33%. Morphologically, these xenografted tumors closely resembled the primary tumor. Drug sensitivity assays indicated that PDAC-X3 cells exhibited resistance to oxaliplatin but demonstrated sensitivity to 5-Fluorouracil (5-FU), gemcitabine, and paclitaxel. Immunohistochemical analysis revealed that CK7, CK19, E-cadherin, Vimentin, CA19-9 were positively expressed in PDAC-X3 cells. Meanwhile, the expression rate for Ki-67 was 30%, and that for CEA was not detected. Our findings underscore that PDAC-X3 represents a novel pancreatic cancer cell line, positioning it as a valuable model for basic research and the advancement of therapeutic strategies against pancreatic cancer.

Integration of single-cell and bulk RNA sequencing revealed immune heterogeneity and its association with disease activity in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease characterized by cartilage, bone damage, synovial inflammation, hyperplasia, autoantibody production, and systemic features. To obtain an overall profile of the immune environment in RA patients and its association with clinical features, we performed single-cell transcriptome and T-cell receptor sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SF) from RA patients, integrated with two large cohorts with bulk RNA sequencing for further validation and investigation. Dendritic cells (DCs) exhibited relatively high functional heterogeneity and tissue specificity in relation to both antigen presentation and proinflammatory functions. Peripheral helper T cells (TPHs) are likely to originate from synovial tissue, undergo activation and exhaustion, and are subsequently released into the peripheral blood. Notably, among all immune cell types, TPHs were found to have the most intense associations with disease activity. In addition, CD8 effector T cells could be clustered into two groups with different cytokine expressions and play distinct roles in RA development. By integrating single-cell data with bulk sequencing from two large cohorts, we identified interactions among TPHs, CD8 cells, CD16 monocytes, and DCs that strongly contribute to the proinflammatory local environment in RA joints. Of note, the swollen 28-joint counts exhibited a more pronounced association with this immune environment compared to other disease activity indexes. The immune environment alternated significantly from PBMCs to SF, which indicated that a series of immune cells was involved in proinflammatory responses in the local joints of RA patients. By integrating single-cell data with two large cohorts, we have uncovered associations between specific immune cell populations and clinical features. This integration provides a rapid and precise methodology for assessing local immune activation, offering valuable insights into the pathophysiological mechanisms at play in RA.

A horizontal and perpendicular interlaminar approach for intrathecal nusinersen injection in patients with spinal muscular atrophy and scoliosis: an observational study.

BACKGROUND: Lumbar puncture is challenging for patients with scoliosis. Previous ultrasound-assisted techniques for lumbar puncture used the angle of the probe as the needle trajectory; however, reproducing the angle is difficult and increases the number of needle manipulations. In response, we developed a technique that eliminated both the craniocaudal and lateromedial angulation of the needle trajectory to overall improve this technique. We assessed the feasibility and safety of this method in patients with scoliosis and identify factors related to difficult lumbar puncture. METHODS: Patients with spinal muscular atrophy and scoliosis who were referred to the anesthesia department for intrathecal nusinersen administrations were included. With a novel approach that utilized patient position and geometry, lumbar puncture was performed under ultrasound guidance. Success rates, performance times and adverse events were recorded. Clinical-demographic and spinal radiographic data pertaining to difficult procedures were analyzed. RESULTS: Success was achieved in all 260 (100%) lumbar punctures for 44 patients, with first pass and first attempt success rates of 70% (183/260) and 87% (226/260), respectively. Adverse events were infrequent and benign. Higher BMI, greater skin dural sac depth and smaller interlaminar size might be associated with greater difficulty in lumbar puncture. CONCLUSIONS: The novel ultrasound-assisted horizontal and perpendicular interlaminar needle trajectory approach is an effective and safe method for lumbar puncture in patients with spinal deformities. This method can be reliably performed at the bedside and avoids other more typical and complex imaging such as computed tomography guided procedure.

Pantothenate-encapsulated liposomes combined with exercise for effective inhibition of CRM1-mediated PKM2 translocation in Alzheimer's therapy.

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.

In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii.

Toxoplasma gondii (T. gondii) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-T. gondii activity of broxaldine (BRO) in vitro and in vivo and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 µg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of T. gondii and reduced the size and number of cysts in vitro. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of T. gondii was observed, including disintegration of T. gondii, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in T. gondii treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-T. gondii activity in vitro and in vivo; therefore, it has the potential to be used as a lead compound for anti-T. gondii treatment.

Nonreciprocal magnetoacoustic waves with out-of-plane phononic angular momenta.

Surface acoustic wave (SAW) can carry phononic angular momentum, showing great potential as an energy-efficient way to control magnetism. Still, out-of-plane phononic angular momentum in SAW and its interaction with magnetism remain elusive. Here, we studied the SAW-induced magnetoacoustic waves and spin pumping in Ni-based films on LiNbO3 with selected SAW propagation direction. The crystal inversion asymmetry induces circularly polarized phonons with large out-of-plane angular momenta so that up to 60% of the SAW power attenuates nonreciprocally controlled by the out-of-plane magnetization component. The SAW propagation direction dependence of the nonreciprocity verifies the crystal origin of the phononic angular momentum, and a chiral spin pumping demonstrates that the circular polarization can control the spin current generation efficiency. These results provide an additional degree of freedom for the acoustic control of magnetism and open an avenue for applying circularly polarized phonons.

Homology in Sex Determination in Two Distant Spiny Frogs, Nanorana quadranus and Quasipaa yei.

Sex determination is remarkably diverse, with frequent transitions between sex chromosomes, in amphibians. Under these transitions, some chromosomes are more likely to be recurrently co-opted as sex chromosomes, as they are often observed across deeply divergent taxa. However, little is known about the pattern of sex chromosome evolution among closely related groups. Here, we examined sex chromosome and sex determination in two spiny frogs, Nanorana quadranus and Quasipaa yei. We conducted an analysis of genotyping-by-sequencing (GBS) data from a total of 34 individuals to identify sex-specific makers, with the results verified by PCR. The results suggest that chromosome 1 is a homologous sex chromosome with an XY pattern in both species. This chromosome has been evolutionarily conserved across these closely related groups within a period of time. The DMRT1 gene is proposed to be implicated in homology across two distantly related spiny frog species as a putative candidate sex-determining gene. Harboring the DMRT1 gene, chromosome 1 would have been independently co-opted for sex determination in deeply divergent groups of anurans.

Modeling Interface Damage with Random Interface Strength on Asphalt Concrete Impervious Facings.

Asphalt concrete impervious facings, widely adopted as the impervious structures for rockfill dams and upper reservoirs in pumped storage power stations, typically have a multilayer structure with a thin sealing layer, a thick impervious layer, and a thick leveling bonding layer. The properties of the interfaces between these layers are crucial for the overall performance of the facings. This paper develops a model to investigate the complex interface damage behavior of the facing under static water pressure and gravity. The model considers two damage origins: one is the interface adhesion-decohesion damage, which is described by the cohesive zone model (CZM) combined with the Weibull-type random interface strength distribution, and the other is the bulk damage of each layer, described by Mazars' model. Primarily, a comparison between numerical simulation and indoor direct shear tests validates the reliability of the CZM for the asphalt concrete layer interface. Then, the damage distribution of the two interfaces is simulated, and the characteristics of the interface stress are analyzed in detail. The interface shear stresses of the ogee sections, which have different curvatures, all show an interesting oscillation between the thin sealing layer and the impervious layer, and the interface damage at this interface exhibits high heterogeneity. Furthermore, tension stress exists in the local zones of the ogee section, and the damage in this section is significantly greater than in other parts of the facings.

Visible-Light-Driven Coupling of 1,3,4-Oxadiazoles and Hydroxamic Acid Derivatives.

A visible-light-induced radical-radical cross-coupling reaction between 1,3,4-oxadiazoles and hydroxamic acid derivatives has been realized under base- and metal-free conditions. The protocol was characterized by broad substrate scope, excellent functional group tolerance, and simple operation procedures. By using this protocol, a variety of biologically important 5-aryl-1,3,4-oxadiazole-2-methylamines were obtained in good yields with excellent chemoselectivity.

Investigating the genetic determination of duration-of-fertility trait in breeding hens.

The duration-of-fertility (DF), which was defined as the number of days when breeding hens lay fertile eggs following copulation or artificial insemination (AI), is an important economic trait in chick production when it has strong effects on fertile egg output and production costs. Little is known about the underlying genes and molecular markers related to DF trait to date. Here, we measured the DF of 701 Chinese Jinghong hens and 408 Jingfen hens. The DF showed high individual variability and potential for genetic improvement. Then, 192 Jinghong breeding hens were provided for a genome-wide association study, 27 SNPs respectively located in three genomic linkage regions (GGA1:41Kb; GGA3:39Kb and GGA8:39Kb) were suggested to be significantly associated with DF. Particularly, 6 of these 27 SNPs were further verified to be associated with DF in the 701 Jinghong and 408 Jingfen hens using PCR-RFLP genotyping method. These 27 SNPs were also mapped to 7 genes according to their genomic position. Furtherly, 5 of these 7 genes were tested using qPCR. Results show that the CYP2D6, WBP2NL, ESR1 and TGFBR3 mRNA expression levels of hens with long DF were significantly higher than the hens with short DF (P < 0.05). Overall, findings in our research provide new insight into the genetic basis of duration-of-fertility in breeding hens while providing new clues for further functional validation on the DF-related genetic regulation mechanism and improvement of DF through chicken breeding.

N-Salicyloyl Tryptamine Derivatives as Potent Neuroinflammation Inhibitors by Constraining Microglia Activation via a STAT3 Pathway.

Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood-brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N-salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N-salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure-activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects. Among them, both in vitro and in vivo compound 18 exerted the best antineuroinflammatory effects by suppressing the activation of microglia, which is the culprit of neuroinflammation. The underlying mechanism of its antineuroinflammatory effect may be related to the inhibition of transcription, expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) that subsequently regulated downstream cyclooxygenase-2 (COX-2) expression and activity. With its excellent BBB permeability and pharmacokinetic properties, compound 18 exhibited significant neuroprotective effects in the hippocampal region of lipopolysaccharides (LPS)-induced mice than former N-salicyloyl tryptamine derivative L7. In conclusion, compound 18 has provided a new approach for the development of highly effective antineuroinflammatory therapeutic drugs targeting microglia activation.

Associations between particulate matter exposure during pregnancy and executive function of toddlers in a prospective cohort study.

BACKGROUND: Exposure to particulate matter (PM) has been found to be associated with impaired cognitive function. However, limited evidence is available on the relationship between PM exposure in the prenatal period and toddler executive function (EF), and the potential influence of breastfeeding. METHODS: The study included 1106 mother-toddler pairs recruited between 2015 and 2019. We assessed mothers' PM1, PM2.5, and PM10 prenatal exposure with a satellite-based dataset at a 1 × 1 km spatial resolution and assigned to participants based on residential addresses. Toddler EF was measured using the Behavior Rating Inventory of Executive Function for Preschoolers (BRIEF-P) questionnaire, higher BRIEF-P scores indicated poorer EF in toddlers. We determined the associations of PM exposure during pregnancy with BRIEF-P scores using multiple linear regression models. RESULTS: In the first trimester, a 10 µg/m3 increase of PM was associated with 1.49 (95% confidence interval [CI]: 0.14-2.83; PM1), 0.68 (95% CI: 0.10-1.26; PM2.5), and 0.63 (95% CI: 0.07-1.20; PM10) elevated toddler global executive composite index scores, respectively. In the stratified analysis, a 10 µg/m3 increase in first trimester PM1 exposure was related to 0.54 (95% CI: 0.19-0.89) higher inhibition scores in toddlers who received complementary breastfeeding for less than six months and -0.15 (95% CI: 0.81-0.51) higher inhibition scores in toddlers who received complementary breastfeeding for six months or more (P for interaction: 0.046). Additionally, a 10 µg/m3 increment in first trimester PM1 exposure was related to 0.36 (95% CI: 0.13-0.59) higher emotional control scores in toddlers who received breastfeeding for less than 12 months and -0.54 (95% CI: 1.25-0.18) higher inhibition scores in toddlers who received breastfeeding for no less than 12 months (P for interaction: 0.043). CONCLUSIONS: PM exposure during the first trimester, especially PM1, has been linked to lower toddler EF performance in toddlers; feeding with breast milk may be a potential protective measure.

Stabilizing atomic Ru species in conjugated sp2 carbon-linked covalent organic framework for acidic water oxidation.

Suppressing the kinetically favorable lattice oxygen oxidation mechanism pathway and triggering the adsorbate evolution mechanism pathway at the expense of activity are the state-of-the-art strategies for Ru-based electrocatalysts toward acidic water oxidation. Herein, atomically dispersed Ru species are anchored into an acidic stable vinyl-linked 2D covalent organic framework with unique crossed π-conjugation, termed as COF-205-Ru. The crossed π-conjugated structure of COF-205-Ru not only suppresses the dissolution of Ru through strong Ru-N motifs, but also reduces the oxidation state of Ru by multiple π-conjugations, thereby activating the oxygen coordinated to Ru and stabilizing the oxygen vacancies during oxygen evolution process. Experimental results including X-ray absorption spectroscopy, in situ Raman spectroscopy, in situ powder X-ray diffraction patterns, and theoretical calculations unveil the activated oxygen with elevated energy level of O 2p band, decreased oxygen vacancy formation energy, promoted electrochemical stability, and significantly reduced energy barrier of potential determining step for acidic water oxidation. Consequently, the obtained COF-205-Ru displays a high mass activity with 2659.3 A g-1, which is 32-fold higher than the commercial RuO2, and retains long-term durability of over 280 h. This work provides a strategy to simultaneously promote the stability and activity of Ru-based catalysts for acidic water oxidation.