Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.

Total synthesis of (6R,12R)-6,12-dimethylpentadecan-2-one, the sex pheromone of Diabrotica balteata LeConte.

Diabrotica balteata LeConte is one of the most important polyphagous agricultural pests. The sex pheromone of this pest was synthesized using Evans asymmetric alkylation, ring-opening reaction of (R)-2-methyloxirane, SN 2 alkylation of secondary tosylate, and coupling of chiral tosylate with Grignard reagent as central strategies. The sex pheromone prepared herein would be useful to control D. balteata.

Aspherical interferometric probe with wave-plate-array detection: system design and nonlinearity analysis.

Optical probes are the preferred choice for high-precision surface metrology, necessitating improved flexibility and a broader range of motion to adapt to the increasing complexity of surfaces. This study introduces an interferometric probe designed for measuring aspheric surfaces, utilizing a wave-plate-array detection component. By integrating splitter elements into the detector, the probe improves integration and dynamic scanning performance, while maintaining high-precision measurement capability. The system design and working principle are explored, and comprehensive nonlinear models based on the Jones matrix theory are established. These models focus on the nonlinear errors arising from alignment errors in various cases. Moreover, rigorous numerical simulations and optical experiments are conducted to validate the proposed models. When the alignment error reaches 10°, it results in a maximum nonlinear error of 3.02 nm. The experimental results demonstrate the effectiveness of the models in capturing nonlinear errors induced by alignment errors, providing a theoretical foundation for error reduction and compensation.

Labeling and Diagnostic Value of miRNA-28-3p in Patients with Nasopharyngeal Carcinoma.

Objective: To explore how miRNA-28-3p targets BIN1 and affects the biological behavior of nasopharyngeal carcinoma cells, and to evaluate its potential as a predictive biomarker for NPC. Methods: We studied 100 nasopharyngeal carcinoma patients who underwent surgery between January 2021 and January 2022. Tissues from tumors and adjacent normal areas were analyzed. Participants were categorized into two groups: one with nasopharyngeal carcinoma and another with adjacent normal tissue. Additionally, the nasopharyngeal carcinoma cell line CNE-2 was divided into three groups: an untreated control, a negative control with NC plasmid, and a test group treated with a miRNA-28-3p inhibitor. Key techniques included PCR, Western blotting, CCK-8, flow cytometry, focusing on the interactions between miRNA-28-3p and BIN1 and their predictive significance for NPC. Results: miRNA-28-3p levels were significantly higher in nasopharyngeal carcinoma tissues compared to adjacent normal tissues (P < .05). The predictive performance of miRNA-28-3p for NPC featured an AUC > 0.75 with sensitivity and specificity both exceeding 70% (P < .001). In nasopharyngeal carcinoma cells, miRNA-28-3p levels were significantly elevated compared to normal cells (P < .05). Transfection with the miRNA-28-3p inhibitor increased apoptosis and BIN1 protein levels while reducing cell proliferation, invasion, and migration significantly (P < .05). Conclusion: miRNA-28-3p is overexpressed in nasopharyngeal carcinoma and inhibits tumor cell proliferation, migration, and invasion, while promoting apoptosis by targeting BIN1. The level of miRNA-28-3p expression serves as a sensitive indicator for predicting nasopharyngeal carcinoma, affirming its potential as a diagnostic biomarker and underscoring the significance of these findings in enhancing understanding and clinical management of NPC.

Development of aptamer surface-enhanced Raman spectroscopy sensor based on Fe3O4@Pt and Au@Ag nanoparticles for the determination of acetamiprid.

As a common chlorinated nicotinic pesticide with high insecticidal activity, acetamiprid has been widely used for pest control. However, the irrational use of acetamiprid will pollute the environment and thus affect human health. Therefore, it is crucial to develop a simple, highly sensitive, and rapid method for acetamiprid residue detection. In this study, the capture probe (Fe3O4@Pt-Aptamer) was connected with the signal probe (Au@DTNB@Ag CS-cDNA) to form an assembly with multiple SERS-enhanced effects. Combined with magnetic separation technology, a SERS sensor with high sensitivity and stability was constructed to detect acetamiprid residue. Based on the optimal conditions, the SERS intensity measured at 1333 cm-1 is in relation to the concentration of acetamiprid in the range 2.25 × 10-9-2.25 × 10-5 M, and the calculated limit of detection (LOD) was 2.87 × 10-10 M. There was no cross-reactivity with thiacloprid, clothianidin, nitenpyram, imidacloprid, and chlorpyrifos, indicating that this method has good sensitivity and specificity. Finally, the method was applied to the detection of acetamiprid in cucumber samples, and the average recoveries were 94.19-103.58%, with RSD < 2.32%. The sensor can be used to analyse real samples with fast detection speed, high sensitivity, and high selectivity.

Evidence from mendelian randomization identifies several causal relationships between primary membranous nephropathy and gut microbiota.

BACKGROUND: Research has showcased a correlation between disruptions in gut microbiota and primary membranous nephropathy (pMN), giving rise to the concept of the 'gut-kidney axis'. However, the precise relationship between gut microbiota and pMN remains elusive. Hence, this study endeavors to investigate whether a causal relationship exists between gut microbiota and pMN utilizing Mendelian randomization (MR) analysis. METHODS: The primary method employed for MR analysis is the inverse variance weighting method, supplemented by MR-Egger and the weighted median method, to infer causality. This approach was validated within the pMN cohort across two distinct populations. RESULTS: At the species level, the abundance of Bifidobacterium bifidum and Alistipes indistinctus was negatively correlated with the risk of pMN. Conversely, pMN was positively associated with Bacilli abundance at the class level, Lachnospiraceae abundance at the family level, and Dialister abundance at the genus level. Specifically, at the species level, pMN was positively correlated with the abundance of Ruminococcus lactaris, Dialister invisus, and Coprococcus_sp_ART55_1. CONCLUSION: These findings lay the groundwork for future research exploring the interplay between pMN and the gut microbiota, with substantial implications for the prevention and treatment of pMN and its associated complications.

Total Synthesis of the Sex Pheromone of Clania variegata Snellen and Its Stereoisomers.

The paulownia bagworm, Clania variegata Snell, is an economically important pest of agriculture and forests. The sex pheromone of this pest and its stereoisomers were synthesized, and two of the stereoisomers were prepared for the first time. Our strategy was efficient and mainly included the ring-opening reaction of (S)-2-methyloxirane, the coupling of chiral sulfonate, the oxidative cleavage of olefin, and Yamaguchi esterification. Moreover, the overall yields of our synthesis were 23-29%, with eight steps in the longest route.

Perspectives on dementia care self-learning platform: A focus group study of family and professional caregivers.

OBJECTIVE: To compare perspectives of family and professional caregivers regarding an online self-learning platform. METHODS: Family and professional caregivers were interviewed separately. A thematic analysis was conducted with 12 family caregivers and 13 professional caregivers of people living with dementia in Macao using six semi-structured focus group interviews. RESULTS: Family and professional caregivers had different perspectives regarding the application of online learning program Four main themes emerged from the focus groups, including similarities and differences, namely 1) Need for services; 2) Accessibility to services; 3) Barriers to online learning; 4) Adjustments to the platform. CONCLUSIONS: The psychological assurance offered by an online learning program is imperative to the well-being of family caregivers. By identifying the gap between the needs and abilities of family caregivers and those imagined by professional caregivers, it allows for the development of support programs and interventions tailored to meet the specific needs of family caregivers.

A Novel Catheter Distal Contact Force Sensing for Cardiac Ablation Based on Fiber Bragg Grating with Temperature Compensation.

OBJECTIVE: To accurately achieve distal contact force, a novel temperature-compensated sensor is developed and integrated into an atrial fibrillation (AF) ablation catheter. METHODS: A dual elastomer-based dual FBGs structure is used to differentiate the strain on the two FBGs to achieve temperature compensation, and the design is optimized and validated by finite element simulation. RESULTS: The designed sensor has a sensitivity of 90.5 pm/N, resolution of 0.01 N, and root-mean-square error (RMSE) of 0.02 N and 0.04 N for dynamic force loading and temperature compensation, respectively, and can stably measure distal contact forces with temperature disturbances. CONCLUSION: Due to the advantages, i.e., simple structure, easy assembly, low cost, and good robustness, the proposed sensor is suitable for industrial mass production.

The impact of cumulative exposure to diverse lipid profiles on carotid intima-media thickness among an asymptomatic population.

BACKGROUND AND AIMS: We aimed to investigate the relationship between the cumulative exposure to different lipid parameters and carotid intima-media thickness(CIMT), which is considered a marker for the early stage of atherosclerosis. This is due to the shift in research focus from assessing individual lipoproteins to considering their cumulative exposure. METHODS AND RESULTS: The study included 2,348 participants who had their lipid parameters measured biennially since 2006.To calculate the cumulative lipid burden, the weighted sum of the difference between the measured value and the cutoff value of each parameter, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and non-HDLC, was added. Carotid ultrasound was used to detect CIMT. The association between cumulative lipid burden and CIMT was evaluated using linear and logistic analyses. TC and LDLC burden were significantly associated with thickening CIMT (p<0.05). A 2.65-fold, 1.67-fold increased risk of abnormal CIMT was documented in the highest quartile of these two lipid burdens. Notably, a dose-dependent relationship was observed in the overall population when taking non-HDLC burden as a continuous variable (fully-adjusted ß coefficient=0.0013, 95%CI 0.0004-0.0022). CONCLUSIONS: Out of the five lipid parameters, TC and LDLC burden showed independent associations with abnormal CIMT. it is crucial to attain optimal lipid levels for the prevention and treatment of subclinical atherosclerosis.

White light interference demodulation of optical fiber Fabry-Perot micro-pressure sensors based on the Karhunen-Loeve transform and singular value decomposition.

In this paper, the Karhunen-Loeve transform (KLT) and wavelength domain interferometric spectral singular value decomposition (SVD) are used for the first time to demodulate the pressure of an optical fiber Fabry-Perot (F-P) micro-pressure sensor, and the feasibility of the proposed method is demonstrated experimentally. The eigenvalue decomposition of the dominant frequency part of the beam-domain interferometric spectrum after the fast Fourier transform (FFT) is performed using KLT, and the singular value decomposition of the wavelength domain interferometric spectrum is additionally performed using SVD. Both methods use high-order eigenvalues as a new metric and then derive the relation between the new metric and the reference pressure. The two demodulation methods are experimentally compared, and we used an optical fiber F-P pressure sensor with unknown structure and material for pressure measurements. Even though the interferometric spectral signal is acquired using a coarse spectrometer (2.5 nm wavelength resolution), one can still achieve high demodulation accuracy with both algorithms. However, the SVD demodulation accuracy decreases significantly after reducing the spectral data points in the wavelength domain from 1566 to 783. KLT still has high demodulation accuracy and linearity after spectral data points are reduced from 1024 to 256 in the wavenumber domain. The satisfactory linearity of the measured pressure versus reference pressure and low reading errors validate the feasibility of the proposed demodulation algorithm.

Immune priming with Candida albicans induces a shift in cellular immunity and gene expression of Musca domestica.

Many insects are capable of developing enhanced resistance in response to repeated infection with the same pathogen, which is defined "immune priming". However, little is known in housefly, an ideal insect model for studying immunity. Here, Candida albicans (C. albicans) was used as the pathogen to explore whether housefly larvae are capable of eliciting immune priming. Firstly, we found that 2nd-instar larvae pre-exposure to heat-killed C. albicans could confer protection upon re-infection with C. albicans, as evidenced by the survival rate was higher in C. albicans primed larvae. Moreover, the hemocyte density was increased by priming, but phenoloxidase (PO) activity was not affected. For this reason, RNA sequencing (RNA-seq) was performed and found that 145 genes were differentially expressed after priming, in which 22 genes were related to immune response. Then, KEGG enrichment showed that Toll signaling pathway and Phagosome signaling pathway, as well as many other signaling pathways were enriched. Finally, qPCR was performed and found that the expression of 2 pattern recognition receptor (PRR) genes (PGRP-SD-like precursor and lectin subunit alpha-like) and 6 immune effector genes (phormicin, cecropin-A2-like, defensin-1, attacin-A-like, sarcotoxin-1C and lysozyme 1-like) in C. albicans primed larvae was significantly up-regulated after challenge. Taken together, our findings suggested that housefly larvae are capable of eliciting immune priming against C. albicans, and cellular immunity as well as the gene expression, especially genes involved in Toll signaling pathway were induced by immune priming with C. albicans.

Synthesis and antidepressant activity of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives selectively targeting SSRI/5-HT1A.

A series of novel 1-(1-benzoylpiperidin-4-yl) methanamine derivatives were synthesized and evaluated for the serotonin reuptake inhibitory abilities and binding affinities to the 5-HT1A receptor. The metabolic stabilities of these compounds were measured in vitro using human or mouse liver microsomes and the antidepressant activities were explored In vivo using the forced swimming test (FST) and tail suspension test (TST) in mice. The results indicated that the compound 12a exhibited strongest serotonin reuptake inhibition (IC50 = 8.2 nM) and marked 5-HT1A receptor affinity (Ki = 0.069 nM), which were significantly superior to lead compounds Ⅰ and Ⅱ. Meanwhile, compound 12a showed good metabolic stability in vitro and exhibited potential antidepressant-like effects in the FST and TST in mice.

Nonalcoholic fatty liver disease and risk of intracerebral hemorrhage.

BACKGROUND AND AIMS: This study aimed to investigate the association between the steatosis severity of nonalcoholic fatty liver disease (NAFLD) and future intracerebral hemorrhage (ICH) risk. METHODS AND RESULTS: We used data from the Kailuan study. Participants without a history of stroke, myocardial infarction, cancer, other liver diseases or alcohol abuse were enrolled. NAFLD and the severity of liver steatosis were assessed by abdominal ultrasonography. We stratified the participants into different groups according to the severity changes in liver steatosis status across the first 4-year follow-up period. The outcome was the first occurrence of ICH during the next 6-year follow-up period. Hazard ratios (HRs) and 95% CI of ICH were estimated using Cox models adjusted for potential risk factors. A total of 49,906 participants were enrolled in this study. During a median of 6.79 years of follow-up, 193 incident ICH cases were identified. Compared with persistent nonfatty liver participants, the hazard ratios (HRs) for participants with persistent mild steatosis, persistent moderate steatosis, persistent severe steatosis, alleviating steatosis, and aggravating steatosis were 1.28 (95% CI, 0.75-2.18), 2.33 (95% CI, 1.24-4.38), 1.63 (95% CI, 0.22-12.11), 1.41 (95% CI, 0.91-2.18), and 1.37 (95% CI, 0.94-2.00), respectively, in the fully adjusted model. CONCLUSIONS: NAFLD with persistent moderate steatosis was significantly related to an increased risk of future ICH, independent of other conventional risk factors.

Lower low-density lipoprotein cholesterol levels are associated with an increased risk of hematoma expansion and ensuing mortality in acute ICH patients.

BACKGROUND AND PURPOSE: The relationship between lipid levels and the prognosis of acute intracerebral hemorrhage (ICH) remains controversial. Thus, we aimed to investigate whether lower low-density lipoprotein cholesterol (LDL-C) levels increased the risk of adverse outcomes, as well as the current situation of statin treatment in acute ICH patients with premorbid lipid-lowering therapy. METHODS: From August 1, 2015, to July 31, 2019, a total of 73,098 ICH patients were included in our study from the Chinese Stroke Center Alliance program. Patients were grouped by LDL-C levels of < 1.4 mmol/L, 1.4-1.8 mmol/L, 1.8-2.6 mmol/L, and > 2.6 mmol/L. Logistic regression was used to assess the association between LDL-C levels and the composite risk of hematoma expansion (HE) or in-hospital death. Moreover, statin treatment in ICH patients with cardio-cerebrovascular diseases was analyzed. RESULTS: In total, 6368 (8.7%) patients were identified as a composite of HE or in-hospital death with a mean LDL-C level of 2.9 ± 1.7 mmol/L. In the univariate analysis, patients who achieved lower LDL-C concentrations under 1.4 mmol/L had a 36% higher risk of adverse outcomes compared with the ≥ 2.6 mmol/L group (OR 1.36, 95%CI 1.23-1.51). Similar results were obtained in multivariate analyses, especially for patients with GCS scores of 9-15. For acute ICH patients with concomitant atherosclerotic disease, statin treatment was discontinued in the majority of Chinese population. CONCLUSIONS: Lower LDL-C levels (< 1.4 mmol/L) are associated with an increased risk of HE and ensuing mortality in acute ICH patients. Maintaining an optimal LDL-C range may have therapeutic potential against HE which merits further investigation.

Antifungal activity of MAF-1A peptide against Candida albicans.

Invasive candidiasis is a major threat to human health, and Candida albicans is the most common pathogenic species responsible for this condition. The incidence of drug-resistant strains of C. albicans is rising, necessitating the development of new antifungal drugs. Antimicrobial peptides (AMPs) have recently attracted attention due to their unique ability to evade the drug resistance of microorganisms. However, the mechanism of their activity has not yet been identified. The current study analyzed the mode of action of MAF-1A by confocal microscopy, scanning electron microscopy, fluorescent staining, flow cytometry, and qRT-PCR. The results indicate that MAF-1A disrupts the cell membrane of C. albicans and enters the cell where it binds and interacts with nucleic acids. qRT-PCR demonstrated that the expression of several sterol biosynthesis-related genes in C. albicans was increased after MAF-1A treatment. Together, these findings suggest that MAF-1A exerts antifungal action by affecting both the cell membrane and intracellular components. The antifungal mechanism of MAF-1A is unique, and its identification has great research and clinical significance.

Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes.

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

High prevalence and risk factors of multiple antibiotic resistance in patients who fail first-line Helicobacter pylori therapy in southern China: a municipality-wide, multicentre, prospective cohort study.

BACKGROUND: We aimed to study the prevalence of secondary antibiotic resistance of Helicobacter pylori in southern China and its risk factors, particularly geographical and socio-economic factors. METHODS: This was a municipality-wide, multicentre, prospective cohort study involving five major hospitals. Patients aged ≥18 years who failed first-line bismuth-based quadruple anti-H. pylori therapy between September 2016 and February 2018 were recruited. Participants underwent upper gastrointestinal endoscopy with biopsy from the antrum and body for H. pylori culture and antimicrobial susceptibility testing for six antibiotics (clarithromycin, levofloxacin, metronidazole, amoxicillin, tetracycline and furazolidone). Patients with failure of H. pylori culture were excluded. Participants completed a questionnaire profiling 22 potential risk factors of H. pylori infection and antibiotic resistance, including medical, social, household and birthplace factors. RESULTS: A total of 1113 patients failed first-line therapy, with successful H. pylori culture in 791 (71.1%) [male = 433 (54.7%); median age = 43 years]. Secondary resistance rates of dual antibiotics (clarithromycin + metronidazole and levofloxacin + metronidazole) and triple antibiotics (clarithromycin + levofloxacin + metronidazole) were 34.0%, 38.7% and 17.8%, respectively. Risk factors for clarithromycin + metronidazole resistance were history of ≥2 courses of H. pylori therapies [adjusted OR (aOR) = 1.71; 95% CI = 1.17-2.54], ≥3 household members (aOR = 2.00; 95% CI = 1.07-3.90) and family history of gastric cancer (aOR = 1.85; 95% CI = 1.18-2.85). Risk factors for levofloxacin + metronidazole resistance were age ≥40 years (aOR = 1.94; 95% CI = 1.37-2.75), lower gross domestic product per capita (aOR = 0.29; 95% CI = 0.10-0.80) and higher number of doctors/10 000 population (aOR = 1.59; 95% CI = 1.07-2.39). A higher human development index was of borderline significance (aOR = 2.79; 95% CI = 0.97-8.70). CONCLUSIONS: The rates of secondary resistance of H. pylori to multiple antibiotics were high in southern China. Certain population-level risk factors were associated with levofloxacin + metronidazole resistance.

Identifying and Characterizing a Novel Peritrophic Matrix Protein (MdPM-17) Associated With Antibacterial Response From the Housefly, Musca domestica (Diptera: Muscidae).

Peritrophic matrix/membrane (PM) critically prevents the midgut of insects from external invasion by microbes. The proteins in the peritrophic membrane are its major structural components. Additionally, they determine the formation and function of this membrane. However, the role of PM proteins in immune regulation is unclear. Herein, we isolated a novel PM protein (MdPM-17) from Musca domestica larvae. Further, the function of MdPM-17 in regulating host innate immunity was identified. Results showed that the cDNA of MdPM-17 full is 635 bp in length. Moreover, it consists of a 477-bp open reading frame encoding 158 amino acid residues. These amino acid residues are composed of two Chitin-binding type-2 domain (ChtBD2) and 19 amino acids as a signal peptide. Moreover, tissue distribution analysis indicates that MdPM-17 was enriched expressed in midgut, and moderate levels in the fat body, foregut, and malpighian tubule. Notably, MdPM-17 recombinant protein showed high chitin-binding capacity, thus belongs to the Class III PM protein group. MdPM-17 protein silencing via RNA interference resulted in the expression of antimicrobial peptide (defensin, cecropins, and diptericin) genes, and this occurred after oral inoculation with exogenous microbes Escherichia coli (Enterobacteriales:Enterobacteriaceae), Staphylococcus aureus (Bacillales:Staphylococcaceae), and Candida albicans (Endomycetales:Saccharomycetaceae)). Therefore, all the antimicrobial peptide (AMP) gene expression levels are high in MdPM-17-depleted larvae during microbial infection compared to controls. Consequently, these findings indicate that MdPM-17 protein is associated with the antibacterial response from the housefly.

Synthesis and antidepressant-like activity of novel alkoxy-piperidine derivatives targeting SSRI/5-HT1A/5-HT7.

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.