Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) ...strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC
50
= 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD.
Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC ...risk, requiring effective genetic counseling for risk stratification and individualized prevention.
We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218).
Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%).
This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
Herein, we aimed to determine the clinical efficacy of recombinant human thrombopoietin (rhTPO) combined with glucocorticoids for treating immune thrombocytopenia (ITP).
Clinical data of 87 patients ...with ITP admitted to our hospital were retrospectively analyzed, and patients were divided into two groups according to the treatment employed: 42 patients in the control group (CG) were prescribed glucocorticoids, and 45 patients in the study group (SG) received rhTPO combined with glucocorticoids.
The total effective treatment rate in the SG (95.56%) was higher than that in the CG (76.19%) (P < 0.05). The SG achieved a platelet (PLT) count > 50 × 10
9
/L faster and required fewer PLT transfusions than the CG (P < 0.05). At 1, 7, and 14 days after treatment, the PLT count increased in both groups and was higher in the SG than in the CG (P < 0.05). After treatment, CD3+, CD4+, and CD4+/CD8+ T cells increased, whereas CD8 + decreased in both groups, with the SG exhibiting a superior improvement to the CG (P < 0.05). Considering prothrombin time, activated partial thromboplastin time, and fibrinogen, differences between the two groups were not statistically significant, both before and after treatment (P > 0.05).
rhTPO combined with glucocorticoids for treating ITP can effectively enhance the therapeutic effect, regulate the T lymphocyte subpopulation, rapidly increase the PLT level, and induce no significant effect on the coagulation function of patients, with good safety and high clinical promotion value.
Background & Aims T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to influence autoimmune diseases; however, its function in viral infection has not been ...well-defined. We therefore investigated the expression and regulatory function of Tim-3 in natural killer (NK) cells in chronic Hepatitis B (CHB) infection. Methods Seventy-six CHB patients, 38 healthy controls, and 18 patients with fatty liver disease (FLD) were tested for Tim-3 expression on peripheral blood mononuclear cells (PBMCs) and in the liver tissue by flow cytometry and immunohistochemical stainning. The effects of HBV infection on Tim-3 expression in NK cells and the roles of Tim-3 in regulation of NK-cell function were also studied. Results There was a significant increase of Tim-3 expression in PBMCs, circulating NK cells and liver infiltrating lymphocytes (LILs) from CHB patients compared to that of healthy controls and FLD patients. Increased Tim-3 expression was also detected in NK92 cells that had been transfected with a HBV expression vector and NK cells isolated from the liver of HBV transgenic mice. Importantly, blockage of Tim-3 signaling with anti-Tim-3 antibodies or Tim-3-Fc fusion proteins resulted in an increased cytotoxicity for NK92 cells compared to HepG2 and HepG2.2.15 cells, as well as an elevated interferon-gamma (IFN-γ) production. Similarly, enhanced cytotoxicity was also observed in PBMCs or NK cells from CHB patients treated with the Tim-3 blockade ex vivo. Conclusion HBV infection can up-regulate Tim-3 expression in NK cells, which may in turn suppress NK-cell functions in CHB patients.
Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 ...polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.
Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide ...an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC.
We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date.
Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.
A planar circularly polarized (CP) array antenna based on polarization conversion electromagnetic band‐gap (PCEBG) and sequential phase (SP) feed network with wideband circular polarization and low ...radar cross section (RCS) is presented. The array is formed by 2 × 2 PCEBG elements. The CP performance is obtained due to the PCEBG, and the SP feed network contributes to the wide bandwidth and symmetric radiation pattern. The proposed array antenna, with an overall size of 64 mm × 64 mm × 2.008 mm (1.6 λ0 × 1.6 λ0 × 0.05 λ0 at 7.5 GHz) has been fabricated and measured. The measured results are as follows, an impedance bandwidth of 42.90% (6.61‐10.22 GHz), a 3‐dB axial ratio bandwidth (ARBW) of 28.3% (6.65‐8.83 GHz) and a 3‐dB gain bandwidth of 23.7% (6.7‐8.5 GHz). The antenna exhibits left‐hand CP(LHCP) characteristics with a peak broadside gain of 14.1 dB. The proposed antenna achieves an in‐band and out‐band RCS reduction more than 8 dB under normal incidence. The measured results are in agreement with the simulated results.
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Piezoelectrics exhibit mechanical strain in response to electrical stimuli and vice versa. A high level of electric-field-induced strain with minimal hysteresis is desired for ...piezoelectric materials when used as actuators. The past two decades have seen extensive research into lead-free piezoelectrics to replace Pb(Zr,Ti)O3 and compositional engineering has been demonstrated to be an effective method to tailor their functional properties. Doped (K,Na)NbO3 (KNN) compositions with elaborate compositional tuning can exhibit enhanced electromechanical properties. However, a balance between enhanced properties and non-toxicity of the dopants should be considered. In this work, we propose to use microstructural engineering to enhance the properties. Based on phase-field simulations, we propose to take advantage of depolarization energies generated by polar-nonpolar interfaces, to increase the contribution of domain wall motion to electric-field-induced strain. Heterogeneous ferroelectric-paraelectric microstructures were introduced into a KNN ceramic via a two-step sintering process. Their presence was characterized by high-resolution transmission electron microscopy. Enhanced reversible domain wall motion was verified by in situ high-energy X-ray diffraction. Electric-field-induced strain is enhanced by 62% and 200% at 25 °C and 150 °C, respectively. Considering lead-free piezoelectrics also represent an emerging class of biomaterials for medical technology, the non-toxicity and biocompatibility of the investigated compositions are examined by in vitro cell viability assays. Our results demonstrate that microstructural engineering is a promising alternative approach to enhance the electric-field-induced strain of lead-free piezoelectrics while maintaining biocompatibility
Respiratory tract infection (RTI) in young children is a leading cause of morbidity and hospitalization worldwide. There are few studies assessing the performance for bronchoalveolar lavage fluid ...(BALF) versus oropharyngeal swab (OPS) specimens in microbiological findings for children with RTI. The primary purpose of this study was to compare the detection rates of OPS and paired BALF in detecting key respiratory pathogens using suspension microarray.
We collected paired OPS and BALF specimens from 76 hospitalized children with respiratory illness. The samples were tested simultaneously for 8 respiratory viruses and 5 bacteria by suspension microarray.
Of 76 paired specimens, 62 patients (81.6%) had at least one pathogen. BALF and OPS identified respiratory pathogen infections in 57 (75%) and 49 (64.5%) patients, respectively (P > 0.05). The etiology analysis revealed that viruses were responsible for 53.7% of the patients, whereas bacteria accounted for 32.9% and Mycoplasma pneumoniae for 13.4%. The leading 5 pathogens identified were respiratory syncytial virus, Streptococcus pneumoniaee, Haemophilus influenzae, Mycoplasma pneumoniae and adenovirus, and they accounted for 74.2% of etiological fraction. For detection of any pathogen, the overall detection rate of BALF (81%) was marginally higher than that (69%) of OPS (p = 0.046). The differences in the frequency distribution and sensitivity for most pathogens detected by two sampling methods were not statistically significant.
In this study, BALF and OPS had similar microbiological yields. Our results indicated the clinical value of OPS testing in pediatric patients with respiratory illness.
Respiratory tract diseases are closely related to atmosphere pollution. Ammonia is one of the harmful pollutants in the atmosphere environment, which has a great threat to human and animal ...respiratory tract health, but the mechanism of causing diseases is not clear. In this study, broiler lung tissue was used as a model to study the effect of high ammonia on respiratory tract diseases through the relationship between respiratory microflora, NLRP3 inflammasome, and inflammatory factors. For this, we validated the occurrence of lung tissue inflammation under ammonia exposure and detected the lung tissue microbial constituent by 16S rDNA sequencing. Moreover, the relative expression levels of NLRP3 and caspase-1 mRNA and the content of IL-1β and IL-6 were measured. After 7-D ammonia exposure, the proportion of the phylum Proteobacteria and the genus Escherichia/Shigella in lung tissue was significantly increased, the expression levels of NLRP3 and caspase-1 mRNA were significantly increased, and the content of IL-1β in lung tissue and serum was higher than that in the control group. In conclusion, high ammonia induced lung tissue inflammation via increasing the proportion of Escherichia/Shigella, activating NLRP3 inflammasome, and promoting IL-1β release. These findings provided a reference for the prevention and control of respiratory tract diseases in humans and animals caused by ammonia pollution.
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