Impacts of polyethylene glycol (PEG) dispersity on protein adsorption, pharmacokinetics, and biodistribution of PEGylated gold nanoparticles.

PEGylated gold nanoparticles (PEG-AuNPs) are widely used in drug delivery, imaging and diagnostics, therapeutics, and biosensing. However, the effect of PEG dispersity on the molecular weight (M W) distribution of PEG grafted onto AuNP surfaces has been rarely reported. This study investigates the effect of PEG dispersity on the M W distribution of PEG grafted onto AuNP surfaces and its subsequent impact on protein adsorption and pharmacokinetics, by modifying AuNPs with monodisperse PEG methyl ether thiols (mPEG n -HS, n = 36, 45) and traditional polydisperse mPEG2k-SH (M W = 1900). Polydisperse PEG-AuNPs favor the enrichment of lower M W PEG fractions on their surface due to the steric hindrance effect, which leads to increased protein adsorption. In contrast, monodisperse PEG-AuNPs have a uniform length of PEG outlayer, exhibiting markedly lower yet constant protein adsorption. Pharmacokinetics analysis in tumor-bearing mice demonstrated that monodisperse PEG-AuNPs possess a significantly prolonged blood circulation half-life and enhanced tumor accumulation compared with their polydisperse counterpart. These findings underscore the critical, yet often underestimated, impacts of PEG dispersity on the in vitro and in vivo behavior of PEG-AuNPs, highlighting the role of monodisperse PEG in enhancing therapeutic nanoparticle performance.

Relationship between Brain Natriuretic Peptide and Thromboembolic Events in Elderly Patients with Nonvalvular Atrial Fibrillation.

Objective: To investigate the relationship between brain natriuretic peptide (BNP) and thromboembolic events in elderly patients with nonvalvular atrial fibrillation (NVAF). Methods: This is a prospective cohort study, and based on the inclusion and exclusion criteria, 180 elderly patients with NVAF were included. The patients received follow-up appointments in the clinic or by telephone every 6 months after the beginning of the study. The primary follow-up endpoints were thromboembolic and atherosclerotic events, including ischaemic stroke, myocardial infarction, and systemic embolism. The secondary endpoints were adverse events, including cardiovascular death, all-cause death, and hospitalisation for heart failure. Patients were divided into three groups according to their BNP level at admission: group A (BNP ≤334.5 pg/mL), group B (BNP = 334.5-1,288 pg/mL), and group C (BNP ≥1,288 pg/mL). Results: A total of 180 patients were enrolled in this study, with 50 patients in group A, 68 in group B, and 62 in group C. Compared with groups A and B, group C had a higher CHA2DS2-VASc score (Z = 15.142; P=0.001) and a lower ejection fraction (EF) value (Z = 119.893; P=0.001). The left atrium (LA) and left ventricular end-diastolic diameter (LVEDD) were larger (Z = 105.031; P=0.001 and Z = 74.430; P=0.001), respectively, suggesting that patients with significantly increased BNP had a higher risk of thromboembolism and atherosclerosis, lower EF, larger LA and LVEDD, and worse cardiac function. After 1 year of follow-up, the incidence of primary endpoint events (χ2 = 9.556; P=0.008) and secondary endpoint events (χ2 = 59.485; P=0.001) in group C were higher than those in groups A and B. Conclusion: Higher BNP levels may be an independent risk factor for thromboembolic and atherosclerotic events in elderly patients with NVAF. The higher the BNP level, the greater the risk of thromboembolic and atherosclerotic events.

The Association Between S100A12 Protein and C-Reactive Protein with Malignant Ventricular Arrhythmias Following Acute Myocardial Infarction in the Elderly.

Objective: To investigate the association of S100A12 protein and C-reactive protein (CRP) with the onset of malignant ventricular arrhythmias (MVA) after acute myocardial infarction (AMI) in the elderly. Methods: A total of 159 elderly AMI patients admitted to Chongming Hospital affiliated to Shanghai University of Medicine & Health Sciences from January 2018 to January 2023 were enrolled in the study. CRP levels were determined using an automatic biochemical analyzer, and S100A12 levels were measured using enzyme-linked immunosorbent assay (ELISA). Patients were categorized based on the Lown classification into groups without MVA and with MVA. Univariate analysis was initially performed to identify independent variables, followed by multivariate logistic regression to determine the risk factors for malignant ventricular arrhythmias post-AMI. The predictive value of S100A12 protein and CRP for malignant ventricular arrhythmias after acute myocardial infarction in the elderly was analyzed using the receiver operating characteristic (ROC) curve. Results: Among the 159 patients with AMI, 27 (17%) had MVA. Multivariate logistic regression analysis indicated that both S100A12 protein and CRP could be independent risk factors for malignant ventricular arrhythmias following acute myocardial infarction in the elderly (p < 0.05). The area under the ROC curve showed the area under the curve (AUC) for S100A12 protein to be 0.7147, for CRP 0.7356, and for the combined diagnosis 0.8350 (p < 0.05). Conclusion: S100A12 protein and CRP are independent risk factors for MVA after MI in the elderly. The combined application of S100A12 protein and CRP has higher diagnostic sensitivity and specificity.

Genetic Architecture and Functional Implications of the CSF-Contacting Nucleus.

We previously identified a unique nucleus, the cerebrospinal fluid (CSF)-contacting nucleus. This study aims to understand its gene architecture and preliminarily suggest its functions. The results showed that there were about 19,666 genes in this nucleus, of which 913 were distinct from the dorsal raphe nucleus (non-CSF contacting). The top 40 highly-expressed genes are mainly related to energy metabolism, protein synthesis, transport, secretion, and hydrolysis. The main neurotransmitter is 5-HT. The receptors of 5-HT and GABA are abundant. The channels for Cl-, Na+, K+, and Ca2+ are routinely expressed. The signaling molecules associated with the CaMK, JAK, and MAPK pathways were identified accurately. In particular, the channels of transient receptor potential associated with nociceptors and the solute carrier superfamily members associated with cell membrane transport were significantly expressed. The relationship between the main genes of the nucleus and life activities is preliminarily verified.

Effects of different interventions on prognosis and quality of life in patients with atrial fibrillation.

OBJECTIVE: To compare the effects of different intervention measures on prognosis and quality of life in patients with atrial fibrillation, in order to provide clinical basis for diagnosis and treatment. METHODS: A total of 160 patients who visited several hospitals including Shanghai Xinhua Hospital from June 2019 to June 2021 were selected. Among them, 40 cases were in the drug treatment group (DRUG group), 40 cases in the radiofrequency ablation group (Radiofrequency ablation, RFA group), and 40 cases in the catheter ablation combined with percutaneous left atrial appendage occlusion group (""one-stop"" procedure group) and 40 cases in the percutaneous left atrial appendage closure group (Left atrial appendage closure, LAAC group). The Minnesota quality of life score (MLHFQ), ejection fraction (LVEF), and left atrial anterior and posterior diameters (LAD) were compared between the groups at 1-year follow-up, and the differences in adverse events were compared between the groups. RESULTS: (1) After a 1-year follow-up, overall comparison, the MLHFQ scores and the LVEF and the LAD among the four groups were statistically different (p < .01); (2) Multiple comparisons, ① the MLHFQ scores: The RFA group was the lowest, the "one-stop" operation group was lower than the DRUG group, the LAAC group was the highest (p < .01). ② LVEF: The RFA group was the highest, the "one-stop" procedure group was higher than the drug treatment group, the LAAC group was the lowest (p < .01). ③ LAD: the RFA group and the "one-stop" procedure group were smaller than the DRUG group, the DRUG group was smaller than the LAAC group (p < .01).(3) Compared with the baseline data after 1-year follow-up in each group, in the RFA group and in the "one-stop" procedure group, the MLHFQ scores was decreased, the LVEF was increased, and the LAD was decreased (p < .01); in the DRUG group: the difference was not statistically significant (p > .05); in the LAAC group, the MLHFQ scores was increased, the LVEF was decreased, and the LAD was increased (p < .01). (4) There were significant differences in the incidence of adverse events among the four groups (p < .01), the lowest in the RFA group and the highest in the LAAC group. CONCLUSION: Compared with drug treatment, radiofrequency ablation and "one-stop" procedure group can improve the quality of life of patients with atrial fibrillation, improve cardiac function, and reduce the occurrence of adverse events. Percutaneous left atrial appendage occlusion affects patients' quality of life and improves cardiac function, and increases the incidence of adverse events.

Cerebrospinal fluid contacting nucleus and its 5-HT: A new insight into the regulation mechanism of general intravenous anesthesia.

General anesthesia is one of the most common clinical anesthesia methods. Many studies have suggested that 5-HT plays an important role in the mechanism of general anesthesia, but its basic principle is still unclear. The cerebrospinal fluid (CSF)-contacting nucleus, which we identified 30 years ago, contains a large number of 5-HT neurons. In the brain, many of the nuclei involved in regulating the effects of general anesthesia send projections to the CSF-contacting nucleus. Does the CSF-contacting nucleus and its 5-HT neurons participate in regulating the effect of general anesthesia? This is a new and interesting scientific question. To answer this question, rats underwent general anesthesia by intravenous injection of propofol. During the maintenance of and recovery from general anesthesia, the protein expression of c-Fos in the CSF-contacting nucleus was significantly increased. "Knockout" of this nucleus significantly increased the of number of low-frequency δ waves, which are indicative of deep anesthesia, during general anesthesia maintenance; however, the number of high-frequency ß waves, which indicate consciousness, was significantly decreased. During recovery from general anesthesia, the recovery of the righting reflex (RORR) time of rats with CSF-contacting nucleus ablation was significantly prolonged; activation of 5-HT neurons in the CSF-contacting nucleus promoted recovery from general anesthesia, while inhibition of 5-HT neurons in the CSF-contacting nucleus delayed recovery from general anesthesia. The above results suggest that the CSF-contacting nucleus and its 5-HT neurons play a key role in regulating the effect of intravenous anesthesia, especially during recovery from general anesthesia.

Characterizing the spatiotemporal distribution of dissolved organic matter (DOM) in the Yongding River Basin: Insights from flow regulation.

Artificial flow regulation is an important measure to alleviate water shortages and improve the ecological quality of river basins. Dissolved organic matter (DOM) plays a crucial role in the carbon cycle and regulates biogeochemical and ecological processes in aquatic systems. Among the numerous studies on the effects of anthropogenic activities on the quality and quantity of river DOM, few studies have focused on the influence of different artificially regulated flow on the composition, source, and fate of fluvial DOM. This study aims to elucidate the impact of different artificial regulation modes of river flows on the source, migration, and transformation of DOM. The optical properties of DOM were used to explore the temporal and spatial distribution characteristics of DOM in the Yongding River Basin, where artificial regulation of river flows by cross-basin and inner-basin water transfers were implemented. Excitation-emission matrix fluorescence spectroscopy coupled with parallel factor analysis revealed four fluorescent substances of DOM in the water: one microbial humic-like (C1), one terrestrial humic-like (C2), one non-point source pollution humic-like (C4), and one tryptophan-like (C3) substance. Due to cross-basin water transfer from the Yellow River, the flow is the highest (21.79 m3/s) during spring, which was the reason that the signal of C2 was stronger during spring (71.45 QSU) compared to summer (57.12 QSU) and autumn (51.78 QSU). Due to inner-basin water transfer from upstream reservoirs, C3 derived from autochthonous sources were higher during autumn (130.81 QSU) than during spring (77.17 QSU) and summer (93.16 QSU). With no water transfer, more C1 were present at higher temperatures during summer (141.51 QSU) than during spring (126.73 QSU) and autumn (128.8 QSU). Moreover, C4 originating from urban and/or agricultural non-point source runoff increased during summer (57.07 QSU) than during spring (33.29 QSU) and autumn (52.27 QSU) because of increased rainfall. The different modes of artificial regulation of river flows changed the hydrological characteristics of the basin, which in turn altered the temporal and spatial distribution characteristics of the quantity and quality of DOM. The finding of this study can help promote the development of appropriate management strategies for artificial regulation of river flows in the basin. Furthermore, this study provides a basis for investigating the effects of different artificial flow regulations on the carbon cycles and ecological risks of rivers in the basin.

Effect of Normalization Methods on Accuracy of Estimating Low- and High-Molecular Weight PAHs Distribution in the Soils of a Coking Plant.

Mapping spatial distribution of soil contaminants at contaminated sites is the basis of risk assessment. Hotspots can cause strongly skewed distribution of the raw contaminant concentrations in soil, and consequently can require suitable normalization prior to interpolation. In this study, three normalization methods including normal score, Johnson, and Box-Cox transformation were performed on the concentrations of two low-molecular weight (LMW) PAHs (i.e., acenaphthene (Ace) and naphthalene (Nap)) and two high-molecular weight (HMW) PAHs (i.e., benzo(a)pyrene (BaP) and benzo(b)fluoranthene (BbF)) in soils of a typical coking plant in North China. The estimating accuracy of soil LMW and HMW PAHs distribution using ordinary kriging with different normalization methods was compared. The results showed that all transformed data passed the Kolmogorov-Smirnov test, indicating that all three data transformation methods achieved normality of raw data. Compared to Box-Cox-ordinary kriging, normal score-, and Johnson-ordinary kriging had higher estimating accuracy of the four soil PAHs distribution. In cross-validation, smaller root-mean-square error (RMSE) and mean error (ME) values were observed for normal score-ordinary kriging for both LMW and HMW PAHs compared to Johnson- and Box-Cox-ordinary kriging. Thus, normal score transformation is suitable for alleviating the impact of hotspots on estimating accuracy of the four selected soil PAHs distribution at this coking plant. The findings can provide insights into reducing uncertainty in spatial interpolation at PAHs-contaminated sites.

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats.

Objective: To assess the receptors of TRPV1 and GABAB1 receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain. Methods: A rat model of CIP was constructed by plantar injection of complete Freund's adjuvant (CFA), and the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured 1, 3, 5, 7, 10, and 14 days after plantar injection. In the first part of the experiment, rats with CIP were divided into the immunofluorescence group and the coimmunoprecipitation (Co-IP) group (n = 6). Rats in the immunofluorescence group were injected with the retrograde tracer CB conjugated with Alexa Fluor 594 into the lateral ventricle two days before the injection of CFA into the plantar surface of the left paw. Three days later, rats that exhibited hyperalgesia were perfused, and their brains were extracted and used for double immunofluorescence staining of the CSF-contacting nucleus. Rats in the Co-IP group were anesthetized and dissected 3 days after CFA injection, and fresh brain segments containing the CSF-contacting nucleus were collected for Co-IP to assess the colocalization of TRPV1 and GABAB1 in the CSF-contacting nucleus (n = 6). In the second part of the experiment, SD rats were divided into the normal saline group (control group) and the CFA group. Fresh CSF-contacting nucleus-containing tissues were collected for Western blot analysis 3 days after plantar injection to observe the changes in TRPV1 and GABAB1 expression in the CSF-contacting nucleus. Results: TRPV1 and GABAB1 were co-expressed in the CSF-contacting nucleus in rats with CIP, and their expression was upregulated. Conclusion: TRPV1 and GABAB1 in the CSF-contacting nucleus are jointly involved in CIP in rats, and there is a direct or indirect link between TRPV1 and GABAB1.

Structural and functional underpinnings of precentral abnormalities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons. Studies using various magnetic resonance imaging (MRI) analytical approaches have consistently identified significant precentral abnormalities in ALS, whereas their structural and functional underpinnings remain poorly understood. METHODS: Using cortical thickness, fractional anisotropy (FA), and effective connectivity, we performed a multimodal MRI study to examine the structural and functional alterations associated with precentral abnormalities in patients with ALS (n = 60) compared with healthy controls (n = 60). RESULTS: Cortical thickness analysis revealed significant cortical thinning in the right precentral gyrus (PCG), superior frontal gyrus, and superior temporal gyrus in patients with ALS. Tractwise white matter microstructure analyses revealed decreased FA in the tracts connected to the PCG cluster in patients with ALS involving the right corticospinal tract and the middle posterior body of the corpus callosum. Additionally, the cortical thickness of the PCG cluster was found to be positively correlated with FA of the tracts connected to the PCG cluster, suggesting that these two structural features are tightly coupled. Using spectral dynamic causal modelling, effective connectivity analysis among the three regions with cortical thinning revealed decreased self-inhibitory influence in the PCG cluster in patients with ALS, which might be an endophenotypic manifestation of an imbalance in inhibitory and excitatory neurotransmitters in this region. CONCLUSIONS: The present data shed new light on the structural and functional underpinnings of precentral abnormalities in ALS.

Exploration of spatially varying relationships between Pb and Al in urban soils of London at the regional scale using geographically weighted regression (GWR).

In this study, geographically weighted regression (GWR) was applied to reveal the spatially varying relationships between Pb and Al in urban soils of London based on 6467 samples collected by British Geological Survey. Results showed that the relationships between Pb and Al were spatially varying in urban soils of London, with different relationships in different areas. The strong negative relationships between Pb and Al were found in the northeast and north areas and weak relationships were located in central areas, implying the links with the impact of anthropogenic activities on Pb concentration, while road traffic, industry activities and construction in centre of London may be linked to the weakened or changed direction of the relationship. However, positive relationships between Pb and Al were found in large parklands and greenspaces in the southeast and southwest as well as a small area in central London, due to less influences from human activities where the natural geochemical signatures were preserved. This study suggests that GWR is an effective tool to reveal spatially varying relationships in environmental variables, providing improved understanding of the complicated relationships in environmental parameters from the spatial aspect, which could be hardly achieved using conventional statistical analysis.

Simultaneous measurement of fifteen rare earth elements using diffusive gradients in thin films.

A new method for simultaneous measurement of fifteen rare earth elements (REEs) [La (Ⅲ), Ce (Ⅲ), Pr (Ⅲ), Nd (Ⅲ), Sm (Ⅲ), Eu (Ⅲ), Gd (Ⅲ), Tb (Ⅲ), Dy (Ⅲ), Ho (Ⅲ), Er (Ⅲ), Tm (Ⅲ), Yb (Ⅲ), Lu (Ⅲ), and Y (Ⅲ)] was established in this study using the diffusive gradients in thin films (DGT) technique with Chelex®100 binding gel. Five different types of ion exchange resins (Chelex®100, D418, D001-cc, 001 × 7, and HSTY®-SS) were selected for the initial investigation of their adsorption performance for REEs. The Chelex®100 binding gel had the greatest uptake efficiencies of >95% for the fifteen REE ions, which was used for all subsequent experiments. The binding gel exhibited rapid binding dynamics to REEs in mixed solution of the fifteen REE ions. Elution efficiencies ranging from 86.5% to 93.8% for these REEs were obtained based on extraction using 2.0 M HCl. The Chelex®100 DGT uptake of the fifteen REE ions increased linearly with the deployment time and found to be independent of pH (3-9) and ionic strength (3 mM-100 mM). The capacities of Chelex®100 DGT for measurement of the mixed elements were determined at a range of 5.39-6.75 µg cm-2. Application of the DGT for soil analysis showed that Chelex®100 DGT was a useful tool in simultaneous measurement of the fifteen REE ions, even in a soil with high concentrations of REEs. This study demonstrated the advantage of Chelex®100 DGT in simultaneous measurement of the fifteen REE ions due to high uptake efficiencies and a wide tolerance to environmental interference.

Efficient unrestricted identity-based aggregate signature scheme.

An aggregate signature scheme allows anyone to compress multiple individual signatures from various users into a single compact signature. The main objective of such a scheme is to reduce the costs on storage, communication and computation. However, among existing aggregate signature schemes in the identity-based setting, some of them fail to achieve constant-length aggregate signature or require a large amount of pairing operations which grows linearly with the number of signers, while others have some limitations on the aggregated signatures. The main challenge in building efficient aggregate signature scheme is to compress signatures into a compact, constant-length signature without any restriction. To address the above drawbacks, by using the bilinear pairings, we propose an efficient unrestricted identity-based aggregate signature. Our scheme achieves both full aggregation and constant pairing computation. We prove that our scheme has existential unforgeability under the computational Diffie-Hellman assumption.

Leber's hereditary optic neuropathy is associated with the T12338C mutation in mitochondrial ND5 gene in six Han Chinese families.

PURPOSE: To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families. DESIGN: Six Han Chinese families who seem to have maternally transmitted LHON were studied by clinical, genetic, and molecular evaluations. PARTICIPANTS: One hundred twenty-seven subjects from 6 Chinese families with a wide range of age-at-onset and severity of visual impairment. METHODS: All subjects underwent clinical examination, genetic evaluation, and molecular analysis of mitochondrial DNA (mtDNA). MAIN OUTCOME MEASURES: The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. The mtDNA analysis included the polymerase chain reaction (PCR) amplification of entire mtDNA and subsequent sequence determination. RESULTS: Six families exhibited low penetrance of visual impairment, with an average of 10.8%. In particular, 9 (6 males/3 females) of 86 matrilineal relatives in these families exhibited variable severity and age at onset in visual dysfunction. The average age at onset of visual loss was 20 years. Molecular analysis of mtDNA in these families identified the homoplasmic ND5T12338C mutation and distinct set of variants belonging to the Asian haplogroup F2. The T12338C mutation is only present in the maternal lineage of those pedigrees and not in 178 Chinese controls. This mutation resulted in the replacement of the first amino acid, a translation-initiating methionine with a threonine, shortening 2 amino acids of ND5 polypeptide. The T12338C mutation is also located in 2 nucleotides adjacent to the 3' end of the tRNA(Leu(CUN)). Thus, this mutation may alter ND5 mRNA metabolism and the processing of RNA precursors. As a result, this mutation impairs respiratory function, leading to visual impairment. CONCLUSIONS: Several lines of evidence suggest that the mitochondrial ND5T12338C mutation is associated with LHON. The tissue specificity of this mutation is likely due to the involvement of nuclear modifier genes. The identification of nuclear modifiers is important for the elucidation of the pathogenic mechanism of LHON and an open avenue for therapeutic interventions. The T12338C mutation should be added to the list of inherited risk factors for future molecular diagnosis. Our findings are helpful for counseling families with LHON.

The effect of lumbrokinase on P-selectin and E-selectin in cerebral ischemia model of rat.

PURPOSE: To find the effect of lumbrokinase (LK) on P-selectin and E-selectin in ischemic rats. METHODS: Male healthy Spragur-Dawley rats weighing 180-220 g (n = 90) were divided into 4 groups: (1) normal control group (n = 5), (2) sham-operated group (n = 35), (3) ischemic group (n = 35), (4) LK group (n = 15). LK 10 mg/kg (2000 UK activity of LK) was given by intraperitoneal injection in the LK group 30 minutes before experiment. Same volume of normal saline was given in the sham-operated group and ischemic group. The ischemic model was made by modified Haruo Nagasawa's method. Immunohistochemistry was used to observe the P-selectin and E-selectin positive cells in the ischemic region. RESULTS: P-selectin and E-selectin positive cells in ischemic regions were observed in the ischemic group, and the peak of expression was at 6 hours and 12 hours, respectively. The similar changes were not observed in normal control group. There were only a few positive cells in the sham-operated group. In LK group, the P-selectin and E-selectin positive cells were significantly less than those in the ischemic group (P < 0.05 at 3 hours after the onset, P < 0.01 at 6 hours and P < 0.01 at 12 hours, respectively). CONCLUSIONS: LK might significantly decrease the immunoreactions of P-selectin and E-selectin in ischemic lesion.