Changes of Gut Microbiota in Maintenance Hemodialysis Patients and Their Impact on Patient's Microinflammation Status.

This study was to investigate the changes in gut microbiota in maintenance hemodialysis patients and analyze their impact on patient's microinflammation status. For this purpose, thirty-nine chronic kidney disease (CKD) maintenance hemodialysis patients admitted to our hospital from March 2019 to March 2022 were selected as the experimental group, and 40 healthy individuals with examination results during the same period were selected as the control group. The levels of gut microbiota (Lactobacillus, Bifidobacterium, Escherichia coli, and Enterococcus faecalis) and microinflammation indicators [interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP)] were measured in both groups. The relationship between changes in gut microbiota and microinflammation in maintenance hemodialysis CKD patients was analyzed. Results showed that the levels of Lactobacillus and Bifidobacterium in the experimental group were significantly lower than those in the control group (all, P<0.05), while the levels of Escherichia coli and Enterococcus faecalis in the experimental group were significantly higher than those in the control group (all, P<0.05). The IL-6, TNF-α, and hs-CRP levels in the experimental group were significantly higher than those in the control group (all, P<0.05). Using microinflammation indicators as dependent variables and microbiota indicators as independent variables for stepwise regression analysis, the results showed that the levels of Lactobacillus were negatively correlated with IL-6 and TNF-α levels in patients (r=-0.358, -0.942, P<0.05); the levels of Bifidobacterium were negatively correlated with IL-6, TNF-α, and hs-CRP levels in patients (r=-0.394, -0.211, -0.547, P<0.05); the levels of Escherichia coli were positively correlated with IL-6 and TNF-α levels in patients (r=0.221, 0.268, P<0.05); the levels of Enterococcus faecalis were positively correlated with IL-6 and hs-CRP levels in patients (r=0.253, 0.378, P<0.05). In conclusion, patients with maintenance hemodialysis for CKD commonly exhibit gut microbiota dysbiosis and varying degrees of low-grade inflammation. Compared to healthy individuals, maintenance hemodialysis patients with CKD have lower levels of Bifidobacterium and Lactobacillus and higher levels of Escherichia coli and Enterococcus in their gut. Bifidobacterium, Lactobacillus, Escherichia coli, and Enterococcus all have a certain impact on the low-grade inflammation status of patients with maintenance hemodialysis for CKD.

Altered local spontaneous brain activity pattern in children with right-eye amblyopia of varying degrees: evidence from fMRI.

PURPOSE: To investigate the abnormal changes of local brain activity in children with right-eye amblyopia of varying degrees. METHODS: Data of resting-state functional magnetic resonance imaging were collected from 16 children with severe amblyopia, 17 children with mild to moderate amblyopia, and 15 children with normal binocular vision. Local brain activity was analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo). RESULTS: There were extensive ALFF differences among the three groups in 10 brain regions. There were extensive differences in ReHo among the three groups in 11 brain regions. The ALFF and ReHo of the right orbital part of the middle frontal gyrus displayed a significantly positive correlation with the best-corrected visual acuity of the right eye, respectively. The ALFF value and ReHo value of the right orbital part of the middle frontal gyrus followed the pattern of normal control < mild to moderate amblyopia < severe amblyopia. CONCLUSION: This study demonstrated that there were changes in specific patterns of ALFF and ReHo in children with right-eye amblyopia of different degrees in brain regions performing visual sensorimotor and attentional control functions.

Altered time-varying local spontaneous brain activity pattern in patients with high myopia: a dynamic amplitude of low-frequency fluctuations study.

PURPOSE: To investigate the abnormal time-varying local spontaneous brain activity in patients with high myopia (HM) on the basis of the dynamic amplitude of low-frequency fluctuations (dALFF) approach. METHODS: Age and gender matching were performed based on resting-state functional magnetic resonance imaging data from 86 HM patients and 87 healthy controls (HCs). Local spontaneous brain activities were evaluated using the time-varying dALFF method. Support vector machine combined with the radial basis function kernel was used for pattern classification analysis. RESULTS: Inter-group comparison between HCs and HM patients has demonstrated that dALFF variability in the left inferior frontal gyrus (orbital part), left lingual gyrus, right anterior cingulate and paracingulate gyri, and right calcarine fissure and surrounding cortex was decreased in HM patients, while increased in the left thalamus, left paracentral lobule, and left inferior parietal (except supramarginal and angular gyri). Pattern classification between HM patients and HCs displayed a classification accuracy of 85.5%. CONCLUSION: In this study, the findings mentioned above have suggested the association between local brain activities of HM patients and abnormal variability in brain regions performing visual sensorimotor and attentional control functions. Several useful information has been provided to elucidate the mechanism-related alterations of the myopic nervous system. In addition, the significant role of abnormal dALFF variability has been highlighted to achieve an in-depth comprehension of the pathological alterations and neuroimaging mechanisms in the field of HM.

Neurovascular coupling dysfunction in high myopia patients: Evidence from a multi-modal magnetic resonance imaging analysis.

BACKGROUND AND PURPOSE: To investigate neurovascular coupling dysfunction in high myopia (HM) patients. MATERIALS AND METHODS: A total of 37 HM patients and 36 healthy controls were included in this study. Degree centrality (DC), regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), and fractional ALFF (fALFF) maps were employed to represent neuronal activity. Cerebral blood perfusion was characterized by cerebral blood flow (CBF). The correlation coefficient was calculated to reflect the relationship between neuronal activity and cerebral blood perfusion. Pearson partial correlation analysis was utilized to evaluate the association between HM dysfunction and clinical indicators. RESULTS: HM patients exhibited significant alterations in neurovascular coupling across 37 brain regions compared to healthy controls. The brain regions with marked changes varied among the four neurovascular coupling patterns, including the middle frontal gyrus, superior occipital gyrus, middle occipital gyrus, and fusiform gyrus. Additionally, the superior frontal gyrus orbital part, medial superior frontal gyrus, inferior occipital gyrus, and dorsolateral superior frontal gyrus displayed significant changes in three coupling patterns. In HM patients, the ReHo-CBF changes in the inferior frontal gyrus orbital part were positively correlated with best-corrected visual acuity (BCVA) and refractive diopter changes. Similarly, the ALFF-CBF changes in the inferior frontal gyrus orbital part showed a positive correlation with refractive diopter changes. ReHo-CBF and ALFF-CBF alterations in the paracentral lobule were positively correlated with BCVA and refractive diopter changes. CONCLUSION: Our findings underscore the abnormal alterations in neurovascular coupling across multiple brain regions in HM patients. These results suggest that neurovascular dysfunction in HM patients may be associated with an aberrant visual regulation mechanism.

The role of histogram analysis in diffusion-weighted imaging in the differential diagnosis of benign and malignant breast lesions.

BACKGROUND: The present study aims to investigate the role of histogram analysis of intravoxel incoherent motion (IVIM) in the differential diagnosis of benign and malignant breast lesions. METHODS: The magnetic resonance imaging and clinical data of 55 patients (63 lesions) were retrospectively analyzed. The multi-b-valued diffusion-weighted imaging image was processed using the MADC software to obtain the gray-scaled maps of apparent diffusion coefficient (ADC)-slow, ADC-fast and f. The MaZda software was used to extract the histogram metrics of these maps. Combined with the conventional sequence images, the region of interest (ROI) was manually drawn along the edge of the lesion at the maximum level of the gray-scale image, and the difference of the data was analyzed between the benign and malignant breast lesions. RESULTS: There were 29 patients with 37 benign lesions, which included 23 fibroadenomas, 6 adenosis, 1 breast cysts, 4 intraductal papillomas, and 3 inflammations of breast. Furthermore, 26 malignant lesions in 26 patients, which included 20 non-specific invasive ductal carcinomas, 5 intraductal carcinomas and 1 patient with squamous cell carcinoma. The ADC-slow (mean and the 50th percentile) and f (minimum, mean, kurtosis, the 10th percentile and 50th percentile) of these malignant breast lesions were significantly lower than those of benign lesions (P < 0.05), while ADC-fast (kurtosis) and f (variance, skewness) of these malignant breast lesions were significantly higher than those of benign lesions (P < 0.05). CONCLUSION: The histogram analysis of ADC-slow (mean and the 50th percentile), ADC-fast (kurtosis) and f (minimum, mean, kurtosis, the 10th percentile and 50th percentile. Variance, skewness) can provide a more objective and accurate basis for the differential diagnosis of benign and malignant breast lesions.

Redox Components: Key Regulators of Epigenetic Modifications in Plants.

Epigenetic modifications including DNA methylation, histone modifications, and chromatin remodeling are crucial regulators of chromatin architecture and gene expression in plants. Their dynamics are significantly influenced by oxidants, such as reactive oxygen species (ROS) and nitric oxide (NO), and antioxidants, like pyridine nucleotides and glutathione in plants. These redox intermediates regulate the activities and expression of many enzymes involved in DNA methylation, histone methylation and acetylation, and chromatin remodeling, consequently controlling plant growth and development, and responses to diverse environmental stresses. In recent years, much progress has been made in understanding the functional mechanisms of epigenetic modifications and the roles of redox mediators in controlling gene expression in plants. However, the integrated view of the mechanisms for redox regulation of the epigenetic marks is limited. In this review, we summarize recent advances on the roles and mechanisms of redox components in regulating multiple epigenetic modifications, with a focus of the functions of ROS, NO, and multiple antioxidants in plants.

Signal-Enhanced Detection of Multiplexed Cardiac Biomarkers by a Paper-Based Fluorogenic Immunodevice Integrated with Zinc Oxide Nanowires.

Using a single test to comprehensively evaluate multiple cardiac biomarkers for early diagnosis and prevention of acute myocardial infarction (AMI) has faced enormous challenges. Here, we have developed paper-based fluorogenic immunodevices for multiplexed detection of three cardiac biomarkers, namely, human heart-type fatty acid binding protein (FABP), cardiac troponin I (cTnI), and myoglobin, simultaneously. The detection is based on a strategy using zinc oxide nanowires (ZnO NWs) to enhance fluorescence signals (∼5-fold compared to that on pure paper). The immunodevices showed high sensitivity and selectivity for FABP, cTnI, and myoglobin with detection limits of 1.36 ng/mL, 1.00 ng/mL, and 2.38 ng/mL, respectively. Additionally, the paper-based immunoassay was rapid (∼5 min to complete the test) and portable (using a homemade chamber with a smartphone and an ultraviolet lamp). The developed devices integrated with ZnO NWs enable quantitative, sensitive, and simultaneous detection of multiple cardiac biomarkers in point-of-care settings, which provides a useful approach for monitoring AMI diseases and may be extended to other medical diagnostics and environmental assessments.

A transparent paper-based platform for multiplexed bioassays by wavelength-dependent absorbance/transmittance.

This communication describes the rational design of a transparent paper-based chemosensing platform for multi-target detection by wavelength-dependent absorbance/transmittance. The platform was successfully applied in the examination of bovine serum albumin (BSA) and cholesterol in serum with a low detection limit of 0.1 µM and 0.1 mM, respectively. With low cost and high sensitivity, the paper-based platform shows great promise for multiplexed bioassays.

Prediction of human protein-protein interaction by a domain-based approach.

Protein-protein interactions (PPIs) are vital to a number of biological processes. With computational methods, plenty of domain information can help us to predict and assess PPIs. In this study, we proposed a domain-based approach for the prediction of human PPIs based on the interactions between the proteins and the domains. In this method, an optimizing model was built with the information from InterDom, 3did, DOMINE and Pfam databases. With this model, for 147 proteins in the integrin adhesome PPI network, 736 probable PPIs have been predicted, and the corresponding confidence probabilities of these PPIs were also calculated. It provides an opportunity to visualize the PPIs by using network graphs, which were constructed with Cytoscape, so that we can indicate underlying pathways possible.

Individualized functional connectome abnormalities obtained using two normative model unveil neurophysiological subtypes of obsessive compulsive disorder.

The high heterogeneity observed among patients with obsessive-compulsive disorder (OCD) underscores the need to identify neurophysiological OCD subtypes to facilitate personalized diagnosis and treatment. In this study, our aim was to identify potential OCD subtypes based on individualized functional connectome abnormalities. We recruited a total of 99 patients with OCD and 104 healthy controls (HCs) matched for demographic characteristics. Individualized functional connectome abnormalities were obtained using normative models of functional connectivity strength (FCS) and used as features to unveil OCD subtypes. Sensitivity analyses were conducted to assess the reproducibility and robustness of the clustering outcomes. Patients exhibited significant intersubject heterogeneity in individualized functional connectome abnormalities. Two subtypes with distinct patterns of FCS abnormalities relative to HCs were identified. Subtype 1 patients primarily exhibited significantly decreased FCS in regions including the frontal gyrus, insula, hippocampus, and precentral/postcentral gyrus, whereas subtype 2 patients demonstrated increased FCS in widespread brain regions. When all patients were combined, no significant differences were observed. Additionally, the identified subtypes showed significant differences in age of onset. Furthermore, sensitivity analyses confirmed the reproducibility of our subtyping results. In conclusion, the identified OCD subtypes shed new light on the taxonomy and neurophysiological heterogeneity of OCD.

Technical Success and Reliability of Magnetic Resonance Elastography in Patients with Hepatic Iron Overload.

RATIONALE AND OBJECTIVES: This study aimed to evaluate the technical success rate and stiffness measurement reliability of two specific hepatic magnetic resonance elastography (MRE) sequences dedicated to solving susceptibility artifacts in patients with various degrees of hepatic iron overload. MATERIALS AND METHODS: Thirty-seven patients with iron-overloaded liver confirmed by R2* value measurement who underwent two-dimensional (2D) spin-echo (SE) MRE and 2D SE-echo-planar-imaging (EPI) MRE were reviewed retrospectively. According to four categories based on R2* value (mild, moderate, severe elevation, and extremely severe iron overload), we compared the success rate, quality score, and liver stiffness of the two sequences. In addition, Spearman's correlation was performed to evaluate the relationship between the R2* value and liver stiffness. RESULTS: The overall success rates of SE MRE and SE-EPI MRE in patients with hepatic iron overload were 91.89% and 78.38%, respectively, and 100% and 78.57%, respectively, for severe elevation iron overload. In all patients, the MRE quality scores were 54 and 48 for SE MRE and SE-EPI MRE, respectively (P = 0.107). There were no significant differences in liver stiffness measurements between the two MRE methods in patients with mild, moderate, and severe elevation iron-overloaded livers (P > 0.6 for all), respectively. For both MRE methods, R2* value had no significant effect on the liver stiffness measurements (correlation coefficient <0.1, P >0.6 for both). CONCLUSION: In the mild and moderate elevation iron-overloaded liver, both SE MRE and fast SE-EPI MRE can provide successful and reliable liver stiffness measurement. In severe elevation iron-overloaded livers, SE MRE may be a better choice than SE-EPI MRE.

Integrative neurovascular coupling and neurotransmitter analyses in anisometropic and visual deprivation amblyopia children.

The association between visual abnormalities and impairments in cerebral blood flow and brain region potentially results in neural dysfunction of amblyopia. Nevertheless, the differences in the complex mechanisms of brain neural network coupling and its relationship with neurotransmitters remain unclear. Here, the neurovascular coupling mechanism and neurotransmitter activity in children with anisometropic amblyopia (AA) and visual deprivation amblyopia (VDA) was explored. The neurovascular coupling of 17 brain regions in amblyopia children was significantly abnormal than in normal controls. The classification abilities of coupling units in brain regions differed between two types of amblyopia. Correlations between different coupling effects and neurotransmitters were different. The findings of this study demonstrate a correlation between the neurovascular coupling and neurotransmitter in children with AA and VDA, implying their impaired neurovascular coupling function and potential molecular underpinnings. The neuroimaging evidence revealed herein offers potential for the development of neural therapies for amblyopia.

Novel indoline-2,3-dione derivatives as inhibitors of aminopeptidase N (APN).

Aminopeptidase N (APN/CD13), as a zinc-containing ectoenzyme, plays a critical role in the process of tumor angiogenesis, invasion and metastasis. Through the docking-based virtual screening of chemical databases and the further activity assay, we discovered that compound 10c exhibits potent and selective inhibitory ability towards APN. In addition, a series of indoline-2,3-dione derivates have been designed and synthesized as APN inhibitors. The results of preliminary activity evaluation showed that compound 12a (IC(50) = 0.074 ± 0.0026 µM) exhibited the best inhibitory activity against APN, which could be used for further anticancer agent research.

Design, synthesis and biological evaluation of novel L-isoserine tripeptide derivatives as aminopeptidase N inhibitors.

Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50 = 2.51 ± 0.2 µM) showed similar inhibitory effect compared with control compound Bestatin (IC50 = 6.25 ± 0.4 µM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future.

Design, synthesis and preliminary activity evaluation of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as aminopeptidase N/CD13 inhibitors.

Aminopeptidase N (APN/CD13) over expressed on tumour cells, plays a critical role in tumour invasion, metastasis and tumour angiogenesis. In this article, we described the design, synthesis and preliminary activity studies of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as APN inhibitors. The in vitro enzymatic inhibitions on APN from porcine kidney showed that compound 7e had the most potent inhibitory activity against APN with the IC(50) value to 1.26 ± 0.01 µM, which is better than that of bestatin (IC(50) = 2.55 ± 0.11 µM). In addition, compound 7e also showed better inhibitory activity against APN on human ovary clear cell carcinoma cell ES-2 than bestatin with the IC(50) value to 30.19 ± 1.02 µM versus 60.61 ± 0.1 µM. Compound 7e could be used as the lead compound in the future for anti-cancer agent research.

A cross-sectional study on gut microbiota in patients with chronic kidney disease undergoing kidney transplant or hemodialysis.

OBJECTIVE: To investigate whether the gut microbiota differs in patients with chronic kidney disease receiving kidney transplant or hemodialysis, and to explore the relationship between the gut microbiota and clinical indicators. METHODS: A total of 72 patients with kidney transplantation (RT) and 78 patients with hemodialysis (HD) admitted to the First Affiliated Hospital of Soochow University from January 2019 to October 2022 were selected as the research subjects. The V3-V4 region sequences of 16S rRNA were used for high-throughput sequencing to analyze the differences in gut microbiome between the two groups and its relationship with clinical indicators. RESULTS: Gut microbial α diversity (Chao1, Ace, Shannon, Simpson) was significantly decreased in RT patients compared with that in HD patients (P<0.05). The relative abundance of Bacteroides, Megamonas, and Prevotella was significantly higher in HD patients than that in RT patients (P<0.05). There was a negative association between the Bacteroides and ß2-microglobulin (ß2-MG) (P<0.05). Lactobacillus was negatively correlated with uric acid (UA) (P<0.05). CONCLUSION: This study elucidates the composition and changes of the gut microbiota in RT and HD patients and its association with clinical indicators, providing a scientific basis for the regulatory mechanism of gut microbiota in the treatment of chronic kidney disease.

Diversity of Bacteria Associated with Guts and Gonads in Three Spider Species and Potential Transmission Pathways of Microbes within the Same Spider Host.

Microbial symbiosis plays a crucial role in the ecological and evolutionary processes of animals. It is well known that spiders, with their unique and diverse predatory adaptations, assume an indispensable role in maintaining ecological balance and the food chain. However, our current understanding of spider microbiomes remains relatively limited. The gut microbiota and gonad microbiota of spiders can both potentially influence their physiology, ecology, and behavior, including aspects such as digestion, immunity, reproductive health, and reproductive behavior. In the current study, based on high-throughput sequencing of the 16S rRNA V3 and V4 regions, we detected the gut and gonad microbiota communities of three spider species captured from the same habitat, namely, Eriovixia cavaleriei, Larinioides cornutus, and Pardosa pseudoannulata. In these three species, we observed that, at the phylum level classification, the gut and gonad of E. cavaleriei are primarily composed of Proteobacteria, while those of L. cornutus and P. pseudoannulata are primarily composed of Firmicutes. At the genus level of classification, we identified 372 and 360 genera from the gut and gonad bacterial communities. It is noteworthy that the gut and gonad bacterial flora of E. cavaleriei and L. cornutus were dominated by Wolbachia and Spiroplasma. Results show that there were no differences in microbial communities between females and males of the same spider species. Furthermore, there is similarity between the gut and ovary microbial communities of female spiders, implying a potential avenue for microbial transmission between the gut and gonad within female spiders. By comprehensively studying these two microbial communities, we can establish the theoretical foundation for exploring the relationship between gut and gonad microbiota and their host, as well as the mechanisms through which microbes exert their effects.

A novel aminopeptidase N inhibitor developed by virtual screening approach.

A virtual screening was performed to discover novel lead structures as potent aminopeptidase N(APN) inhibitors. A commercial database containing about 1,60,000 molecules in SPECS was filtered by rule of five, zinc binding groups, pharmacophore models and binding pattern analysis. At last, 24 molecules were selected for enzyme inhibition assay and compound 2 exhibited the inhibition constant (K(i)) of 2.79±0.32 µM against APN compared with Bestatin (K(i)= 3.37±0.24 µM). Our results indicated that compound 2 exhibited good antiproliferative activities against a broad spectrum of human cancer cell lines, and induced cell cycle arrest at G1 phase and eventual apoptosis. Moreover, compound 2 can inhibit the invasion of MDA-MB-231 cells. In summary, our results suggest that compound 2, a potent APN inhibitor, is worthy of further development.

Accelerated Brain Aging in Patients With Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) may be accompanied by an accelerated structural decline of the brain with age compared to healthy controls (HCs); however, this has yet to be proven. To answer this question, we built a brain age prediction model using mean gray matter volumes of each brain region as features, which were obtained by voxel-based morphometry derived from T1-weighted MRI scans. The prediction model was built using two Chinese Han datasets (dataset 1, N = 106 for HCs and N = 90 for patients with OCD; dataset 2, N = 270 for HCs) to evaluate its performance. Then, a new prediction model was trained using data for HCs in dataset 1 and applied to patients with OCD to investigate the brain aging trajectory. The brain-predicted age difference (brain-PAD) scores, defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with matched HCs in dataset 1. It was demonstrated that the prediction model performs consistently across different datasets. Patients with OCD presented higher brain-PAD scores than matched HCs, suggesting that patients with OCD presented accelerated brain aging. In addition, brain-PAD scores were negatively correlated with the duration of illness, suggesting that brain-PAD scores might capture progressive structural brain changes. These results identified accelerated brain aging in patients with OCD for the first time and deepened our understanding of the pathogenesis of OCD.

Design, synthesis and biological evaluation of novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as aminopeptidase N/CD13 inhibitors.

A series of novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were designed, synthesized and assayed for their activities against aminopeptidase N (APN/CD13) and MMP-2. The results showed that most compounds exhibited higher inhibitory activities against APN than that of MMP-2. Within this series, compound 12h (IC(50)=6.28 ± 0.11 µM) showed similar inhibitory activities compared with Bestatin (IC(50)=5.55 ± 0.01 µM), and it could be used as novel lead compound for the future APN inhibitors development as anticancer agents.