Search

Luoyang is one of the eight ancient capitals in China. During Empress Wu's period, Luoyang boasted of strong political color. She spent 49 years of her life in Luoyang. In the following 15 years after she assumed the title of Empress regnant, she lived in Luoyang for 13 years. As Empress Wu was deeply in love with Luoyang, Luoyang was not only transformed into the western capital of Tang Dynasty but also developed into an international metropolis next only to the eastern capital--Chang' an. The prosporous city promoted the development of urban tourism. Colorful festival tourism, different social strata of tourist subjects and various types of tourism service displayed highlights of urban tourism in Louyang during Empress Wu's period. [ABSTRACT FROM AUTHOR]

Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency., Competing Interests: Declaration of interests W.-J.C., Z.-Q.X., X.C., M.Z., Y.-H.Z., and L.C. have filed patents (CN2023113708968) to protect the application of CRACE therapy for the treatment of brain calcification., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aberrant inorganic phosphate (Pi) homeostasis causes brain calcification and aggravates neurodegeneration, but the underlying mechanism remains unclear. Here, we found that primary familial brain calcification (PFBC)-associated Pi transporter genes Pit2 and Xpr1 were highly expressed in astrocytes, with importer PiT2 distributed over the entire astrocyte processes and exporter XPR1 localized to astrocyte end-feet on blood vessels. This polarized PiT2 and XPR1 distribution endowed astrocyte with Pi transport capacity competent for brain Pi homeostasis, which was disrupted in mice with astrocyte-specific knockout (KO) of either Pit2 or Xpr1. Moreover, we found that Pi uptake by PiT2, and its facilitation by PFBC-associated galactosidase MYORG, were required for the high Pi transport capacity of astrocytes. Finally, brain calcification was suppressed by astrocyte-specific PiT2 re-expression in Pit2-KO mice. Thus, astrocyte-mediated Pi transport is pivotal for brain Pi homeostasis, and elevating astrocytic Pi transporter function represents a potential therapeutic strategy for reducing brain calcification., Competing Interests: Declaration of interests X.C., Z.-Q.X., W.-J.C. M.Z., C.W.H., and L.C. have filed a patent [CN2023108906808] for the therapeutic application of astrocyte-targeted replacement gene expression., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The microbiota of perianal abscesses is scarcely investigated. Identifying causative bacteria is essential to develop antibiotic therapy. However, culture-based methods and molecular diagnostics through 16S PCR technology are often hampered by the polymicrobial nature of perianal abscesses. We sought to characterize the microbiota composition of perianal abscesses via metagenomic next-generation sequencing (mNGS). Fourteen patients suffering from perianal abscesses between March 2023 and August 2023 underwent retrospective assessment. Information from medical records was used, including clinical information, laboratory data, and culture and mNGS results. Forty bacterial taxa were identified from perianal abscesses through mNGS, with Bilophila wadsworthia (71.4%), Bacteroides fragilis (57.1%), and Escherichia coli (50.0%) representing the most prevalent species. mNGS identified an increased number of bacterial taxa, with an average of 6.1 compared to a traditional culture-based method which only detected an average of 1.1 in culture-positive perianal abscess patients, predominantly E. coli (75.0%), revealing the polymicrobial nature of perianal abscesses. Our study demonstrates that a more diverse bacterial profile is detected by mNGS in perianal abscesses, and that Bilophila wadsworthia is the most prevalent microorganism, potentially serving as a potential biomarker for perianal abscess.IMPORTANCEAccurately, identifying the bacteria causing perianal abscesses is crucial for effective antibiotic therapy. However, traditional culture-based methods and 16S PCR technology often struggle with the polymicrobial nature of these abscesses. This study employed metagenomic next-generation sequencing (mNGS) to comprehensively analyze the microbiota composition. Results revealed 40 bacterial taxa, with Bilophila wadsworthia (71.4%), Bacteroides fragilis (57.1%), and Escherichia coli (50.0%) being the most prevalent species. Compared to the culture-based approach, mNGS detected a significantly higher number of bacterial taxa (average 6.1 vs 1.1), highlighting the complex nature of perianal abscesses. Notably, Bilophila wadsworthia emerged as a potential biomarker for these abscesses. This research emphasizes the importance of mNGS in understanding perianal abscesses and suggests its potential for improving diagnostic accuracy and guiding targeted antibiotic therapy in the future., Competing Interests: The authors declare no conflict of interest.

Importance: Tuberculous meningitis is a life-threatening infection with high mortality and disability rates. Current diagnostic methods using cerebrospinal fluid (CSF) samples have limited sensitivity and lack predictive biomarkers for evaluating prognosis. This study's findings reveal excessive activation of the immune response during tuberculous meningitis (TBM) infection. Notably, a strong negative correlation was observed between CSF levels of monokine induced by interferon-γ (MIG) and the CSF/blood glucose ratio in TBM patients. MIG also exhibited the highest area under the curve with high sensitivity and specificity. This study suggests that MIG may serve as a novel biomarker for differentiating TBM infection in CSF or serum, potentially leading to improved diagnostic accuracy and better patient outcomes., Competing Interests: The authors declare no conflict of interest.

Primary familial brain calcification (PFBC) is a chronic progressive neurogenetic disorder. Its clinical symptoms mainly include dyskinesia, cognitive disorder and mental impairment; and the pathogenesis remains unclear. Studies have shown that SLC20A2 is the most common pathogenic gene of the disease. Since the Slc20a2 gene knockout mouse model could result in fetal growth restriction, in order to better understand the pathogenesis of PFBC, the present study used the CRISPR/Cas9 technology to construct a conditional knockout model of Slc20a2 gene in the striatum of mice. First, three sgRNAs (single guide RNAs) were designed to target the exon3 of Slc20a2 gene. The activity of the respective sgRNA was verified by constructing expression plasmids, transfecting cells and Surveyor assay. Second, the SgRNA with the highest activity was selected to generate the recombinant AAV-Cre virus, which was injected into the striatum of mice by stereotactic method. In vitro experiments showed that the three sgRNAs could effectively mediate Cas9 cleavage of the respective target DNA. The activity of Cre recombinase of the AAV-Cre was confirmed by immunofluorescence assay. Immunohistochemistry, TA clone, high-throughput sequencing and Western blot were used to detect and evaluate the efficiency of Slc20a2 gene knockout. The results showed that the Slc20a2 expression in the striatum of mice in the experimental group decreased significantly. In this study, three sgRNAs capable of knockout of Slc20a2 were successfully designed, and the conditional knockout of the Slc20a2 gene in the striatum of mouse was successfully established by the CRISPR/Cas9 technology, thereby providing an effective animal model for studying the pathogenesis of PFBC.

Background: Until recently, primary familial brain calcification (PFBC) has been determined by four genes, SLC20A2, PDGFRB, PDGFB and XPR1. No studies have been carried out to analyze the gene mutation of PDGFB in Chinese population., Objective: To screen mutations of PDGFB gene in a large cohort of Chinese PFBC patients with no SLC20A2 mutations., Methods: We recruited 192 PFBC patients, including 21 index cases and 171 sporadic cases, in our study. Peripheral venous blood samples of all included participants were collected for genomic DNA extraction. The coding sequence of PDGFB was amplified by polymerase chain reaction (PCR) followed by direct sequencing. The potential effects of the identified variants on protein function were assessed by bioinformatics analysis., Results: Three missense variants (c.35G>T, c.232C>T, and c.610C>A) and one nonsense variant (c.220G>T) of PDGFB were identified in five sporadic PFBC patients. The variant c.35G>T was found in 2 healthy controls from the same ethnic background, whereas c.220G>T, c.232C>T and c.610C>A were absent from 500 controls. c.220G>T (p.E74*) produced a stop codon in the place of the glutamicacid residue number 74. c.232C>T (p.R78C) occurred at highly conserved regions and were predicted as damaging by at least two computational predictive programs, suggesting that this variant were likely to have a causal role in PFBC. Although variant c.610C>A (p.P204T) also occurred at a highly conserved region, it was predicted to be most likely benign by two computational predictive programs, suggesting an uncertain role of this variant on PFBC., Conclusions: The present study identified one likely pathogenic variant (p.E74*) and two variants of uncertain significance (p.R78C and p.P204T) in PDGFB. Further studies of PDGF-B functional expression for these variants are still required to confirm the pathogenic effect., (Copyright © 2016. Published by Elsevier B.V.)