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Objective According to the diagnosis-related group (DRG) requirement, issues of diagnosis and procedure coding in the gastroenterology department of our hospital were analyzed and improvement plans were proposed to lay the foundation for effective implementation of DRGs. Methods The title page of case-history of 1600 patients admitted to the Department of Gastroenterology of this hospital from January 1, 2021 to December 31, 2021 was sampled as a data source, and the primary and other diagnostic codes, operation or procedure codes involved in the title page of case-history were categorized and statistically analyzed. Results Of the 531 cases treated with gastrointestinal endoscopy in our hospital in 2021, coding errors were identified in 66 cases and unsuccessful DRG enrollment in 35 cases, including 14 cases with incorrect coding of the primary diagnosis (8 cases with unsuccessful DRG enrollment), 37 cases with incorrect coding of the primary operation (23 cases with unsuccessful DRG enrollment), and 8 cases with incorrect coding of both the primary diagnosis and the primary operation (4 cases with unsuccessful DRG enrollment). Analysis of 66 inpatient cases with coding problems showed a total of 167 deficiencies, including 36 deficiencies in major diagnoses, 84 deficiencies in other diagnoses, and 47 deficiencies in surgery or operation coding. Conclusion The accuracy of coding of disease diagnosis and surgical operation is the basis for the smooth implementation of DRGs. The medical staff of this hospital has poor cognition of DRGs coding and fails to recognize the important role of the title page of case-history quality to DRGs system, and their attention to DRGs and knowledge base of disease classification coding should be improved. In addition, the high incidence of coding errors, especially the omission of disease diagnosis, requires increased training of physicians and nurses on clinical knowledge and requirements for DRGs medical records, thereby improving the quality of medical cases and ensuring the accuracy of DRGs information.

Glial cells play crucial roles in brain homeostasis and pathogenesis of central nervous system (CNS) injuries and diseases. However, the roles of these cells and the molecular mechanisms toward regeneration in the CNS have not been fully understood, especially the capacity of them toward demyelinating diseases. Therefore, there are still very limited therapeutic strategies to restore the function of adult CNS in diseases such as multiple sclerosis (MS). Remyelination, a spontaneous regeneration process in the CNS, requires the involvement of multiple cellular and extracellular components. Promoting remyelination by therapeutic interventions is a promising novel approach to restore the CNS function. Herein, we review the role of glial cells in CNS diseases and injuries. Particularly, we discuss the roles of glia and their functional interactions and regulatory mechanisms in remyelination, as well as the current therapeutic strategies for MS.

Astrocytes have a beneficial role in tissue repair after central nervous system (CNS) injury. Although astrocyte proliferation is activated in response to injury, the intracellular mechanisms of astrocyte proliferation during acute phase of injury are not fully clarified. In this study, by functionally screening the highly expressed genes in the pathological state of spinal astrocytes, heterogeneous nuclear ribonucleoprotein U (Hnrnpu) is identified as a potential endogenous molecule that regulates astrocyte proliferation and the following scar formation. Inhibition of Hnrnpu in astrocytes impairs the formation of astrocytic glial scar, motor function recovery, and neuronal regeneration after spinal cord injury (SCI) in mice. In human astrocytes, HNRNPU knockdown downregulates the genes related to the astrocyte functions in scar formation and neuronal regeneration. These findings uncover that modulation of endogenous astrocytic function would be a promising therapeutic avenue to restore neurological function after CNS injury.

The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked heterodimer with CD98 heavy chain (CD98hc, 4F2hc or SLC3A2), but the mechanism of assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1–CD98hc heterodimer at 3.3-Å resolution. LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through the extracellular, transmembrane and putative cholesterol-mediated interactions. We also show that two anti-CD98 antibodies recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities. These results reveal the principles of glycoprotein-solute carrier assembly and provide templates for improving preclinical drugs and antibodies targeting LAT1 or CD98hc.Cryo-EM structure of the LAT1–CD98hc heterodimer in complex with two antibodies offers insights into the assembly and function of LAT1–CD98hc, and reveals the epitopes targeted by the potentially therapeutic antibodies with an antitumor activity.

Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2. EAAT2 is an amino acid transporter implicated in glutamate homeostasis in brain and therapy resistance of cancer cells. Here, the authors report cryo-EM structures and reveal inhibitory mechanisms via selective inhibitor WAY213613.

Background Tumor angiogenesis is regarded as a rational anti-cancer target. The efficacy and indications of anti-angiogenic therapies in clinical practice, however, are relatively limited. Therefore, there still exists a demand for revealing the distinct characteristics of tumor endothelium that is crucial for the pathological angiogenesis. L-type amino acid transporter 1 (LAT1) is well known to be highly and broadly upregulated in tumor cells to support their growth and proliferation. In this study, we aimed to establish the upregulation of LAT1 as a novel general characteristic of tumor-associated endothelial cells as well, and to explore the functional relevance in tumor angiogenesis. Methods Expression of LAT1 in tumor-associated endothelial cells was immunohistologically investigated in human pancreatic ductal adenocarcinoma (PDA) and xenograft- and syngeneic mouse tumor models. The effects of pharmacological and genetic ablation of endothelial LAT1 were examined in aortic ring assay, Matrigel plug assay, and mouse tumor models. The effects of LAT1 inhibitors and gene knockdown on cell proliferation, regulation of translation, as well as on the VEGF-A-dependent angiogenic processes and intracellular signaling were investigated in in vitro by using human umbilical vein endothelial cells. Results LAT1 was highly expressed in vascular endothelial cells of human PDA but not in normal pancreas. Similarly, high endothelial LAT1 expression was observed in mouse tumor models. The angiogenesis in ex/in vivo assays was suppressed by abrogating the function or expression of LAT1. Tumor growth in mice was significantly impaired through the inhibition of angiogenesis by targeting endothelial LAT1. LAT1-mediated amino acid transport was fundamental to support endothelial cell proliferation and translation initiation in vitro. Furthermore, LAT1 was required for the VEGF-A-dependent migration, invasion, tube formation, and activation of mTORC1, suggesting a novel cross-talk between pro-angiogenic signaling and nutrient-sensing in endothelial cells. Conclusions These results demonstrate that the endothelial LAT1 is a novel key player in tumor angiogenesis, which regulates proliferation, translation, and pro-angiogenic VEGF-A signaling. This study furthermore indicates a new insight into the dual functioning of LAT1 in tumor progression both in tumor cells and stromal endothelium. Therapeutic inhibition of LAT1 may offer an ideal option to potentiate anti-angiogenic therapies.

Amidst the mounting global challenges associated with climate change and resource depletion, achieving sustainable development is paramount. Focusing on cities as vital scenarios for pursuing sustainability, this research measured urban sustainability and identified its obstacles. Employing the DPSIR (Driver–Pressure–State–Impact–Response) framework, we establish a metric system with 25 indicators to assess the urban sustainability of six innovation zones in China and identify their developmental impediments to sustainability with an obstacle model. The core findings of the study are as follows: First, over the five-year period, all six cities demonstrated a consistent increase in their urban sustainability levels except for Shenzhen, which experienced a decline from its top position among these cities due to a decrease in its score from 0.44296 to 0.36942 in 2017. Second, there was consistent urban sustainability progress in five cities, with the exception of Shenzhen, from 2016 to 2020. Third, inadequate government response emerges as a primary obstacle across all six cities, marked by shortcomings in public expenditure, R&D investment, and healthcare. Every year, all six cities experienced more than 60% obstacle degrees in terms of response, with the exception of Shenzhen in 2016. The urban sustainability pursuit model we developed bridges urban sustainability theory with practical interventions, promoting adaptive governance. In addition, this study provides scholars and policymakers with a comprehensive approach to gauging urban sustainability, recognizing obstacles, and designing strategies for a sustainable urban future.

Chronic enteropathy associated with SLCO2A1 gene (CEAS) is caused by loss-of-function mutations in SLCO2A1 , which encodes a prostaglandin (PG) transporter. In this study, we report a sibling case of CEAS with a novel pathogenic variant of the SLCO2A1 gene. Compound heterozygous variants in SLCO2A1 were identified in an 8-year-old boy and 12-year-old girl, and multiple chronic nonspecific ulcers were observed in the patients using capsule endoscopy. The splice site mutation (c.940 + 1G>A) of the paternal allele was previously reported to be pathogenic, whereas the missense variant (c.1688T>C) of the maternal allele was novel and had not yet been reported. The affected residue (p.Leu563Pro) is located in the 11th transmembrane domain (helix 11) of SLCO2A1. Because SLCO2A1 mediates the uptake and clearance of PGs, the urinary PG metabolites were measured by liquid chromatography coupled to tandem mass spectrometry. The urinary tetranor-prostaglandin E metabolite levels in the patients were significantly higher than those in unaffected individuals. We established cell lines with doxycycline-inducible expression of wild type SLCO2A1 (WT-SLCO2A1) and the L563P mutant. Immunofluorescence staining showed that WT-SLCO2A1 and the L563P mutant were dominantly expressed on the plasma membranes of these cells. Cells expressing WT-SLCO2A1 exhibited time- and dose-dependent uptake of PGE 2 , while the mutant did not show any uptake activity. Residue L563 is very close to the putative substrate-binding site in SLCO2A1, R561 in helix 11. However, in a molecular model of SLCO2A1, the side chain of L563 projected outside of helix 11, indicating that L563 is likely not directly involved in substrate binding. Instead, the substitution of Pro may twist the helix and impair the transporter function. In summary, we identified a novel pathogenic variant of SLCO2A1 that caused loss-of-function and induced CEAS.

Abstract PurposeSevoflurane is a common used inhaled anesthetic that was reported to regulate the progression of multiple cancers. Here, we aimed to investigate the function and regulatory mechanism underlying sevoflurane in glioma cells.MethodsA172 and U251 cells were treated with different concentrations of sevoflurane. Colony formation, EdU satining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), flow cytometry, and transwell assays were performed to evaluate cell proliferation, apoptosis, migration and invasion, respectively. Circ_VCAN, microRNA-146b-5p (miR-146b-5p) and nuclear factor I B (NFIB) expression levels were assessed by real-time quantitative PCR (RT-qPCR) or western blot. Bioinformatics analysis and dual-luciferase reporter assay were applied to evaluate the correlation between miR-146b-5p and circ_VCAN or NFIB. A xenograft glioma mice model was established to verify the effect of sevoflurane on tumor growth in vivo.ResultsSevoflurane (Sev) inhibited proliferation, migration, invasion, and elevated apoptosis of A172 and U251 cells. Sevoflurane treatment inhibited the expression of circ_VCAN and NFIB, but elevated the expression of miR-146b-5p in glioma cells. Overexpression of circ_VCAN alleviated the inhibition effects of sevoflurane on the malignant phenotypes of glioma in vitro and in vivo. Besides, miR-146b-5p is a target of circ_VCAN and negatively regulated NFIB expression. Overexpression of miR-146b-5p partly reversed the effects of circ_VCAN in Sev-treated glioma cells. Furthermore, miR-146b-5p deletion enhanced glioma progression in sevoflurane treated glioma cells by targeting NFIB. Moreover, circ_VCAN could upregulate NFIB expression by sponging miR-146b-5p in Sev-treated glioma cells.ConclusionSevoflurane alleviated proliferation, migration and invasion, but enhanced apoptosis of glioma cells through regulating circ_VCAN/miR-146b-5p/NFIB axis.

Human papillomavirus (HPV) is a major pathogen that causes cervical cancer and many other related diseases. HPV infection related cervical microbiome could be an induce factor of cervical cancer. However, it is uncommon to find a single test on the market that can simultaneously provide information on both HPV and the microbiome. Herein, a novel method was developed in this study to simultaneously detect HPV infection and microbiota composition promptly and accurately. It provides a new and simple way to detect vaginal pathogen situation and also provide valuable information for clinical diagnose. This approach combined multiplex PCR, which targeted both HPV16 E6E7 and full-length 16S rRNA, and Nanopore sequencing to generate enough information to understand the vagina condition of patients. One HPV positive liquid-based cytology (LBC) sample was sequenced and analyzed. After comparing with Illumina sequencing, the results from Nanopore showed a similar microbiome composition. An instant sequencing evaluation showed that 15 min sequencing is enough to identify the top 10 most abundant bacteria. Moreover, two HPV integration sites were identified and verified by Sanger sequencing. This approach has many potential applications in pathogen detection and can potentially aid in providing a more rapid clinical diagnosis.