OBJECTIVE: To explore the incidence, clinical features, genetic variant characteristics and prognosis of Glutaric acidemia type I (GA1) among neonates from Henan Province. METHODS: A total of 814 625 neonates undergoing screening for inherited metabolic diseases by tandem mass spectrometry (MS/MS) at the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were selected as the study subjects. A retrospective method was adopted to collect the clinical data of the patients. Whole exome sequencing was carried out to detect GCDH gene variants in individuals with positive results by GA1 newborn screening, and Sanger sequencing was used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital (Ethics Number: 2019 Medical Ethics Review No. 67). RESULTS: Eight cases of GA1 were diagnosed among the 814 625 neonates. Blood glutaryl carnitine (C5DC) and urine glutaric acid (GA) levels of the 8 children were higher than the normal reference values. In total 12 variants were detected, all of which were missense variants. c.1064G>A (p.Arg355His) was the most common one, accounting for 21.4% (3/14). Three GCDH gene variants, including 1297G>C (p.Ala433Pro), c.467G>A (p.Gly156Asp) and c.1125T>G (p.Cys375Trp), were previously unreported. REVEL software analysis predicted that all of the three variants were harmful. 3D protein structure modeling indicated that the three variants may cause amino acid residue alterations, and c.1297G>C (p.Ala433Pro) and c.1125T>G (p.Cys375Trp) may result in increase in hydrogen bonds and affect the function of GCDH protein. By December 2023, one of the eight children had deceased, and another child had severe clinical symptoms with poor prognosis. Six children had a good prognosis, of which two had mild motor development delay and four had normal development without clinical symptoms. CONCLUSION The incidence of GA1 in newborns screened by MS/MS in Henan Province is 1/101 828, and the carrier rate of pathogenic GCDH variants is 1/160. The c.1064G>A (p.Arg355His) may be the hotspot variant of the GCDH gene among children with GA1 in Henan. Discovery of the three novel variants has enriched the mutational spectrum of the GCDH gene and provide a basis for the early diagnosis, treatment, prognosis and genetic counseling of this disease.
Humans ; Amino Acid Metabolism, Inborn Errors/epidemiology* ; Glutaryl-CoA Dehydrogenase/chemistry* ; Infant, Newborn ; Female ; Neonatal Screening/methods* ; Male ; Brain Diseases, Metabolic/epidemiology* ; China/epidemiology* ; Retrospective Studies ; Mutation ; Genetic Variation ; Glutarates

Objective: To explore the effect and mechanism of lycorine on oxaliplatin ( OXA) induced chemotherapy pain in mice． Methods : 40 mice were randomly divided into 4 groups，10 mice per group，which were respectively divided into control group，model group，administration group，and inhibitor group．A mouse model of chemotherapy induced pain was established by intraperitoneal injection of OXA for 5 consecutive days．Intrathecal administration of lycorine was performed．Behavioral changes and expression levels of inflammatory related proteins were detected . Results : Compared with control group，model group mice exhibited the increased number of spontaneous flinches，decreased mechanical nociceptive threshold，decreased movement distance and latency，and up-regulated expression levels of interleukin-1 β (IL-1 β) ，astrocytic marker glial fibrillary acidic protein ( GFAP) ，cyclooxygenase-2( COX-2) ，NOD-like receptor protein 3 ( NLRP3 ) ，cysteinyl aspartate and specific proteinase 1 ( Caspase- 1) ．Compared with model group，lycorine administration reduced the number of spontaneous flinches，increased mechanical nociceptive threshold ，enhanced the movement distance and latency ，bound and reduced COX-2 expression，down-regulated the expression levels of IL-1 β , GFAP ，NLRP3 and Caspase-1． Conclusion Lycorine reduces COX-2 expression，inhibits NLRP3 inflammasome activation，suppresses spinal inflammation，consequently alleviates pain behaviors and improved motor ability of mice.

Objective:To explore the genetic basis for a child featuring tetrahydrobiopterin deficiency and global developmental delay.Methods:Clinical and laboratory examinations were carried out for the child. Genomic DNA of the patient was subjected to high-throughput sequencing to identify genetic variants associated with hyperphenylalaninemia. Candidate variants were verified by Sanger sequencing.Results:The result of blood tandem mass spectrometry showed that the Phenylalanine in the blood was 642.7 μmol/l, and the ratio of Phenylalanine/Tyrosine was 5.42. Analysis of urinary pterin: neopterin 0.09 mmol/mol Cr, biopterin 0.04 mmol/mol Cr, biopterin% 77%, which suggested tetrahydrobiopterin deficiency. The parents of the proband were first cousins. DNA sequencing revealed that the proband has harbored homozygous c. 353A>T variants in exon 2 of the GCH1 gene, for which his great grandmother, grandfather, mother, uncle, father and elder brother were heterozygous carriers with normal phenotype and no clinical symptoms associated with dopa responsive dystonia. Conclusion:The homozygous c. 353A>T variant of the GCH1 gene probably underlay the tetrahydrobiopterin deficiency in this pedigree of consanguineous marriage.

Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases. Here, to explore the role of the gut microbiome in the host immune responses in COVID-19, we conducted shotgun metagenomic sequencing and immune profiling of 14 severe/critical and 24 mild/moderate COVID-19 cases as well as 31 healthy control samples. We found that the diversity of the gut microbiome was reduced in severe/critical COVID-19 cases compared to mild/moderate ones. We identified the abundance of some gut microbes altered post-SARS-CoV-2 infection and related to disease severity, such as Enterococcus faecium, Coprococcus comes, Roseburia intestinalis, Akkermansia muciniphila, Bacteroides cellulosilyticus and Blautia obeum. We further analyzed the correlation between the abundance of gut microbes and host responses, and obtained a correlation map between clinical features of COVID-19 and 16 severity-related gut microbe, including Coprococcus comes that was positively correlated with CD3⁺/CD4⁺/CD8⁺ lymphocyte counts. In addition, an integrative analysis of gut microbiome and the transcriptome of peripheral blood mononuclear cells (PBMCs) showed that genes related to viral transcription and apoptosis were up-regulated in Coprococcus comes low samples. Moreover, a number of metabolic pathways in gut microbes were also found to be differentially enriched in severe/critical or mild/moderate COVID-19 cases, including the superpathways of polyamine biosynthesis II and sulfur oxidation that were suppressed in severe/critical COVID-19. Together, our study highlighted a potential regulatory role of severity related gut microbes in the immune response of host.
COVID-19 ; Clostridiales ; Gastrointestinal Microbiome ; Humans ; Immunity ; Leukocytes, Mononuclear ; SARS-CoV-2

Objective To investigate the effect of Huatan Qushi Huoxue prescription on the ultrastructure of hepatocyte mitochondria in a rat model of nonalcoholic steatohepatitis (NASH). Methods A total of 48 male Sprague-Dawley rats were randomly divided into blank group, model group, Yishanfu group, and Huatan Qushi Huoxue prescription group, with 12 rats in each group. The rats in the model group and the drug groups were administered and modeled since week 2; the rats in the blank group were given normal diet, and those in the other three groups were given high-fat diet. Based on dose conversion between human and animal, the equivalent dose of Huatan Qushi Huoxue prescription was 1.26 g/100 g body weight, and the equivalent dose of polyene phosphatidylcholine capsules (Yishanfu) was 0.014 18 g/100 g body weight. The rats in the model group were given 0.9% sodium chloride by gavage, those in the Yishanfu group were given polyene phosphatidylcholine suspension by gavage, and those in the traditional Chinese medicine group were given the granules of Huatan Qushi Huoxue prescription by gavage, once a day for 10 consecutive weeks. A transmission electron microscope was used to observe liver ultrastructure and perform a quantitative analysis. A one-way analysis of variance was used for comparison of continuous data between multiple groups; for further pairwise comparison, the least significant difference t -test was used for data with homogeneity of variance, and the Dunnett's T3 was used for data with heterogeneity of variance. Results The model group had a large number of lipid droplets accumulated in hepatocytes, changes in mitochondrial morphology and structure, and reductions in the number of mitochondria and endoplasmic reticulum. The Huatan Qushi Huoxue prescription group had a significant reduction in lipid droplets in hepatocytes and significant increases in the number of mitochondria and endoplasmic reticulum compared with the model group, with intact mitochondrial membrane and structure. The Yishanfu group had a reduction in lipid droplets in hepatocytes, an increase in the number of mitochondria, and a reduction in the number of endoplasmic reticulum, with relatively intact mitochondrial membrane and structure. The quantitative analysis showed that compared with the blank group, the model group had a significant increase in the area of lipid droplets and a significant reduction in mitochondria, with a significant difference in mitochondrial density between the two groups (all P < 0.01); after drug intervention, the Yishanfu group had a significant reduction in the area of lipid droplets and a significant increase in the number of mitochondria, with a significant difference in mitochondrial density between the Yishanfu group and the model group (all P < 0.01); compared with the Yishanfu group, the traditional Chinese medicine group had a significantly greater reduction in the area of lipid droplets and a significant increase in the number of mitochondria, with a significant difference in mitochondrial density between the two groups (all P < 0.05). Conclusion Huatan Qushi Huoxue prescription can improve lipid accumulation, increase mitochondrial density, and protect mitochondrial structure and function, with a better clinical effect than Yishanfu.

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH

Objective: To explore the association between the frequency of prenatal care in childbearing aged women and risk of small for gestational age (SGA) among neonatal twins in Shaanxi Province. Methods: From July to December 2013, a total of 30 027 childbearing aged women, who were pregnant from January 2010 to November 2013 and had definite outcomes, were selected from 30 districts (counties) of Shaanxi Province by using the multi-stage random sampling method. The questionnaires with a face-to-face survey method were used to retrospectively collect demographic information, pregnancy history, lifestyle during pregnancy, disease history, nutritional supplements, and health care during pregnancy. Information on the gestational age and birth weight of the newborn were obtained by consulting the medical certificate of birth and were registered as twin A and twin B by birth order. Finally, 356 childbearing aged women and their twin babies with complete data were included in the analysis. A generalized estimation equation model was used to analyze the association between the frequency of prenatal care and the risk of SGA among neonatal twins. Results: The age of childbearing aged women was (27.44±4.68) years old, of which 79.49% (283 women) were rural residents and 44.38% (158 women) had seven or more times prenatal care. The gestational age and birth weight were (37.64±2.51) weeks and (2 510±497) g, respectively. The prevalence of SGA was 51.40% (183/356) for twin A and 53.37% (190/356) for twin B, respectively. The prevalence of SGA was 44.30% (70/158) for twin A with seven or more times prenatal care and 42.41% (67/158) for twin B with seven or more times prenatal care, which was lower than that for twins with less than seven times prenatal care, respectively [57.07% (113/198) and 62.12% (123/198)] (P values were 0.017 and <0.001). The results of generalized estimation equation model suggested that compared to those with less than seven times prenatal care, after adjusting for parity, birth order, place of residence, maternal age, occupation, education, family wealth index, passive smoking, pregnancy-induced hypertension syndrome, folic acid, and iron supplement during perinatal period, and gender of the newborn, the OR (95%CI) of risk of SGA among childbearing aged women with seven or more times prenatal care was 0.60 (0.40-0.91). Conclusion Seven or more times prenatal care could reduce the risk of SGA among neonatal twins in Shanxi Province.