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Many cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis. Post-translational modifications of phosphoglycerate kinase 1 (PGK1), a glycoytic enzyme, contribute to cancer progression. Here, the authors show that PGK1 is O-GlcNAcylated at T255, which induces its translocation into mitochondria to suppress the tricarboxylic acid cycle for colorectal cancer growth.

Hepatic de novo lipogenesis (DNL) is crucial for maintaining lipid homeostasis, and its dysregulation is implicated in various metabolic diseases. While it is well established that hepatic DNL is tightly regulated by hormones such as insulin and glucagon secreted from the pancreatic islets during feeding and fasting, further investigations are required to identify more hormones affecting hepatic DNL during the feeding-fasting transition. Here, we identify PRXL2A (peroxiredoxin like 2 A), an adipokine secreted during fasting, as an inhibitor of hepatic DNL. Mechanistically, PRXL2A binds to its receptor PTAFR (platelet activating factor receptor), promoting calcium mobilization and activating AMPK (AMP-activated protein kinase), thereby suppressing SREBP1 (sterol regulatory element-binding protein 1)-controlled hepatic DNL. Disruption of this axis by knockout of either Prxl2a or Ptafr increases hepatic DNL and lipid accumulation. Exogenous PRXL2A reduces hepatic DNL, suggesting a potential therapeutic strategy for diseases associated with hepatic lipid accumulation. Therefore, the PRXL2A-PTAFR signaling axis links adipose tissues and the liver to regulate hepatic lipid metabolism. Here the authors report that PRXL2A is a fasting-induced adipokine, which regulates hepatic lipogenesis via targeting platelet activating factor receptor (PTAFR) in the liver and subsequent AMPK activation. Disrupting this pathway promotes lipid accumulation, suggesting a potential therapeutic strategy for diseases associated with hepatic lipid accumulation.

BackgroundChronic enteropathy associated with the SLCO2A1 gene (CEAS) is an enteropathy characterized by multiple small intestinal ulcers of nonspecific histology, also known as chronic nonspecific multiple ulcers of the small intestine. The SLCO2A1 gene encodes a prostaglandin transporter (PGT).AimsThe aim of this study was to investigate the clinical characteristics of ten Chinese patients with intestinal ulcers of unknown origin, screen them for variants of SLCO2A1, and to investigate the expression of PGT in the small intestinal mucosa of patients with CEAS.MethodsTen Chinese patients with intestinal ulcers of unknown origin were included in this study. Blood samples were collected for whole-exome sequencing and Sanger sequencing of candidate gene variants. Immunohistochemical staining was used to investigate the expression of PGT.ResultsThese ten patients were clinically diagnosed with intestinal ulcers of unknown origin based on criteria established according to earlier publications. Three of them were genetically diagnosed as having CEAS and four candidate variants of the SLCO2A1 gene were identified, among which c.941-1G>A, c.178G>A and c.1681C>T were detected in patients with CEAS for the first time. The terminal ileum was involved in all three patients with CEAS in our study, which was different from the results of Japanese patients. The expression of PGT in the vascular endothelial cells of the intestinal mucosa tissues of patients with CEAS was negative or intermediate.ConclusionWe summarized the clinical data of ten Chinese patients with intestinal ulcers of unknown origin and identified three novel SLCO2A1 variants from three patients with CEAS. This study improves our understanding of CEAS and broadens the spectrum of SLCO2A1 variants known to cause CEAS.

The nuclear envelope component proline-rich protein 14 (PRR14) is involved in the nuclear morphological alteration and activation of the mTOR (mammalian target of rapamycin) signaling pathway, and has been repeatedly shown to be upregulated in patients with Parkinson’s disease (PD). The aim of this study was to explore whether PRR14 can be used as a potential biomarker for the diagnosis of PD. We compared PRR14 expression in PD patients and normal controls in gene expression omnibus (GEO) data. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to detect PRR14 expression in PD patients and age- and sex-matched controls. The relationship between serum PRR14 and clinical phenotype was evaluated using correlation analysis and logistic regression. The expression of PRR14 in whole blood, substantia nigra, and medial substantia nigra was significantly higher in PD patients than in the healthy control group. Compared to plasma, serum was more suitable for the detection of PRR14. Furthermore, serum PRR14 level in PD patients was significantly higher than that in age- and sex-matched controls. The area under the curve for serum PRR14 level in the ability to identify PD versus age- and sex-matched controls was 0.786. In addition, serum PRR14 level was found to correlate with constipation in PD patients. Our findings demonstrate for the first time that serum PRR14 is a potential biomarker for PD.

Background Instrumental support, which is defined as practical, tangible, and informational assistance extended to patients, is crucial for older people in transition. However, little is known about instrumental support in transitional care. Thus, the aim of this study was to evaluate the instrumental support of older people in transitional care. Methods This cross-sectional study was conducted using the Questionnaire of Instrumental Support in Transitional Care (QISCT) to collect data from 747 older people in China from September to November 2020. Survey items consisted of a sociodemographic characteristics questionnaire and the QISCT. Multiple regression analyses were conducted to examine the association between independent variables and the QISCT scores. Results The total score of the QISCT was 39.43 (± 9.11), and there was a significant gap between the anticipated support and received support. The satisfaction of instrumental support was low. Multiple regression analyses showed that educational level, the number of intimate relationships, monthly family income, monthly costs of transitional care, diabetes, and chronic obstructive pulmonary disease were associated with instrumental support in transitional care. Conclusions To cope with the burden caused by chronic disease, the government and transitional care teams should establish a demand-oriented transitional care service model and pay more attention to helping older people obtain adequate and satisfactory instrumental support.

ObjectivesWe developed an informational support questionnaire of transitional care (ISQTC) for aged patients with chronic disease and investigated its reliability and validity.SettingThis study was conducted in three large general hospitals in Nantong, Jiangsu Province, China.ParticipantsA total of 130 aged patients with chronic diseases, admitted into outpatient and inpatient departments from three hospitals in China, participated in the study. The inclusion criteria were: (1) patients must provide consent to participate; (2) being 60 years and above; (3) being diagnosed with at least one chronic disease and hospitalised more than two times within the last 1 year; (4) being able to listen, speak, read and write. The exclusion criteria were: (1) refusing to participate; (2) language expression and communication barriers (and having no caregiver to assist in participation); (3) being in intensive care or long-term hospitalisation.Primary and secondary outcome measuresThe developed questionnaire was validated and tested for reliability. The content validity of the questionnaire was determined through experts’ interviews and Delphi expert consultation, and the structure validity of the questionnaire was determined by performing exploratory factor analysis. The coefficient of reliability of the questionnaire was measured using Cronbach’s alpha.ResultsThrough Delphi expert consultation and exploratory factor analysis, the questionnaire was reduced from four dimensions and 12 items to three dimensions and 11 items. A total of 130 patients responded to the questionnaire. The alpha coefficient was 0.747.ConclusionThe ISQTC is a reliable and valid instrument for evaluating aged patients with chronic disease in transitional care.Trial registration detailsChiCTR1900020923. The trial was registered on 22 January 2019.

Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.

Background HINT1 mutations cause an autosomal recessive axonal neuropathy with neuromyotonia. This is a first case report of coexistence of myasthenia gravis (MG) and HINT1 -related motor axonal neuropathy without neuromyotonia. Case presentation A 32-year-old woman presented with recurrent ptosis for 8 years, diplopia for 2 years and limb weakness for 1 year and a half. Neostigmine test, elevated AChR antibody level and positive repetitive nerve stimulation supported the diagnosis of MG. Electroneurography (ENG) and electromyography (EMG) examinations revealed a motor axonal neuropathy without neuromyotonic or myokymic discharges. Next-generation sequencing and Sanger sequencing were performed to identify the gene responsible for suspected hereditary neuropathy. Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at c.278G>T (p. G93V). The patient was treated with pyridostigmine, oral prednisolone and azathioprine. Her ptosis and diplopia have significantly improved at 6-month follow-up. Conclusions Concurrence of MG and hereditary motor axonal neuropathy without neuromyotonia is quite rare. Detection of ptosis with or without ophthalmoplegia, distribution of limb weakness, and reflex can help in recognizing the combination of MG and peripheral neuropathy. Early diagnosis is important for initial treatment and prognosis. The novel homozygous variant c.278G>T(p.G93V) contributes to the pathogenic variants spectrum of the HINT1 gene.

Background Hereditary spherocytosis (HS) is a common type of hereditary hemolytic anemia. According to the current diagnostic criteria of HS, patients with a family history of HS, typical clinical features and laboratory investigations could be diagnosed without the requirement of any additional tests, including genetic analysis. However, the clinical heterogeneities incur difficulties in HS diagnosis. We therefore aimed to investigate the application of genetic diagnosis in a family-based cohort. Case presentation In the present Chinese family, two probands sharing similar clinical manifestations, including jaundice, cholelithiasis, splenomegaly and spherocytes, while the clinical features of other family members were inconclusive. Whole-exome sequencing (WES) unexpectedly unveiled two separate disease-causing mutations in the two probands. SPTB R1625X mutation detected in proband D was a de novo mutation; while proband W inherited the SLC4A1 c.G1469A mutation from her mother, which was also inherited by her brother. However, the clinical features of proband W and her mother and brother were discrepant: proband W suffered from significant splenomegaly, jaundice and cholelithiasis, which resulted in cholecystectomy and splenectomy; while her mother and brother’s HS were not complicated by cholelithiasis, and their splenomegaly and elevated serum bilirubin were moderate. In addition, additional genomic defects involved with HS-related symptoms have not been detected in this family. Conclusions Both genotypes and phenotypes could be heterogeneous in the same HS family. The analysis of pathogenic gene mutations may endeavor to play an indispensable role in the accurate diagnosis and genetic consultation of HS individuals and their family members.

Autosomal recessive congenital ichthyosis (ARCI) is a rare form of keratinization disorder of the skin, which can be caused by mutations in 14 ARCI genes. We present a rare case of ARCI that carried a novel null mutation and a novel splice site mutation in the CYP4F22 gene. Autosomal recessive congenital ichthyosis (ARCI) is a rare form of keratinization disorder of the skin, which can be caused by mutations in 13 ARCI genes. We present a rare case of ARCI that carried a novel null mutation and a novel splice site mutation in the CYP4F22 gene. The patient was a 3‐year‐old girl of Chinese origin. She was from non‐consanguineous Chinese parents and born full‐term to a G1P1 mother. The patient was ichthyotic at birth. She presented clinical aspects of generalized LI with brown, plate‐like scale, which was more pronounced in the periumbilical region, on the lower part of the body and on the buttocks. Hyperlinearity of palms and soles was observed in the patient, like that found in ichthyosis vulgaris. The proband’s exome sequencing indicated a compound heterozygous nonsense mutation (c.1084C>T) and an acceptor splicing mutation (c.1137‐2delA) in the CYP4F22 gene. In conclusion, this study reports the first novel mutation of CYP4F22 resulting in ARCIs in Chinese, which could provide insights into the molecular diagnosis and genetic counseling of families.