The pathogenesis of pulmonary fibrosis (PF) is complex. It is characterized by myofibroblast hyperplasia and deposition of collagen protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in lung fibroblasts and epithelial cells, but its functions in lung homeostasis and diseases remain elusive. Here, we characterize the critical role of IDO1 in PF patients and bleomycin (BLM)-induced PF mouse models. We find that IDO1 is significantly upregulated in the fibrotic lungs of patients and mice, showing a positive correlation with genes characteristic of fibrosis. Functionally, IDO1 knockout inhibits lung fibroblast proliferation, differentiation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation. Conversely, IDO1 overexpression and accumulation of kynurenine (Kyn) exacerbate progressive lung fibrosis. Mechanistically, IDO1-deletion activated profound mitochondrial fusion-enhanced potentially the capacity for fatty acid oxidation, along with activation of de novo glycolytic serine/glycine synthesis pathways and mitochondrial one-carbon metabolism. Wedelolactone (WEL), a small molecule IKK inhibitor, is found to strongly bind to IDO1 and effectively protect mice from PF in an IDO1-dependent manner. Collectively, this study characterizes a promotor role for IDO1 in PF and suggests a potential avenue of targeting IDO1 to treat lung diseases.

染色质许可和DNA复制因子1（Cdt1）是复制起始许可的主要调控因子，也是组成复制前复合物的核心成员。细胞通过依赖Cdt1的波动水平，且在每个周期中通过调节其总量以确保DNA仅复制一次。Cdt1功能缺陷会造成DNA过度复制，最终导致基因组不稳定。虽然酵母中cdt1和人类Meier-Gorlin综合征（MGS）患者中的CDT1已被广泛研究，但缺乏脊椎动物模型。我们发现在硬骨鱼类分支的几个鲤形目物种（包括斑马鱼）中，Cdt1蛋白在其N末端插入一段其他脊椎动物中没有的独特无序序列。通过分析在cdt1基因中携带移码缺失的遗传性斑马鱼突变体（命名为cdt1^zju1 ），我们发现突变胚胎虽然几乎无任何早期胚胎表型异常，但成年突变斑马鱼却表现出侏儒症、生存能力降低的症状，以及性腺发育不全且不育。此外，我们同样发现除转录本cdt1-201外，斑马鱼还存在第二个cdt1转录本——cdt1-202，它是通过跳过外显子2产生，这在其他生物中暂无报道。有意思的是cdt1-202在cdt1-201纯合突变体中显著上调。上述研究结果表明，cdt1-202转录本可能可以补偿cdt1-201在早期发育过程中的功能损失，但不能补偿后期生长，这可支持斑马鱼作为研究人类MGS的遗传模型。
Animals ; Humans ; Zebrafish ; Growth Disorders ; Cell Cycle Proteins ; Gonads

OBJECTIVE To explore the efficacy of Sour Jujube Seed Decoction combined with Huanglian Wendan Decoction on adult chronic insomnia and its effect on hypnotic withdrawal.METHODS 187 patients with chronic insomnia were included for anal-ysis,including 102 in the traditional Chinese medicine(TCM)group and 85 in the western medicine group.The TCM group was trea-ted with Sour Jujube Seed Decoction combined with Huanglian Wendan Decoction,while the western medicine group was treated with benzodiazepine under the consideration of doctor.The intervention period was 1 month,with assessments using the Pittsburgh Sleep Quality Index(PSQI)conducted before and after the intervention.Follow-up evaluations were performed at 3 months and 6 months re-spectively after the intervention.RESULTS There was no significant difference between the two groups at baseline.After the inter-vention,the PSQI scores of patients in both groups were significantly improved(P<0.01).Among them,the TCM group was better than the western medicine group in the improvement of sleep quality and sleeping pills,total PSQI score reduction(P<0.01).The re-sults of linear regression analysis showed that after controlling for confounding factors,the regression coefficients of the TCM group in two different models were1.821 and 1.922 respectively,and the former was statistically significant(P<0.05).By screening patients who took hypnotics at baseline in the TCM group and comparing them with those in the western medicine group,the influencing factors of hypnotic withdrawal were analyzed.During the 3-month follow-up,25 out of 39 patients in the TCM group and 17 out of 80 patients in the western medicine group had hypnotic withdrawal(χ2= 19.25,P<0.001);during the 6-month follow-up,23 of the 39 patients in the TCM group and 18 of the 79 patients in the western medicine group had hypnotic withdrawal(χ2= 13.53,P<0.001),the with-drawal rate of patients in the TCM group was significantly higher than that in the western medicine group.Further regression analysis showed that after adjusting for confounding factors,the results showed that the western medicine group had a significantly higher rate of not withdrawal than the TCM group at 3 months(OR=5.50,95%CI:2.30～13.72)and 6 months(OR=6.43,95%CI:2.54～17.77),and the results were statistically different(P<0.05).CONCLUSION Sour Jujube Seed Decoction combined with Huangli-an Wendan Decoction is effective in treating adult chronic insomnia and assisting in hypnotic withdrawal.

Objective:To explore the risk factors that may affect the stabilization of dorsal intra-articular fragment in distal radius fracture after volar internal fixation.Methods:A retrospective analysis was performed of the patients with distal radius fracture who had been treated by volar internal fixation at Department of Traumatic Orthopedics, Tongji Hospital Affiliated to Tongji University from July 2016 to July 2020. After 3D reconstruction of their preoperative CT scans by software Mimics 20.0, 66 patients with a dorsal intra-articular fragment were screened out. They were 31 males and 35 females, aged from 23 to 78 years (average, 53.4 years). By the AO classification, there were 17 case of type C1, 22 cases of type C2, and 27 cases of type C3. The displacement of dorsal intra-articular fragment was judged by X-ray observation on postoperative day 2 and X-ray follow-up at the outpatient department. The 13 patients with displacement of dorsal intra-articular fragment>2 mm were assigned into a displacement group while the other 53 ones into a displacement-free group. The 2 groups were compared in terms of preoperative general data and anatomical data of the dorsal intra-articular fragment (total preoperative displacement, radius-ulnar length, dorsal-volar length, aspect ratio, proximal-distal length and volume) to analyze the correlations between them and displacement.Results:There was no significant difference in preoperative general data (age, gender, affected side, cause of injury or AO classification) between the 2 groups, showing comparability between groups ( P>0.05). All patients were followed up for 6 to 24 months (mean, 14 months) after surgery. There were no postoperative complications like neurovascular lesion or infection. None of the patients in the displacement group underwent revision surgery, and the fractures healed successfully during the postoperative follow-up. The total preoperative displacement in the displacement group was(10.0±1.3) mm, significantly larger than that in the displacement-free group [(7.8±1.5) mm]; the radius-ulnar length in the displacement group was (8.2±1.3) mm, significantly shorter than that in the displacement-free group [(10.8±2.3) mm]; the aspect ratio of the fragment in the displacement group was 1.2±0.2, significantly lower than that in the displacement-free group (1.4±0.2); the fragment volume in the displacement group was (690.5± 201.4) mm 3, significantly smaller than that in the displacement-free group [(995.8±295.0) mm 3]. There were significant differences in the above items between the 2 groups ( P<0.05). Conclusion:The total preoperative displacement, radius-ulnar length, aspect ratio and volume of a dorsal intra-articular fragment are important factors which may affect the displacement of the dorsal fragment after volar internal fixation.

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β ₃-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

Prevotella copri and its related taxa are widely detected in mammalian gut microbiomes and have been linked with an enterotype in humans.However,their microevolution and macroevolution among hosts are poorly characterized.In this study,extensively collected marker genes and genomes were analyzed to trace their evolutionary history,host specificity,and biogeographic distribution.Investigations based on marker genes and genomes suggest that a P.copri-containing lineage(PCL)harbors diverse species in higher primates.Firstly,P.copri in the human gut consisted of multiple groups exhibiting high genomic divergence and conspicuous but non-strict biogeographic patterns.Most African strains with high genomic divergence from other strains were phylogenetically located at the root of the species,indicating the co-evolutionary his-tory of P.copri and Homo sapiens.Secondly,although long-term co-evolution between PCL and higher primates was revealed,sporadic signals of co-speciation and extensive host jumping of PCL members were suggested among higher primates.Metagenomic and phylogenetic analyses indicated that P.copri and other PCL species found in domesticated mammals had been recently transmitted from humans.Thirdly,strong evidence was found on the extensively horizontal transfer of genes(e.g.,genes encoding carbohydrate-active enzymes)among sympatric P.copri groups and PCL species in the same primate host.Our study provides panoramic insights into the combined effects of vertical and horizontal transmission,as well as potential niche adaptation,on the microevolutionary and macroevolutionary history for an enterotype-representative lineage.

Oligodontia is the congenital absence of six or more teeth and comprises the more severe forms of tooth agenesis. Many genes have been implicated in the etiology of tooth agenesis, which is highly variable in its clinical presentation. The purpose of this study was to identify associations between genetic mutations and clinical features of oligodontia patients. An online systematic search of papers published from January 1992 to June 2021 identified 381 oligodontia cases meeting the eligibility criteria of causative gene mutation, phenotype description, and radiographic records. Additionally, ten families with oligodontia were recruited and their genetic etiologies were determined by whole-exome sequence analyses. We identified a novel mutation in WNT10A (c.99_105dup) and eight previously reported mutations in WNT10A (c.433 G > A; c.682 T > A; c.318 C > G; c.511.C > T; c.321 C > A), EDAR (c.581 C > T), and LRP6 (c.1003 C > T, c.2747 G > T). Collectively, 20 different causative genes were implicated among those 393 cases with oligodontia. For each causative gene, the mean number of missing teeth per case and the frequency of teeth missing at each position were calculated. Genotype-phenotype correlation analysis indicated that molars agenesis is more likely linked to PAX9 mutations, mandibular first premolar agenesis is least associated with PAX9 mutations. Mandibular incisors and maxillary lateral incisor agenesis are most closely linked to EDA mutations.
Humans ; Phenotype ; Wnt Proteins

Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.

Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.