SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis.

BACKGROUND: Aberrant alternative splicing (AS) is a pervasive event during colorectal cancer (CRC) development. SF3B3 is a splicing factor component of U2 small nuclear ribonucleoproteins which are crucial for early stages of spliceosome assembly. The role of SF3B3 in CRC remains unknown. METHODS: SF3B3 expression in human CRCs was analyzed using publicly available CRC datasets, immunohistochemistry, qRT-PCR, and western blot. RNA-seq, RNA immunoprecipitation, and lipidomics were performed in SF3B3 knockdown or overexpressing CRC cell lines. CRC cell xenografts, patient-derived xenografts, patient-derived organoids, and orthotopic metastasis mouse models were utilized to determine the in vivo role of SF3B3 in CRC progression and metastasis. RESULTS: SF3B3 was upregulated in CRC samples and associated with poor survival. Inhibition of SF3B3 by RNA silencing suppressed the proliferation and metastasis of CRC cells in vitro and in vivo, characterized by mitochondria injury, increased reactive oxygen species (ROS), and apoptosis. Mechanistically, silencing of SF3B3 increased mTOR exon-skipped splicing, leading to the suppression of lipogenesis via mTOR-SREBF1-FASN signaling. The combination of SF3B3 shRNAs and mTOR inhibitors showed synergistic antitumor activity in patient-derived CRC organoids and xenografts. Importantly, we identified SF3B3 as a critical regulator of mTOR splicing and autophagy in multiple cancers. CONCLUSIONS: Our findings revealed that SF3B3 promoted CRC progression and metastasis by regulating mTOR alternative splicing and SREBF1-FASN-mediated lipogenesis, providing strong evidence to support SF3B3 as a druggable target for CRC therapy.

Pain symptoms are associated with two-point discrimination threshold in patients with temporomandibular disorders.

OBJECTIVE: This study aimed to explore the associations of orofacial two-point discrimination (2-PD) test result with pain symptoms and psychological factors in patients with Temporomandibular Disorders (TMDs). METHODS: 193 patients with TMDs were included in this study. Patients' demographics, pain intensity, and psychological status were recorded. The 2-PDs in the bilateral temporal, zygomatic, mandibular, and temporomandibular joint (TMJ) regions of the patients were measured. Statistical analyses were conducted to observe the associations between variables. RESULTS: For Pain-related TMDs (PT) patients, Monthly Visual Analogue Scale (VAS-M) and Current Analogue Scale (VAS-C) were correlated with TMJ, zygomatic and temporal 2-PDs. Patients with PT tended to have higher TMJ 2-PDs[Right: ß = 1.827 mm, 95%CI(0.107, 3.548), P = 0.038], zygomatic 2-PDs[Right: ß = 1.696 mm, 95%CI(0.344, 3.048), P = 0.014], temporal 2-PDs[Left: ß = 2.138 mm, 95%CI(0.127, 4.149), P = 0.037; Right: ß = 1.893 mm, 95%CI(0.011, 3.775), P = 0.049]. Associations were also observed between VAS-C and TMJ 2-PDs[Left: ß = 0.780, 95%CI(0.190, 1.370), P = 0.01; Right: ß = 0.885, 95%CI(0.406, 1.364), P = 0.001], Zygomatic 2-PDs[Right: ß = 0.555, 95%CI(0.172, 0.938), P = 0.005]; VAS-M and TMJ 2-PDs[Left: ß = 0.812, 95%CI(0.313, 1.311), P = 0.002; Right: ß = 0.567, 95%CI(0.152, 0.983), P = 0.008], zygomatic 2-PDs[Left: ß = 0.405, 95%CI(0.075, 0.735), P = 0.016; Right: ß = 0.545, 95%CI(0.221, 0.870), P = 0.001], and temporal 2-PDs [Left: ß = 0.741, 95%CI(0.258, 1.224), P = 0.003; Right: ß = 0.519, 95%CI(0.063, 0.975), P = 0.026]. CONCLUSION: TMJ, zygomatic, and temporal 2-PDs were significantly associated with PT and pain intensity. Age, gender and psychological factors were not associated with orofacial 2-PDs. PT patients exhibited weaker tactile acuity compared to Non-PT patients. Further discussion on the underlying mechanism is needed. CLINICAL RELEVANCE: Orofacial tactile acuity of TMDs patients was associated with their pain symptoms, which researchers should take account into when performing 2-PD tests for TMDs patients. The 2-PD test can be considered as a potential tool along with the current procedures for the differentiations of PT and Non-PT.

The effects of microgravity on stem cells and the new insights it brings to tissue engineering and regenerative medicine.

Conventional two-dimensional (2D) cell culture techniques may undergo modifications in the future, as life scientists have widely acknowledged the ability of three-dimensional (3D) in vitro culture systems to accurately simulate in vivo biology. In recent years, researchers have discovered that microgravity devices can address many challenges associated with 3D cell culture. Stem cells, being pluripotent cells, are regarded as a promising resource for regenerative medicine. Recent studies have demonstrated that 3D culture in microgravity devices can effectively guide stem cells towards differentiation and facilitate the formation of functional tissue, thereby exhibiting advantages within the field of tissue engineering and regenerative medicine. Furthermore, We delineate the impact of microgravity on the biological behavior of various types of stem cells, while elucidating the underlying mechanisms governing these alterations. These findings offer exciting prospects for diverse applications.

Single-embryo transcriptomic atlas of oxygen response reveals the critical role of HIF-1α in prompting embryonic zygotic genome activation.

Adaptive response to physiological oxygen levels (physO2; 5% O2) enables embryonic survival in a low-oxygen developmental environment. However, the mechanism underlying the role of physO2 in supporting preimplantation development, remains elusive. Here, we systematically studied oxygen responses of hallmark events in preimplantation development. Focusing on impeded transcriptional upregulation under atmospheric oxygen levels (atmosO2; 20% O2) during the 2-cell stage, we functionally identified a novel role of HIF-1α in promoting major zygotic genome activation by serving as an oxygen-sensitive transcription factor. Moreover, during blastocyst formation, atmosO2 impeded H3K4me3 and H3K27me3 deposition by deregulating histone-lysine methyltransferases, thus impairing X-chromosome inactivation in blastocysts. In addition, we found atmosO2 impedes metabolic shift to glycolysis before blastocyst formation, thus resulting a low-level histone lactylation deposition. Notably, we also reported an increased sex-dimorphic oxygen response of embryos upon preimplantation development. Together, focusing on genetic and epigenetic events that are essential for embryonic survival and development, the present study advances current knowledge of embryonic adaptive responses to physO2, and provides novel insight into mechanism underlying irreversibly impaired developmental potential due to a short-term atmosO2 exposure.

Interface fluid syndrome caused by the corneal perforation injury after small incision lenticule extraction: a case report.

BACKGROUND: To report a case of interface fluid syndrome (IFS) following traumatic corneal perforation repair after small incision lenticule extraction (SMILE). CASE PRESENTATION: A 23-year-old woman, with a past history of SMILE, was struck in the left eye with a barbecue prod and subsequently underwent corneal perforation repair at local hospital. Primary wound repaired with a single 10 - 0 nylon suture at the area of leakage. After the surgery, her best corrected visual acuity (BCVA) was 20/30. Four days later, she presented at our hospital with blurred vision, and interface fluid syndrome (IFS) was diagnosed. Intraoperative optical coherence tomography (iOCT) was used to guide the resuturing of the corneal perforation in the left eye, followed by anterior chamber gas injection. At the first postoperative month, the BCVA was 20/25. The corneal cap adhered closely to the stroma, the surface became smooth. CONCLUSIONS: This case illustrates that any corneal perforation following lamellar surgery, including SMILE, may lead to IFS. It is crucial to consider the depth of corneal perforation, and intraoperative optical coherence tomography (iOCT) plays a unique role in the repair procedure.

Lycium barbarum L. Balanced intestinal flora with YAP1/FXR activation in drug-induced liver injury.

Drug-induced liver injury (DILI) is a common and severe adverse drug reaction that can result in acute liver failure. Previously, we have shown that Lycium barbarum L. (wolfberry) ameliorated liver damage in acetaminophen (APAP)-induced DILI. Nevertheless, the mechanism needs further clarification. Herein, we utilized APAP-induced DILI mice to investigate how wolfberry impacts the gut-liver axis to mitigate liver damage. We showed that the abundance of Akkermansia muciniphila (A. muciniphila) was decreased, and intestinal microbiota was disrupted, while the expression levels of YAP1 and FXR-mediated CYP7A1 were reduced in the liver of DILI mice. Furthermore, wolfberry increased the abundance of A. muciniphila and the number of goblet cells in the intestines, while decreasing AST, ALT, and total bile acids (TBA) levels in the serum. Interestingly, A. muciniphila promoted YAP1 and FXR expression in hepatocytes, leading to the inhibition of CYP7A1 expression and a decrease in TBA content. Notably, wolfberry did not exert the beneficial effects mentioned above after the removal of intestinal bacteria by antibiotics (ATB)-containing water. Additionally, Yap1 knockout downregulated FXR expression and enhanced CYP7A1 expression in the liver of hepatocyte-specific Yap1 knockout mice. Therefore, wolfberry stimulated YAP1/FXR activation and reduced CYP7A1 expression by promoting the balance of intestinal microbiota, thereby suppressing the overproduction of bile acids.

Simulated microgravity altered the gene expression profiles and inhibited the proliferation of Kupffer cells in the early phase by downregulating LMO2 and EZH2.

Microgravity is a primary challenge that need to overcome, when human travel to space. Our study provided evidence that Kupffer cells (KCs) are sensitive to simulated microgravity (SMG), and no similar research report has been found in the literature. Using transcriptome sequencing technology, it was showed that 631 genes were upregulated and 801 genes were downregulated in KCs after treatment under SMG for 3 days. The GO analysis indicated that the proliferation of KCs was affected when exposed to SMG for 3 days. CCK-8 assay confirmed that the proliferation of KCs was inhibited in the third day under the environment of SMG. Furthermore, we identified 8 key genes that affect the proliferation of KCs and predicted 2 transcription factors (TFs) that regulate the 8 key genes. Significantly, we found that microgravity could affect the expression of LMO2 and EZH2 to reduce the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, Bub1b, which resulting in the reduction in KCs proliferation. These finding suggested that the inhibition of KCs proliferation under microgravity may influence the homeostasis of liver, and LMO2 and EZH2 can be the targets in management of KCs' disturbance in the future practice of space medicine.

Holes can be perilous: A rare presentation of intestinal obstruction - Herniation through the broad ligament.

A 57-year-old lady presented with symptoms of intestinal obstruction preceded by a 2-day history of lower abdomen pain. Clinically, she had a distended abdomen with tenderness in her lower abdomen. Laboratory investigations were unremarkable. An abdominal radiograph showed a dilated small bowel with no extensive bowel gas. A computed tomography (CT) scan showed suspected intestinal obstruction secondary to herniation into the right broad ligament. The decision was made to proceed with surgery, and the intraoperative results confirmed the CT results. The literature review is outlined here, and this instance illustrates a surprising discovery.

A prognostic exosome-related long non-coding RNAs risk model related to the immune microenvironment and therapeutic responses for patients with liver hepatocellular carcinoma.

Background: Liver hepatocellular carcinoma (LIHC) is the third largest cause of cancer mortality. Exosomes are vital regulators in the development of cancer. However, the mechanisms regarding the association of exosome-related long non-coding RNAs (lncRNAs) in LIHC are not clear. Methods: LIHC RNA sequences and exosome-associated genes were collected according to The Cancer Genome Atlas (TCGA), Hepatocellular Carcinoma Cell DataBase (HCCDB) and ExoBCD databases, and exosome-related lncRNAs with prognostic differential expression were screened as candidate lncRNAs using Spearman's method and univariate Cox regression analysis. Candidate lncRNAs were then used to construct a prognostic model and mRNA-lncRNA co-expression network. Differentially expressed genes (DEGs) in low- and high-risk groups were identified and enrichment analysis was performed for up- and down-regulated DEGs, respectively. The expression of immune checkpoint-related genes, immune escape potential and microsatellite instability among different risk groups were further analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) and transwell assay were applied for detecting gene expression levels and invasion and migration ability. Results: Based on 17 prognostical exosome-associated lncRNAs, four hub lncRNAs (BACE1_AS, DSTNP2, PLGLA, and SNHG3) were selected for constructing a prognostic model, which was demonstrated to be an independent prognostic variable for LIHC. High risk score was indicative of poorer overall survival, lower anti-tumor immune cells, higher genomic instability, higher immune escape potential, and less benefit for immunotherapy. The qRT-PCR test verified the expression level of the lncRNAs in LIHC cells, and the inhibitory effect of BACE1_AS on immune checkpoint genes levels. BACE1_AS silence also depressed the ability of migration and invasion of LIHC cells. Conclusion: The Risk model constructed by exosome-associated lncRNAs could well predict immunotherapy response and prognostic outcomes for LIHC patients. We comprehensively reveal the clinical features of prognostical exosome-related lncRNAs and their potential ability to predict immunotherapeutic response of patients with LIHC and their prognosis.

Copper Catalyst-Promoted Regioselective Multicomponent Cascade Cyclization of 3-Aza-1,5-enynes with Sulfur Dioxide and Cycloketone Oxime Esters to Access Cyanoalkylsulfonylated 1,2-Dihydropyridines.

Radical cascade cyclization via the cracking of alkenyl C-H has emerged as an attractive and remarkable tool for the rapid construction of ring frameworks with endocyclic double bonds. We developed a cascade reaction of 3-aza-1,5-enynes with sulfur dioxide and cycloketone oxime esters to access cyanoalkylsulfonylated 1,2-dihydropyridines, which can be easily converted to pyridine derivatives. This protocol involves radical addition to the C≡C bond and 6-endo cyclization and features high regioselectivity and a broad substrate scope.

Bovine mammary epithelial cells can grow and express milk protein synthesis genes at reduced fetal bovine serum concentration.

Milk proteins produced by lactating cells isolated from bovine mammary tissue can offer a sustainable solution to the high protein demand of a global growing population. Serum is commonly added to culture systems to provide compounds necessary for optimal growth and function of the cells. However, in a cellular agricultural context, its usage is desired to be decreased. This study aims at examining the minimum level of fetal bovine serum (FBS) required for the growth and functionality of bovine mammary epithelial cells (MECs). The cells were isolated from dairy cows in early and mid-lactation and cultured in reduced concentrations of FBS (10%, 5%, 1.25%, and 0%). Real-time cell analysis showed a significant effect of lactation stage on growth rate and 5% FBS resulted in similar growth rate as 10% while 0% resulted in the lowest. The effect of reducing FBS on cell functionality was examined by studying the expressions of selected marker genes involved in milk protein and fat synthesis, following differentiation. The gene expressions were not affected by the level of FBS. A reduction of FBS in the culture system of MEC, at least down to 5%, does not assert any negative effect on the growth and expression levels of studied genes. As the first attempt in developing an in-vitro model for milk component production using MEC, our results demonstrate the potential of MEC to endure FBS-reduced conditions.

Three molecular subtypes and a five-gene signature for hepatocellular carcinoma based on m7G-related classification.

BACKGROUND: The current research investigated the heterogeneity of hepatocellular carcinoma (HCC) based on the expression of N7-methylguanosine (m7G)-related genes as a classification model and developed a risk model predictive of HCC prognosis, key pathological behaviors and molecular events of HCC. METHODS: The RNA sequencing data of HCC were extracted from The Cancer Genome Atlas (TCGA)-live cancer (LIHC) database, hepatocellular carcinoman database (HCCDB) and Gene Expression Omnibus database, respectively. According to the expression level of 29 m7G-related genes, a consensus clustering analysis was conducted. The least absolute shrinkage and selection operator (LASSO) regression analysis and COX regression algorithm were applied to create a risk prediction model based on normalized expression of five characteristic genes weighted by coefficients. Tumor microenvironment (TME) analysis was performed using the MCP-Counter, TIMER, CIBERSORT and ESTIMATE algorithms. The Tumor Immune Dysfunction and Exclusion algorithm was applied to assess the responses to immunotherapy in different clusters and risk groups. In addition, patient sensitivity to common chemotherapeutic drugs was determined by the biochemical half-maximal inhibitory concentration using the R package pRRophetic. RESULTS: Three molecular subtypes of HCC were defined based on the expression level of m7G-associated genes, each of which had its specific survival rate, genomic variation status, TME status and immunotherapy response. In addition, drug sensitivity analysis showed that the C1 subtype was more sensitive to a number of conventional oncolytic drugs (including paclitaxel, imatinib, CGP-082996, pyrimethamine, salubrinal and vinorelbine). The current five-gene risk prediction model accurately predicted HCC prognosis and revealed the degree of somatic mutations, immune microenvironment status and specific biological events. CONCLUSION: In this study, three heterogeneous molecular subtypes of HCC were defined based on m7G-related genes as a classification model, and a five-gene risk prediction model was created for predicting HCC prognosis, providing a potential assessment tool for understanding the genomic variation, immune microenvironment status and key pathological mechanisms during HCC development.

A worldwide bibliometric analysis of the research trends and hotspots of bruxism in adults during 1991-2021.

BACKGROUND AND OBJECTIVES: With the increasing attention to bruxism, the research on bruxism is increasing rapidly. However, there is still a lack of systematic bibliometric analysis in the field of bruxism in adults. This study aimed to comprehensively explore and visualize the global trends and research hotspots in the field of bruxism in adults during 1991-2021. METHODS: The study searched the literature published during 1991-2021 in the Web of Science Core Collection database without language restrictions. VOSviewer, CiteSpace and Microsoft Excel were applied to analyse the authors, institutions, journals, countries, cited references, keywords and other information of the included publications, and construct visualized cooperation networks. RESULTS: A total of 878 articles were finally included. The top two most productive authors in the past 30 years were Lobbezoo F and Manfredini D. ACTA-Amsterdam, Univ Sao Paulo, Univ Helsinki, Univ Padua, Univ Montreal, et al. were prominent institutions in this field. Journal of Oral Rehabilitation made outstanding contributions in this field. The United States produced the most documents in this field, followed by Brazil. Both countries and authors cooperated closely around the world. The two most cited articles focused on the definition, assessment and classification of bruxism. In recent years, diagnostic criteria and stress have begun to receive a lot of attention. CONCLUSION: From 1991 to 2021, the attention to bruxism in adults continued to increase. Diagnostic criteria and stress may be potential research hotspots in this field. This study references relevant scholars on development trends and research hotspots.

Field outcomes of laparoscopic ovum pick-up combined with in vitro embryo production in sheep: Effects of long-acting recombinant ovine FSH pre-stimulation, collection frequency, and donor breed.

Laparoscopic ovum pick-up (LOPU) combined with in vitro embryo production (IVEP) is a technology platform that improves the utilization rate of the elite ewe's ovarian oocytes and increases the number of obtained offspring. This study aimed to evaluate the effects of FSH pre-stimulation, serial oocyte collection, and breed on LOPU-IVEP under field conditions. Donors were randomly assigned to five groups (group A: decreasing doses of pituitary FSH (p-FSH); group B: constant doses of p-FSH; group C: two doses of long-acting recombinant ovine FSH (ro-FSH); group D: single administration of a long-acting ro-FSH in; group E: no FSH stimulation). Oocyte yield following LOPU (average recovered oocytes: 20.9 ± 0.5; average viable oocytes: 17.2 ± 0.4) and oocyte developmental competence (average blastocysts: 7.0 ± 0.2) in group C were significantly better than these of group D and group E, and similar to these of groups A and B. Meanwhile, there were no differences in oocyte yield and developmental capacity using repeated LOPU session at 1-, 2-, and 3-month intervals (p > 0.05). Finally, we compared LOPU-IVEP outcomes among five sheep breeds. The results indicated that East Friesian × Chinese Mongolian crossbred sheep and purebred East Friesian sheep had the more recovered oocytes and viable oocytes compared with the Suffolk, Dorper, and Texel breeds, and average number of blastocysts in East Friesian × Chinese Mongolian sheep group was also highest among the groups (8.1 ±0.3, p < 0.05). In summary, the results of this study indicate long-acting ro-FSH pre-stimulation combined with 12 times LOPU sessions over one year maximizes embryo production of elite donor ewes under field conditions.

Kefir Ameliorates Alcohol-Induced Liver Injury Through Modulating Gut Microbiota and Fecal Bile Acid Profile in Mice.

SCOPE: Alcoholic liver disease (ALD) is the leading cause of liver-related deaths worldwide. Kefir has been studied for its properties of anti-obesity, rebuilding intestinal homeostasis, and alleviating non-alcoholic fatty liver disease. However, the possible role of kefir in the prevention or treatment of ALD has not been carefully considered. Here, it evaluated the protective effects of kefir supplementation on alcohol-induced liver injury. METHODS AND RESULTS: C57BL/6J mice are fed to Lieber-DeCarli liquid diet containing alcohol to build ALD mouse model, followed by oral administration with kefir. Results indicate that kefir treatment improves liver pathological changes, decreases the expression levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and inflammatory markers, and increases antioxidant levels. Kefir supplementation also restores the intestinal barrier and altered microbial composition, indicates as increases of Blautia, Bacteroides, and Parasutterella and decreases in the Firmicutes/Bacteroidetes (F/B) ratio and populations of Psychrobacter, Bacillus, and Monoglobus. Moreover, kefir supplementation decreases the levels of total bile acids (BAs) and primary BAs and increases the secondary/primary BA ratio. Gut microbes play a key role in the conversion of primary to secondary fecal BAs. CONCLUSION: Kefir can ameliorate ALD through regulating the composition of the gut microbiota.

Comparative analysis of two arecoline-induced oral submucous fibrosis models.

OBJECTIVE: The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment strategies. The lack of suitable animal models is a major hindrance. Therefore, this study aimed to address this issue by comparing commonly used arecoline-induced water drinking and injection mouse models. MATERIALS AND METHODS: The mice were subjected to two protocols: receiving 2 mg/mL arecoline in drinking water and 4 mg/mL arecoline saline solution injections every other day. Tissues were collected at regular 4-week intervals, with a final time point of 20 weeks. Stereo microscopy and histomorphological analysis were performed on live and harvested tissues, respectively. RESULTS: During arecoline treatment, collagen deposition and myofibroblast proliferation progressively increased in both models. Changes in the collagen I/III ratio indicated that both models exhibited characteristics of the early and intermediate stages of OSF after 20 weeks of arecoline induction. The water-drinking model also demonstrated multi-organ fibrosis involving the tongue, lungs, and small intestine. CONCLUSION: Both the water drinking and injection mouse models effectively induced OSF, but the water-drinking model better mirrored the observed pathogenesis in patients with OSF. These models provide valuable tools for investigating the mechanisms underlying OSF.

Association of high-normal albuminuria and vascular aging: Hanzhong adolescent hypertension study.

Normoalbuminuria has recently been associated with increased cardiovascular risk, and vascular aging is proposed as the early manifestation of cardiovascular disease. Here, the authors aimed to examine the association of high-normal albuminuria and vascular aging in a Chinese cohort. From our previously established cohort, 1942 participants with estimated glomerular filtration rate ≥60 mL/min/1.73 m2 or urinary albumin-creatinine ratio (UACR) <30 mg/g were enrolled. Brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s and/or carotid intima-media thickness (CIMT) ≥0.9 mm were used as indicators of vascular aging. Multivariate regression and receiving operating characteristic curve analysis were performed to examine the relationship between continuous and categorical UACR with vascular aging. We found an average UACR value of 8.08 (5.45-12.52) mg/g in this study. BaPWV and CIMT demonstrated positive correlations with lg-UACR (p < .05). High-normal albuminuria (10-29 mg/g) was significantly associated with the presence of vascular aging after adjusting for multiple cardiovascular confounders (OR = 1.540, 95% CI = 1.203-1.972, p = .001). In addition, a lg-UACR cutoff point of 0.918 lg(mg/g) (equal to UACR of 8.285 mg/g) was significantly associated with the presence of vascular aging and its components for all participants and those without hypertension or diabetes and without medication (p < .05). Briefly, high-normal albuminuria was significantly associated with vascular aging in this sample of Chinese adults. These findings implied the warning of elevated UACR even within normal range in clinical practice and the importance of UACR screening in normoalbuminuria for early detection and prevention of cardiovascular disease in otherwise healthy participants.

Regional Citrate Anticoagulation versus No Anticoagulation for CKRT in Patients with Liver Failure with Increased Bleeding Risk.

BACKGROUND: The opinions on the efficacy and safety of no anticoagulation versus regional citrate anticoagulation for continuous KRT (CKRT) were controversial in patients with severe liver failure with a higher bleeding risk. We performed a randomized controlled trial to assess no anticoagulation versus regional citrate anticoagulation for CKRT in these patients. METHODS: Adult patients with liver failure with a higher bleeding risk who required CKRT were considered candidates. The included participants were randomized to receive regional citrate anticoagulation or no-anticoagulation CKRT. The primary end point was filter failure. RESULTS: Of the included participants, 44 and 45 were randomized to receive regional citrate anticoagulation and no-anticoagulation CKRT, respectively. The no-anticoagulation group had a significantly higher filter failure rate (25 [56%] versus 12 [27%], P = 0.003), which was confirmed by cumulative incidence function analysis and sensitive analysis including only the first CKRT sessions. In the cumulative incidence function analysis, the cumulative filter failure rates at 24, 48, and 72 hours of the no-anticoagulation and regional citrate anticoagulation groups were 31%, 58%, and 76% and 11%, 23%, and 35%, respectively. Participants in the regional citrate anticoagulation group had significantly higher incidences of Ca 2+tot /Ca 2+ion >2.5 (7% versus 57%, P < 0.001), hypocalcemia (51% versus 82%, P = 0.002), and severe hypocalcemia (13% versus 77%, P < 0.001). However, most (73%) of the increased Ca 2+tot /Ca 2+ion ratios were normalized after the upregulation of the calcium substitution rate. In the regional citrate anticoagulation group, there was no significant additional increase in the systemic citrate concentration after 6 hours. CONCLUSIONS: For patients with liver failure with a higher bleeding risk who required CKRT, regional citrate anticoagulation resulted in significantly longer filter lifespan than no anticoagulation. However, regional citrate anticoagulation in patients with liver failure was associated with a significantly higher risk of hypocalcemia, severe hypocalcemia, and Ca 2+tot /Ca 2+ion >2.5. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: RCA for CRRT in Liver Failure and High Risk Bleeding Patients, NCT03791190 .

"Meiosis arrester" C-natriuretic peptide directly stimulates oocyte mtDNA accumulation and is implicated in aging-associated oocyte mtDNA loss.

C-natriuretic peptide (CNP) is the central regulator of oocyte meiosis progression, thus coordinating synchronization of oocyte nuclear-cytoplasmic maturation. However, whether CNP can independently regulate cytoplasmic maturation has been long overlooked. Mitochondrial DNA (mtDNA) accumulation is the hallmark event of cytoplasmic maturation, but the mechanism underlying oocyte mtDNA replication remains largely elusive. Herein, we report that CNP can directly stimulate oocyte mtDNA replication at GV stage, and deficiency of follicular CNP may contribute largely to lower mtDNA copy number in in vitro matured oocytes. The mechanistic study showed that cAMP-PKA-CREB1 signaling cascade underlies the regulatory role of CNP in stimulating mtDNA replication and upregulating related genes. Of interest, we also report that CNP-NPR2 signaling is inhibited in aging follicles, and this inhibition is implicated in lower mtDNA copy number in oocytes from aging females. Together, our study provides the first direct functional link between follicular CNP and oocyte mtDNA replication, and identifies its involvement in aging-associated mtDNA loss in oocytes. These findings, not only update the current knowledge of the functions of CNP in coordinating oocyte maturation but also present a promising strategy for improving in vitro fertilization outcomes of aging females.

Atomic-scale probing of short-range order and its impact on electrochemical properties in cation-disordered oxide cathodes.

Chemical short-range-order has been widely noticed to dictate the electrochemical properties of Li-excess cation-disordered rocksalt oxides, a class of cathode based on earth abundant elements for next-generation high-energy-density batteries. Existence of short-range-order is normally evidenced by a diffused intensity pattern in reciprocal space, however, derivation of local atomic arrangements of short-range-order in real space is hardly possible. Here, by a combination of aberration-corrected scanning transmission electron microscopy, electron diffraction, and cluster-expansion Monte Carlo simulations, we reveal the short-range-order is a convolution of three basic types: tetrahedron, octahedron, and cube. We discover that short-range-order directly correlates with Li percolation channels, which correspondingly affects Li transport behavior. We further demonstrate that short-range-order can be effectively manipulated by anion doping or post-synthesis thermal treatment, creating new avenues for tailoring the electrochemical properties. Our results provide fundamental insights for decoding the complex relationship between local chemical ordering and properties of crystalline compounds.