Dihydrolipoamide S-acetyltransferase activation alleviates diabetic kidney disease via AMPK-autophagy axis and mitochondrial protection.

Diabetic kidney disease (DKD), a severe complication of diabetes marked by deregulated glucose metabolism, remains enigmatic in its pathogenesis. Herein, we delved into the functional role of Dihydrolipoamide S-acetyltransferase (DLAT), a pivotal E2 component of the pyruvate dehydrogenase complex (PDC), in the context of DKD. Our findings revealed a downregulation of DLAT in the kidneys of diabetic patients, correlating inversely with kidney function. Parallel downregulation was observed in both high-fat diet/streptozotocin (HFD/STZ) and db/db mouse models, as well as in human proximal tubular epithelial cells (HK-2) cultured under hyperglycemic conditions. To further elucidate the role of endogenous DLAT in DKD, we employed genetic ablation of Dlat in mouse models. Dlat haploinsufficient mice exhibited exacerbated renal dysfunction, structural damage, fibrosis, and mitochondrial dysfunction under DKD conditions. Consistent with these findings, modulation of DLAT expression in HK-2 cells highlighted its influence on fibrosis, with overexpression attenuating Fibronectin and Collagen I levels, while downregulation exacerbated fibrosis. Mechanistically, we discovered that DLAT activates mitochondria autophagy through the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby mitigating mitochondrial dysfunction associated with DKD progression. Inhibition of AMPK abrogated the protective effects of DLAT against mitochondrial dysfunction and DKD. Notably, we identified Hyperforin (HPF), a phytochemical, as a potential therapeutic agent. HPF activates DLAT and AMPK, subsequently ameliorating renal dysfunction, injuries, and fibrosis in both in vivo and in vitro models. In summary, our study underscores the pivotal role of DLAT and AMPK in kidney health and highlights the therapeutic potential of HPF in treating DKD.

RNA transcription assisted universal CRISPR/Cas12a system for programmable analysis of multiple colorectal cancer-associated microRNAs.

Accurate analysis of multiple microRNA (miRNA) levels is significantly valuable for early diagnosis of colorectal cancer noninvasively considering the miRNA expression is highly relevant to the occurrence and progression of cancer. However, the low abundance and high sequence homology of miRNAs make their precise determination extremely challenging. Here, we developed a universal and programmable diagnostic strategy allowing for analyzing multiple colorectal cancer-associated miRNAs. The system combined sequentially programmable rolling circle transcription (RCT) and the CRISPR/Cas12a system with high trans-cleavage activity to achieve highly sensitive and specific detection of four target miRNAs. Owing to the remarkable performance of universal RCT-Cas12a strategy, this biosensor could detect miR-21, miR-17, miR-31 and miR-92a with a LOD of 2.1, 1.6, 3.7 and 1.0 pM, respectively. This strategy had a unique advantage in distinguishing human normal colon epithelial cells lines (NCM460) from human colon cancer cells (HT29). In particular, the designed system exhibited superior analytical capability in distinguishing paracancerous and colorectal cancer tissues from patients undergoing colorectal cancer surgery. This arbitrarily programmable, scalable, fast and specific strategy potentially offered an attractive alternative to handle varied challenges encountered with CRISPR-based systems, and held immense promise in scientific research and clinical applications.

Multi-omics PGT: re-evaluation of euploid blastocysts for implantation potential based on RNA sequencing.

STUDY QUESTION: In addition to chromosomal euploidy, can the transcriptome of blastocysts be used as a novel predictor of embryo implantation potential? SUMMARY ANSWER: This retrospective analysis showed that based on differentially expressed genes (DEGs) between euploid blastocysts which resulted and did not result in a clinical pregnancy, machine learning models could help improve implantation rates by blastocyst optimization. WHAT IS KNOWN ALREADY: Embryo implantation is a multifaceted process, with implantation loss and pregnancy failure related not only to blastocyst euploidy but also to the intricate dialog between blastocyst and endometrium. Although in vitro studies have revealed the characteristics of trophectoderm (TE) differentiation in implanted blastocysts and the function of TE placentation at the implantation site, the precise molecular mechanisms of embryo implantation and their clinical application remain to be fully elucidated. STUDY DESIGN, SIZE, DURATION: This study involved 102 patients who underwent 111 cycles for preimplantation genetic testing for aneuploidies (PGT-A) between March 2022 and July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 412 blastocysts biopsied at Day 5 [D5] or Day 6 [D6] for patients who underwent PGT-A. The biopsy lysates were split and subjected to DNA and RNA sequencing (DNA- and RNA-seq). One part was used for PGT-A to detect DNA copy number variations, whereas the other part was assessed simultaneously by RNA-seq to determine the transcriptome characteristics. To validate the reliability and accuracy of RNA-seq obtained from this strategy, we initially analyzed the transcriptome of blastocysts with chromosomal aneuploidies. Subsequently, we compared the transcriptomic features of blastocysts with different rates of formation (D5 vs D6) and investigated the network of interactions between key blastulation genes and the receptive endometrium. Then to evaluate the implantation potential of euploid blastocysts, we identified DEGs between euploid blastocysts that resulted in clinical pregnancy (defined as the presence of a gestational sac detected by ultrasound after 5 weeks) and those that did not. These DEGs were then employed to construct a predictive model for optimizing blastocyst selection. MAIN RESULTS AND THE ROLE OF CHANCE: The successful detection rate of PGT-A was remarkably high at 99.8%. The RNA data may infer aneuploidy for both trisomy and monosomy. Between the euploid blastocysts that formed on D5 and D6, 187 DEGs were predominantly involved in cell differentiation for embryonic placenta development, the PPAR signaling pathway, and the Notch signaling pathway. These D5/D6 DEGs also exhibited a functional dialog with the receptive phase endometrium-specific genes through protein-protein interaction networks, indicating that the embryo undergoes further differentiation for post-implantation development. Furthermore, a modeling strategy using 280 DEGs between blastocysts leading to successful clinical pregnancies or failing to produce clinical pregnancies was implemented to refine the euploid embryo optimization, achieving areas under the curves of 0.88, 0.71, and 0.84 for the random forest (RF), support vector machine, and linear discriminant analysis models, respectively. Finally, a retrospective analysis of 83 transferred euploid blastocysts using the RF model identified three types of euploid embryos with a decreasing trend in implantation potential. Notably, the implantation rate of the good group was significantly higher than that of the moderate group (88.6% vs 50.0% P = 0.001) and that of the moderate group was higher than that of the poor group (50.0% vs 20.8%, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The sample size was insufficient; thus, a prospective study is needed to verify the clinical effectiveness of the above model. Because we did not analyze blastocysts that led only to biochemical pregnancies but failed clinical pregnancies separately, our classification system still must be modified to screen these embryos. WIDER IMPLICATIONS OF THE FINDINGS: Transcriptomic analysis of blastocysts offers a novel approach for predicting embryo implantation potential, which can be utilized to optimize clinical embryo selection. The ranking system may be effective in reducing the times and costs involved in achieving a clinical pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the "Pioneer" and "Leading Goose" R&D Program of Zhejiang (No. 2023C03034), the National Natural Science Foundation of China (82101709), and the National Key Research and Development Program for Young Scientists of China (No. 2022YFC2702300). The authors state no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Screening of Neutralizing Antibodies against FaeG Protein of Enterotoxigenic Escherichia coli.

The misuse of antibiotics in veterinary medicine presents significant challenges, highlighting the need for alternative therapeutic approaches such as antibody drugs. Therefore, it is necessary to explore the application of antibody drugs in veterinary settings to reduce economic losses and health risks. This study focused on targeting the F4ac subtype of the FaeG protein, a key adhesion factor in enterotoxigenic Escherichia coli (ETEC) infections in piglets. By utilizing formaldehyde-inactivated ETEC and a soluble recombinant FaeG (rFaeG) protein, an antibody library against the FaeG protein was established. The integration of fluorescence-activated cell sorting (FACS) and a eukaryotic expression vector containing murine IgG Fc fragments facilitated the screening of anti-rFaeG IgG monoclonal antibodies (mAbs). The results demonstrate that the variable regions of the screened antibodies could inhibit K88-type ETEC adhesion to IPEC-J2 cells. Furthermore, in vivo neutralization assays in mice showed a significant increase in survival rates and a reduction in intestinal inflammation. This research underscores the potential of antibody-based interventions in veterinary medicine, emphasizing the importance of further exploration in this field to address antibiotic resistance and improve animal health outcomes.

Technically feasible solutions to challenges in preimplantation genetic testing for thalassemia: experiences of multiple centers between 2019 and 2022.

PURPOSE: In clinical practice, the success of preimplantation genetic testing for monogenic diseases (PGT-M) for thalassemia was hindered by the absence of probands, incomplete family members, or failure in detecting embryonic gene mutation sites. This study aimed to address these issues. METHODS: This retrospective study included 342 couples undergoing PGT-M for α- or ß-thalassemia at three reproductive medicine centers from 2019 to 2022. Various methods were used to construct parental haplotypes. A total of 1778 embryos were analyzed and selected for transfer based on chromosomal ploidy and PGT-M results. Follow-up involved amniocentesis results and clinical outcomes. RESULTS: Haplotypes were established using DNA samples from probands or parents, as well as sibling blood samples, single sperm, and affected embryos, achieving an overall success rate was 99.4% (340/342). For α-thalassemia and ß-thalassemia, the concordance between embryo single nucleotide polymorphism (SNP) haplotype analysis results and mutation loci detection results was 93.8% (1011/1078) and 98.2% (538/548), respectively. Multiple annealing and looping-based amplification cycles (MALBAC) showed a higher whole genome amplification success rate than multiple displacement amplification (MDA) (98.8% (1031/1044) vs. 96.2% (703/731), p < 0.001). Amniocentesis confirmed PGT-M outcomes in 100% of cases followed up (99/99). CONCLUSION: This study summarizes feasible solutions to various challenging scenarios encountered in PGT-M for thalassemia, providing valuable insights to enhance success rate of PGT-M in clinical practice.

Special Survival Strategy of First-Instar Scorpions Revealed by Synchronous Molting Behavior from Social Facilitation of Maternal Care and Reciprocal Aggregation.

Ecdysis is a well-known developmental feature among arthropods. Because the aggregate and synchronous molting of first-instar scorpions is markedly different from the common independent molting behavior of older scorpions and most arthropods, knowledge on the biological benefits of the unusual behavior of first-instar scorpions remain limited. Before the molting of newborn scorpions, their mothers exhibited a remarkable ability to efficiently locate the fallen offspring and help them climb onto their back, which was supported by strong maternal behavior because they climbed more swiftly than the 7-day postpartum scorpions. Most newborn scorpions molted and survived on the mother's back, with a survival rate of approximately 100%, and most newborn scorpions survived via aggregate molting behavior on sand in the absence of mothers (89.83% ± 1.91%). The important role of the mother scorpion was further highlighted in mothers with one to five first-instar scorpions. While all first-instar scorpions individually or reciprocally molted and survived on the mother's back, only 52.00% ± 7.14% to 79.20% ± 4.24% of newborn scorpions isolated from the mother could individually or reciprocally molt and survive on the sand, and the aggregated states of first-instar scorpions strengthened as their numbers on sand increased before molting. These results highlight collaborative molting as an evolutionary driving force for newborn scorpions. Taken together, both maternal care and collaborative aggregate molting behavior enhanced the survival of first-instar scorpions before and after molting, and these benefits for first-instar scorpions play essential and evolutionary roles in scorpion survival.

Lactobacillus salivarius and Berberine Alleviated Yak Calves' Diarrhea via Accommodating Oxidation Resistance, Inflammatory Factors, and Intestinal Microbiota.

Yaks are important food animals in China; however, bacterial diarrheal diseases frequently occur on the plateau, with limited effective therapies. The objective of this research was to evaluate the effectiveness of Lactobacillus salivarius (LS) and berberine in alleviating diarrhea in yak calves. For this purpose, eighteen healthy yak calves were divided into control (JC), infected (JM), and treatment (JT) groups. Yaks in the JT group were treated with 2 × 1010 CFU/calf L. salivarius and 20 mg/kg berberine, and yaks in the JM and JT groups were induced with multi-drug-resistant Escherichia coli. The results showed that the weight growth rate in the JM group was significantly lower than that in the JC and JT groups. The diarrhea score in the JM group was significantly higher than that in both the JC and JT groups. Additionally, the contents of T-AOC, SOD, GSH-Px, and IL-10 were significantly lower in the JM group than those in the JC and JT groups, while MDA, TNF-α, IL-1ß, and IL-6 were significantly higher in the JM group. Microbiota sequencing identified two phyla and twenty-seven genera as significant among the yak groups. Notably, probiotic genera such as Faecalibaculum and Parvibacter were observed, alongside harmful genera, including Marvinbryantia and Lachnospiraceae UCG-001. Our findings indicate that treatment with L. salivarius and berberine significantly reduced diarrhea incidence, improved growth performance, and positively modulated intestinal microbiota, which could provide novel insights for developing new therapies for ruminant diarrhea.

Efficacy of non-invasive chromosome screening, preimplantation genetic testing for aneuploidy, and morphological grading in selecting embryos of patients with advanced maternal age: a three-armed prospective cohort study.

BACKGROUND: Non-invasive chromosome screening (NICS) and trophectoderm biopsy preimplantation genetic testing for aneuploidy (TE-PGT) were both applied for embryo ploidy detection, However, the cumulative live birth rates (CLBR) of NICS and TE-PGT in older age groups have yet to be reported. This study aimed to ascertain whether NICS and TE-PGT could enhance the cumulative live birth rates among patients of advanced maternal age. METHODS: A total of 384 couples aged 35-40 years were recruited. The patients were assigned to three groups: NICS, TE-PGT, and intracytoplasmic sperm injection (ICSI). All patients received frozen single blastocyst transfer. Patients in the NICS and TE-PGT groups underwent aneuploidy screening. RESULTS: When compared to the ICSI group, the CLBR was significantly higher in the NICS and TE-PGT groups (27.9% vs. 44.9% vs. 51.0%, p = 0.003 for NICS vs. ICSI, p < 0.001 for TE-PGT vs. ICSI). There were no significant differences in the clinical outcomes between the NICS and TE-PGT groups. Adjusting for confounding factors, the NICS and TE-PGT groups still showed a higher CLBR than the ICSI group (adjusted odds ratio (OR) 3.847, 95% confidence interval (CI) 1.939 to 7.634; adjusted OR 3.795, 95% CI 1.981 to 7.270). Additionally, the cumulative pregnancy loss rates of the NICS and TE-PGT groups were significantly lower than that of the ICSI group (adjusted OR 0.277, 95% CI 0.087 to 0.885; adjusted OR 0.182, 95% CI 0.048 to 0.693). There was no significant difference in the birth weights of the three groups (p = 0.108). CONCLUSIONS: In women 35-40 years old, the CLBR can be increased by selecting euploid embryos using NICS and TE-PGT. For elderly women at high risk of embryonic aneuploidy, NICS, characterized by its safety and non-invasive nature, may emerge as an alternative option for preimplantation genetic testing.

Comparative analysis of intestinal microbiota composition between free-ranged captive yak populations in Nimu County.

The intestinal microbiota assumes a pivotal role in modulating host metabolism, immune responses, overall health, and additional physiological dimensions. The structural and functional characteristics of the intestinal microbiota may cause alterations within the host's body to a certain extent. The composition of the gut microbiota is associated with environmental factors, dietary habits, and other pertinent conditions. The investigation into the gut microbiota of yaks remained relatively underexplored. An examination of yak gut microbiota holds promise in elucidating the complex relationship between microbial communities and the adaptive responses of the host to its environment. In this study, yak were selected from two distinct environmental conditions: those raised in sheds (NS, n=6) and grazed in Nimu County (NF, n=6). Fecal samples were collected from the yaks and subsequently processed for analysis through 16S rDNA and ITS sequencing methodologies. The results revealed that different feeding styles result in significant differences in the Alpha diversity of fungi in the gut of yaks, while the gut microbiota of captive yaks was relatively conserved. In addition, significant differences appeared in the abundance of microorganisms in different taxa, phylum Verrucomicrobiota was significantly enriched in group NF while Firmicutes was higher in group NS. At the genus level, Akkermansia, Paenibacillus, Roseburia, Dorea, UCG_012, Anaerovorax and Marvinbryantia were enriched in group NF while Desemzia, Olsenella, Kocuria, Ornithinimicrobium and Parvibacter were higher in group NS (P<0.05 or P<0.01). There was a significant difference in the function of gut microbiota between the two groups. The observed variations are likely influenced by differences in feeding methods and environmental conditions both inside and outside the pen. The findings of this investigation offer prospective insights into enhancing the yak breeding and expansion of the yak industry.

Correction: Current overview on the genetic basis of key genes involved in soybean domestication.

[This corrects the article DOI: 10.1007/s42994-022-00074-5.].

Microbiome analysis reveals alteration in water microbial communities due to livestock activities.

The Baihe River, a tributary of the Yellow River located in the Ngawa Tibetan and Qiang Autonomous Prefecture in Northern Sichuan, is surrounded by natural resources suitable for animal development. However, the impact of livestock activities water microbiome in this area remains unexplored. This study collected water samples from areas with captive yaks and sheep (NS and YS) and compared them with water samples from Hongyuan Baihe River. Through amplicon sequencing, we investigated the impact of livestock activities on aquatic microorganisms. Diversity analysis, significance analysis, and microbial phenotype prediction indicated a significant decrease in microbial community diversity and function in the NS and YS groups. Pathogenic microorganisms such as Bacteroidales and Thelebolaceae and antibiotic-resistant bacteria genes such as Flavobacteriales and Burkholderiaceae were significantly higher in livestock breeding areas. Additionally, bacteria adapted to acidification, hypoxia, and eutrophication (e.g., Acidobacteria, Flavobacteriales, Deltaproteobacteria, Rhodobacterales) were more abundant in these areas. Our results demonstrate that livestock activities significantly alter the structure and function of microbial communities in surrounding water bodies, deteriorating water quality.

Subfunctionalisation and self-repression of duplicated E1 homologues finetunes soybean flowering and adaptation.

Soybean is a photoperiod-sensitive staple crop. Its photoperiodic flowering has major consequences for latitudinal adaptation and grain yield. Here, we identify and characterise a flowering locus named Time of flower 4b (Tof4b), which encodes E1-Like b (E1Lb), a homologue of the key soybean floral repressor E1. Tof4b protein physically associates with the promoters of two FLOWERING LOCUS T (FT) genes to repress their transcription and delay flowering to impart soybean adaptation to high latitudes. Three E1 homologues undergo subfunctionalisation and show differential subcellular localisation. Moreover, they all possess self-repression capability and each suppresses the two homologous counterparts. Subfunctionalisation and the transcriptional regulation of E1 genes collectively finetune flowering time and high-latitude adaptation in soybean. We propose a model for the functional fate of the three E1 genes after the soybean whole-genome duplication events, refine the molecular mechanisms underlying high-latitude adaption, and provide a potential molecular-breeding resource.

Obstructive Sleep Apnea Syndrome Exacerbates NASH Progression via Selective Autophagy-Mediated Eepd1 Degradation.

Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non-alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH-exposed mice, which deviates from human responses. To address this issue, a pair-feeding investigation with CIH-exposed and normoxia-exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome-wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver-specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH-induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH-mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH-mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS.

Soybean hypocotyl elongation is regulated by a MYB33-SWEET11/21-GA2ox8c module involving long-distance sucrose transport.

The length of hypocotyl affects the height of soybean and lodging resistance, thus determining the final grain yield. However, research on soybean hypocotyl length is scarce, and the regulatory mechanisms are not fully understood. Here, we identified a module controlling the transport of sucrose, where sucrose acts as a messenger moved from cotyledon to hypocotyl, regulating hypocotyl elongation. This module comprises four key genes, namely MYB33, SWEET11, SWEET21 and GA2ox8c in soybean. In cotyledon, MYB33 is responsive to sucrose and promotes the expression of SWEET11 and SWEET21, thereby facilitating sucrose transport from the cotyledon to the hypocotyl. Subsequently, sucrose transported from the cotyledon up-regulates the expression of GA2ox8c in the hypocotyl, which ultimately affects the length of the hypocotyl. During the domestication and improvement of soybean, an allele of MYB33 with enhanced abilities to promote SWEET11 and SWEET21 has gradually become enriched in landraces and cultivated varieties, SWEET11 and SWEET21 exhibit high conservation and have undergone a strong purified selection and GA2ox8c is under a strong artificial selection. Our findings identify a new molecular pathway in controlling soybean hypocotyl elongation and provide new insights into the molecular mechanism of sugar transport in soybean.

Similar neurotoxin expression profiles of traditional Chinese scorpion medicine material between juvenile and adult Mesobuthus martensii scorpions revealed by multiple strategic proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: The Mesobuthus martensii scorpions, called as "Quanxie", are known Chinese medicinal material base on the "Combat poison with poison" strategy for more than one thousand years, and still widely used to treat various diseases according to the Pharmacopoeia of the People's Republic of China nowadays. AIM OF STUDY: The study aims to investigate the similarity of scorpion neurotoxins at the protein level between the juvenile and adult Mesobuthus martensii scorpions as Chinese medicine materials. MATERIALS AND METHODS: The second-, third- and fourth-instar, and adult Mesobuthus martensii scorpions were collected for the characterization of neurotoxin expression through multiple strategic proteomics, including undigested scorpion venom, endopeptidase-digested, and undigested scorpion telson extract for the sample analysis. RESULTS: Based on the known 107 scorpion neurotoxins from the genomic and transcriptomic analysis of adult Mesobuthus martensii scorpions, the multiple strategic proteomics first revealed that neurotoxins exhibited more stability in telson extract than secreted venom. In the reported transcripts of scorpion neurotoxins, approximately 53%, 56%, 66% and 78% of neurotoxins were detected through undigested scorpion venom, the endopeptidase Arg-C-, Lys-C-digested telson extract, and undigested telson extract strategies, respectively. Nearly 79% of scorpion neurotoxins detected in third-instar Mesobuthus martensii scorpions represent the largest number of scorpion neurotoxins from proteomic analysis to date. Moreover, a total of 84% of scorpion neurotoxins were successfully identified at the protein level, and similar neurotoxin expression profiles in second-, third- and fourth-instar, and adult Mesobuthus martensii scorpions were first revealed by the multiple strategic proteomics. CONCLUSION: These findings for the first time demonstrate the similar neurotoxin expression profiles between the juvenile and adult Mesobuthus martensii scorpions as Chinese medicinal material, which would serve as a paradigm for further toxin analysis from different venomous animals.

Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis.

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor ß (IR-ß) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-ß phosphorylation, ultimately resulting in IR-ß inactivation. This inactivation of IR-ß suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

A novel non-invasive embryo evaluation method (NICS-Timelapse) with enhanced predictive precision and clinical impact.

The selection of the finest possible embryo in in-vitro fertilization (IVF) was crucial and revolutionary, particularly when just one embryo is transplanted to lessen the possibility of multiple pregnancies. However, practical usefulness of currently used methodologies may be constrained. Here, we established a novel non-invasive embryo evaluation method that combines non-invasive chromosomal screening (NICS) and Timelapse system along with artificial intelligence algorithms. With an area under the curve (AUC) of 0.94 and an accuracy of 0.88, the NICS-Timelapse model was able to predict blastocyst euploidy. The performance of the model was further evaluated using 75 patients in various clinical settings. The clinical pregnancy and live birth rates of embryos predicted by the NICS-Timelapse model, showing that embryos with higher euploid probabilities were associated with higher clinical pregnancy and live birth rates. These results demonstrated the NICS-Timelapse model's significantly wider application in clinical IVF due to its excellent accuracy and noninvasiveness.

Clinical outcomes of single blastocyst transfer with machine learning guided noninvasive chromosome screening grading system in infertile patients.

BACKGROUND: Prospective observational studies have demonstrated that the machine learning (ML) -guided noninvasive chromosome screening (NICS) grading system, which we called the noninvasive chromosome screening-artificial intelligence (NICS-AI) grading system, can be used embryo selection. The current prospective interventional clinical study was conducted to investigate whether this NICS-AI grading system can be used as a powerful tool for embryo selection. METHODS: Patients who visited our centre between October 2018 and December 2021 were recruited. Grade A and B embryos with a high probability of euploidy were transferred in the NICS group. The patients in the control group selected the embryos according to the traditional morphological grading. Finally, 90 patients in the NICS group and 161 patients in the control group were compared statistically for their clinical outcomes. RESULTS: In the NICS group, the clinical pregnancy rate (70.0% vs. 54.0%, p < 0.001), the ongoing pregnancy rate (58.9% vs. 44.7%, p = 0.001), and the live birth rate (56.7% vs. 42.9%, p = 0.001) were significantly higher than those of the control group. When the female was ≥ 35 years old, the clinical pregnancy rate (67.7% vs. 32.1%, p < 0.001), ongoing pregnancy rate (56.5% vs. 25.0%, p = 0.001), and live birth rate (54.8% vs. 25.0%, p = 0.001) in the NICS group were significantly higher than those of the control group. Regardless of whether the patients had a previous record of early spontaneous abortion or not, the live birth rate of the NICS group was higher than that of the control group (61.0% vs. 46.9%; 57.9% vs. 34.8%; 33.3% vs. 0%) but the differences were not statistically significant. CONCLUSIONS: NICS-AI was able to improve embryo utilisation rate, and the live birth rate, especially for those ≥ 35 years old, with transfer of Grade A embryos being preferred, followed by Grade B embryos. NICS-AI can be used as an effective tool for embryo selection in the future.

Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia.

BACKGROUND: There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS: We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS: MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10-5) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10-5)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10-94), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10-5), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10-6)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10-13; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10-09)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10-36) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10-5)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10-07; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10-07)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10-06) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10-05) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS: Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation.