Three amphioxus reference genomes reveal gene and chromosome evolution of chordates.

The slow-evolving invertebrate amphioxus has an irreplaceable role in advancing our understanding of the vertebrate origin and innovations. Here we resolve the nearly complete chromosomal genomes of three amphioxus species, one of which best recapitulates the 17 chordate ancestor linkage groups. We reconstruct the fusions, retention, or rearrangements between descendants of whole-genome duplications, which gave rise to the extant microchromosomes likely existed in the vertebrate ancestor. Similar to vertebrates, the amphioxus genome gradually establishes its three-dimensional chromatin architecture at the onset of zygotic activation and forms two topologically associated domains at the Hox gene cluster. We find that all three amphioxus species have ZW sex chromosomes with little sequence differentiation, and their putative sex-determining regions are nonhomologous to each other. Our results illuminate the unappreciated interspecific diversity and developmental dynamics of amphioxus genomes and provide high-quality references for understanding the mechanisms of chordate functional genome evolution.

Screening of Intermetallic Compounds Based on Intermediate Adsorption Equilibrium for Electrocatalytic Nitrate Reduction to Ammonia.

Electrocatalytic nitrate (NO3-) reduction reaction (NO3RR) holds great potential for the conversion of NO3- contaminants into valuable NH3 in a sustainable method. Unfortunately, the nonequilibrium adsorption of intermediates and sluggish multielectron transfer have detrimental impacts on the electrocatalytic performance of the NO3RR, posing obstacles to its practical application. Herein, we initially screen the adsorption energies of three key intermediates, i.e., *NO3, *NO, and *H2O, along with the d-band centers on 21 types of transition metal (IIIV and IB)-Sb/Bi-based intermetallic compounds (IMCs) as electrocatalysts. The results reveal that hexagonal CoSb IMCs possess the optimal adsorption equilibrium for key intermediates and exhibit outstanding electrocatalytic NO3RR performance with a Faradaic efficiency of 96.3%, a NH3 selectivity of 89.1%, and excellent stability, surpassing the majority of recently reported NO3RR electrocatalysts. Moreover, the integration of CoSb IMCs/C into a novel Zn-NO3- battery results in a high power density of 11.88 mW cm-2.

Heterophase Intermetallic Compounds for Electrocatalytic Hydrogen Production at Industrial-Scale Current Densities.

Heterophase nanomaterials have sparked significant research interest in catalysis due to their distinctive properties arising from synergistic effects of different components and the formed phase boundary. However, challenges persist in the controlled synthesis of heterophase intermetallic compounds (IMCs), primarily due to the lattice mismatch of distinct crystal phases and the difficulty in achieving precise control of the phase transitions. Herein, orthorhombic/cubic Ru2Ge3/RuGe IMCs with engineered boundary architecture are synthesized and anchored on the reduced graphene oxide. The Ru2Ge3/RuGe IMCs exhibit excellent hydrogen evolution reaction (HER) performance with a high current density of 1000 mA cm-2 at a low overpotential of 135 mV. The presence of phase boundaries enhances charge transfer and improves the kinetics of water dissociation while optimizing the processes of hydrogen adsorption/desorption, thus boosting the HER performance. Moreover, an anion exchange membrane electrolyzer is constructed using Ru2Ge3/RuGe as the cathode electrocatalyst, which achieves a current density of 1000 mA cm-2 at a low voltage of 1.73 V, and the activity remains virtually undiminished over 500 h.

Alginate oligosaccharides enhance gut microbiota and intestinal barrier function, alleviating host damage induced by deoxynivalenol in mice.

BACKGROUND: Alginate oligosaccharides (AOS) exhibits notable effects in terms of anti-inflammatory, antibacterial, and antioxidant properties. Deoxynivalenol (DON) has the potential to trigger intestinal inflammation by upregulating proinflammatory cytokines and apoptosis, thereby compromising the integrity of the intestinal barrier function and perturbing the balance of the gut microbiota. OBJECTIVES: We assessed the impact of AOS on mitigating DON-induced intestinal damage and systemic inflammation in mice. METHODS: After a one-week acclimatization period, the mice were divided into four groups. For three weeks, the AOS and AOS + DON groups were gavaged daily with 200 µl of AOS (200 mg/kg body weight (BW)), while the CON and DON groups received an equivalent volume of sterile Phosphate Buffered Saline (PBS). Subsequently, for one week, the DON and AOS + DON groups received 100 µl of DON (4.8 mg/kg BW) daily, whereas the CON and AOS groups continued receiving PBS. RESULTS: After administering DON via gavage to mice, there was a significant decrease (P < 0.05) in body weights compared to the control (CON) group. Interestingly, AOS exhibited a tendency to mitigate this weight loss in the AOS + DON group. In the feces of mice treated with both AOS and DON, the concentration of DON significantly increased (P < 0.05) compared to the DON group alone. Histological analysis revealed that DON exposure caused increased intestinal damage, including shortened villi and eroded epithelial cells, which was ameliorated by pre-supplementation with AOS, alleviating harm to the intestinal barrier function. In both jejunum and colon tissues, DON exposure significantly reduced (P < 0.05) the expression of tight junction proteins (Claudin and Occludin in the colon) and the mucin protein Mucin 2 (MUC2), compared to the CON group. Prophylactic administration of AOS alleviated these reductions, thereby improving the expression levels of these key proteins. Additionally, AOS supplementation protected DON-exposed mice by increasing the abundance of probiotics such as Bifidobacterium, Faecalibaculum, and Romboutsia. These gut microbes are known to enhance (P < 0.05) anti-inflammatory responses and the production of short-chain fatty acids (SCFAs), including total SCFAs, acetate, and valerate, compared to the DON group. CONCLUSIONS: This study unveils AOS not only enhance gut microbiota and intestinal barrier function but also significantly mitigate DON-induced intestinal damage.

iSUMO-RsFPN: A predictor for identifying lysine SUMOylation sites based on multi-features and feature pyramid networks.

SUMOylation is a protein post-translational modification that plays an essential role in cellular functions. For predicting SUMO sites, numerous researchers have proposed advanced methods based on ordinary machine learning algorithms. These reported methods have shown excellent predictive performance, but there is room for improvement. In this study, we constructed a novel deep neural network Residual Pyramid Network (RsFPN), and developed an ensemble deep learning predictor called iSUMO-RsFPN. Initially, three feature extraction methods were employed to extract features from samples. Following this, weak classifiers were trained based on RsFPN for each feature type. Ultimately, the weak classifiers were integrated to construct the final classifier. Moreover, the predictor underwent systematically testing on an independent test dataset, where the results demonstrated a significant improvement over the existing state-of-the-art predictors. The code of iSUMO-RsFPN is free and available at https://github.com/454170054/iSUMO-RsFPN.

Lung-PNet: An Automated Deep Learning Model for the Diagnosis of Invasive Adenocarcinoma in Pure Ground-Glass Nodules on Chest CT.

BACKGROUND. Pure ground-glass nodules (pGGNs) on chest CT representing invasive adenocarcinoma (IAC) warrant lobectomy with lymph node resection. For pGGNs representing other entities, close follow-up or sublobar resection without node dissection may be appropriate. OBJECTIVE. The purpose of this study was to develop and validate an automated deep learning model for differentiation of pGGNs on chest CT representing IAC from those representing atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). METHODS. This retrospective study included 402 patients (283 women, 119 men; mean age, 53.2 years) with a total of 448 pGGNs on noncontrast chest CT that were resected from January 2019 to June 2022 and were histologically diagnosed as AAH (n = 29), AIS (n = 83), MIA (n = 235), or IAC (n = 101). Lung-PNet, a 3D deep learning model, was developed for automatic segmentation and classification (probability of IAC vs other entities) of pGGNs on CT. Nodules resected from January 2019 to December 2021 were randomly allocated to training (n = 327) and internal test (n = 82) sets. Nodules resected from January 2022 to June 2022 formed a holdout test set (n = 39). Segmentation performance was assessed with Dice coefficients with radiologists' manual segmentations as reference. Classification performance was assessed by ROC AUC and precision-recall AUC (PR AUC) and compared with that of four readers (three radiologists, one surgeon). The code used is publicly available (https://github.com/XiaodongZhang-PKUFH/Lung-PNet.git). RESULTS. In the holdout test set, Dice coefficients for segmentation of IACs and of other lesions were 0.860 and 0.838, and ROC AUC and PR AUC for classification as IAC were 0.911 and 0.842. At threshold probability of 50.0% or greater for prediction of IAC, Lung-PNet had sensitivity, specificity, accuracy, and F1 score of 50.0%, 92.0%, 76.9%, and 60.9% in the holdout test set. In the holdout test set, accuracy and F1 score (p values vs Lung-PNet) for individual readers were as follows: reader 1, 51.3% (p = .02) and 48.6% (p = .008); reader 2, 79.5% (p = .75) and 75.0% (p = .10); reader 3, 66.7% (p = .35) and 68.3% (p < .001); reader 4, 71.8% (p = .48) and 42.1% (p = .18). CONCLUSION. Lung-PNet had robust performance for segmenting and classifying (IAC vs other entities) pGGNs on chest CT. CLINICAL IMPACT. This automated deep learning tool may help guide selection of surgical strategies for pGGN management.

The potential mechanism of concentrated mannan-oligosaccharide promoting goldfish's (Carassius auratus Linnaeus) resistance to Ichthyophthirius multifiliis invasion.

Because of the low host specificity, Ichthyophthirius multifiliis (Ich) can widely cause white spot disease in aquatic animals, which is extremely difficult to treat. Prior research has demonstrated a considerable impact of concentrated mannan-oligosaccharide (cMOS) on the prevention of white spot disease in goldfish, but the specific mechanism is still unknown. In this study, transcriptome sequencing, histological analysis, immunofluorescence analysis, phagocytosis activity assay and qRT-PCR assay were used to systematically reveal the potential mechanism of cMOS in supporting the resistance of goldfish (Carrasius auratus) to Ich invasion. According to the transcriptome analysis, the gill tissue of goldfish receiving the cMOS diet showed greater expression of mannose-receptor (MRC) related genes, higher phagocytosis activity, up-regulated expression of phagocytosis-related genes and inflammatory-related genes compared with the control, indicating that cMOS can have an effect on phagocytosis and non-specific immunity of goldfish. After the Ich challenge, transcriptome analysis revealed that cMOS fed goldfish displayed a higher level of phagocytic response, whereas non-cMOS fed goldfish displayed a greater inflammatory reaction. Besides, after Ich infection, cMOS-fed goldfish displayed greater phagocytosis activity, a stronger MRC positive signal, higher expression of genes associated with phagocytosis (ABCB2, C3, MRC), and lower expression of genes associated with inflammation (IL-1ß, IL-17, IL-8, TNF-α, NFKB). In conclusion, our experimental results suggest that cMOS may support phagocytosis by binding to MRC on the macrophage cell membrane and change the non-specific immunity of goldfish by stimulating cytokine expression. The results of this study provide new insights for the mechanism of cMOS on parasitic infection, and also suggest phagocytosis-related pathways may be potential targets for prevention of Ich infection.

Identification of (E)-1-((1H-indol-3-yl)methylene)-4-substitute-thiosemicarbazones as potential anti-hepatic fibrosis agents.

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.

Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene.

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-ß1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

COVID-19 in patients with myasthenia gravis: a single-center retrospective study in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been a great concern since 2019. Patients with myasthenia gravis (MG) may be at higher risk of COVID-19 and a more severe disease course. We examined the associations between COVID-19 and MG. METHODS: This single-center retrospective cohort study involved 134 patients who were diagnosed with MG from June 2020 to November 2022 and followed up until April 2023. They were divided into a COVID-19 group and non-COVID-19 group. Logistic regression analysis was used to detect factors potentially associating COVID-19 with MG. RESULTS: Of the 134 patients with MG, 108 (80.6%) had COVID-19. A higher number of comorbidities was significantly associated with an increased risk of COVID-19 (p = 0.040). A total of 103 patients (95.4%) had mild/moderate COVID-19 symptoms, and 4 patients (3.7%) were severe/critical symptoms (including 2 deaths). Higher age (p = 0.036), use of rituximab (p = 0.037), tumors other than thymoma (p = 0.031), Hashimoto's thyroiditis (p = 0.011), more comorbidities (p = 0.002), and a higher baseline MG activities of daily living (MG-ADL) score (p = 0.006) were risk factors for severe COVID-19 symptoms. The MG-ADL score increased by ≥ 2 points in 16 (15.7%) patients. Dry cough and/or expectoration (p = 0.011), use of oral corticosteroids (p = 0.033), and use of more than one kind of immunosuppressant (p = 0.017) were associated with the increase of the post-COVID-19 MG-ADL score. CONCLUSION: Most patients with MG have a mild course of COVID-19. However, patients with older age, many comorbidities, a high MG-ADL score, and use of a variety of immunosuppressants during COVID-19 may be more prone to severe symptoms.