Decoupling of strain- and intrastrain-level interactions of microbiomes in a sponge holobiont.

Holobionts are highly organized assemblages of eukaryotic hosts, cellular microbial symbionts, and viruses, whose interactions and evolution involve complex biological processes. It is largely unknown which specific determinants drive similarity or individuality in genetic diversity between holobionts. Here, we combine short- and long-read sequencing and DNA-proximity-linkage technologies to investigate intraspecific diversity of the microbiomes, including host-resolved viruses, in individuals of a model marine sponge. We find strong impacts of the sponge host and the cellular hosts of viruses on strain-level organization of the holobiont, whereas substantial overlap in nucleotide diversity between holobionts suggests frequent exchanges of microbial cells and viruses at intrastrain level in the local sponge population. Immune-evasive arms races likely restricted virus-host co-evolution at the intrastrain level, generated holobiont-specific genome variations, and linked virus-host genetics through recombination. Our work shows that a decoupling of strain- and intrastrain-level interactions is a key factor in the genetic diversification of holobionts.

Targeting cell death in NAFLD: mechanisms and targeted therapies.

Nonalcoholic fatty liver disease (NAFLD) is a group of chronic liver disease which ranges from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and is characterized by lipid accumulation, inflammation activation, fibrosis, and cell death. To date, a number of preclinical studies or clinical trials associated with therapies targeting fatty acid metabolism, inflammatory factors and liver fibrosis are performed to develop effective drugs for NAFLD/NASH. However, few therapies are cell death signaling-targeted even though the various cell death modes are present throughout the progression of NAFLD/NASH. Here we summarize the four types of cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis in the NAFLD and the underlying molecular mechanisms by which the pathogenic factors such as free fatty acid and LPS induce cell death in the pathogenesis of NAFLD. In addition, we also review the effects of cell death-targeted therapies on NAFLD. In summary, our review provides comprehensive insight into the roles of various cell death modes in the progression of NAFLD, which we hope will open new avenues for therapeutic intervention.

Observations on the efficacy of edaravone dexborneol in preventing post-stroke depression and its inflammatory mechanism: a prospective, randomized, control trial.

Objective: This study aimed to observe the effect of edaravone dexborneol (EDB) on the incidence of early post-stroke depression (PSD) and explore its inflammatory mechanisms. Methods: A prospective, randomized controlled study was conducted from January 2022 to June 2023, involving patients with acute ischemic stroke (AIS) at the Neurology Department of the Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine. The control group received routine treatment, while the experimental group received routine combined EDB treatment. The main outcome measures included PSD incidence, Patient Health Questionnaire (PHQ-9) and Hamilton Depression Scale (HAMD) scores on days 14 and 30, and inflammatory factor levels on day 14. Results: A total of 93 patients were included in the study, 51 in the experimental group and 42 in the control group. On day 14, the PSD incidence was 13.7% in the experimental group, lower than 31.0% in the control group (95%CI 0.127-0.996; p = 0.044). Compared to the control group, the experimental group showed significantly lower concentrations of pro-inflammatory cytokines IL-1ß (95%CI 3.353-5.184), IL-6 (95%CI 2.694-3.426), TNF-α (95%CI 4.985-12.196), IFN-γ (95%CI 0.163-0.451), MCP-1 (95%CI 0.335-0.787), IL-17A (95%CI 0.543-1.024), and IL-23p19 (95%CI 1.677-1.959) (all p < 0.001), and higher levels of anti-inflammatory cytokines IL-4 (95%CI -1.087 to -0.941), IL-10 (95%CI -6.125 to -1.662), and IL-13 (95%CI -6.078 to -2.953) (all p ≤ 0.001). On day 30, the PSD incidence in the experimental group was 15.7%, lower than 40.5% in the control group (95%CI 0.103-0.725; p = 0.007). Compared with the control group, the experimental group had lower PHQ-9 scores on day 14 (95%CI 0.034-1.577; p = 0.041) and day 30 (95%CI 0.018-1.573; p = 0.045), and also had lower HAMD scores on day 14 (95% CI 0.281-2.856; p = 0.018) and day 30 (95% CI 0.647-3.482; p = 0.005). Conclusion: EDB could reduce the incidence of early PSD, reduce pro-inflammatory cytokine levels, and elevate anti-inflammatory cytokine levels, which was possibly related to the anti-inflammatory mechanism of EDB. Clinical trial registration: http://www.chictr.org.cn/, identifier [ChiCTR2300067750].

Coronary artery segmentation in CCTA images based on multi-scale feature learning.

BACKGROUND: Coronary artery segmentation is a prerequisite in computer-aided diagnosis of Coronary Artery Disease (CAD). However, segmentation of coronary arteries in Coronary Computed Tomography Angiography (CCTA) images faces several challenges. The current segmentation approaches are unable to effectively address these challenges and existing problems such as the need for manual interaction or low segmentation accuracy. OBJECTIVE: A Multi-scale Feature Learning and Rectification (MFLR) network is proposed to tackle the challenges and achieve automatic and accurate segmentation of coronary arteries. METHODS: The MFLR network introduces a multi-scale feature extraction module in the encoder to effectively capture contextual information under different receptive fields. In the decoder, a feature correction and fusion module is proposed, which employs high-level features containing multi-scale information to correct and guide low-level features, achieving fusion between the two-level features to further improve segmentation performance. RESULTS: The MFLR network achieved the best performance on the dice similarity coefficient, Jaccard index, Recall, F1-score, and 95% Hausdorff distance, for both in-house and public datasets. CONCLUSION: Experimental results demonstrate the superiority and good generalization ability of the MFLR approach. This study contributes to the accurate diagnosis and treatment of CAD, and it also informs other segmentation applications in medicine.

Novel order-level lineage of ammonia-oxidizing archaea widespread in marine and terrestrial environments.

Ammonia-oxidizing archaea (AOA) are among the most ubiquitous and abundant archaea on Earth, widely distributed in marine, terrestrial, and geothermal ecosystems. However, the genomic diversity, biogeography, and evolutionary process of AOA populations in subsurface environments are vastly understudied compared to those in marine and soil systems. Here, we report a novel AOA order Candidatus (Ca.) Nitrosomirales which forms a sister lineage to the thermophilic Ca. Nitrosocaldales. Metagenomic and 16S rRNA gene-read mapping demonstrates the abundant presence of Nitrosomirales AOA in various groundwater environments and their widespread distribution across a range of geothermal, terrestrial, and marine habitats. Terrestrial Nitrosomirales AOA show the genetic capacity of using formate as a source of reductant and using nitrate as an alternative electron acceptor. Nitrosomirales AOA appear to have acquired key metabolic genes and operons from other mesophilic populations via horizontal gene transfer, including genes encoding urease, nitrite reductase, and V-type ATPase. The additional metabolic versatility conferred by acquired functions may have facilitated their radiation into a variety of subsurface, marine, and soil environments. We also provide evidence that each of the four AOA orders spans both marine and terrestrial habitats, which suggests a more complex evolutionary history for major AOA lineages than previously proposed. Together, these findings establish a robust phylogenomic framework of AOA and provide new insights into the ecology and adaptation of this globally abundant functional guild.

Gene inversion led to the emergence of brackish archaeal heterotrophs in the aftermath of the Cryogenian Snowball Earth.

Land-ocean interactions greatly impact the evolution of coastal life on earth. However, the ancient geological forces and genetic mechanisms that shaped evolutionary adaptations and allowed microorganisms to inhabit coastal brackish waters remain largely unexplored. In this study, we infer the evolutionary trajectory of the ubiquitous heterotrophic archaea Poseidoniales (Marine Group II archaea) presently occurring across global aquatic habitats. Our results show that their brackish subgroups had a single origination, dated to over 600 million years ago, through the inversion of the magnesium transport gene corA that conferred osmotic-stress tolerance. The subsequent loss and gain of corA were followed by genome-wide adjustment, characterized by a general two-step mode of selection in microbial speciation. The coastal family of Poseidoniales showed a rapid increase in the evolutionary rate during and in the aftermath of the Cryogenian Snowball Earth (∼700 million years ago), possibly in response to the enhanced phosphorus supply and the rise of algae. Our study highlights the close interplay between genetic changes and ecosystem evolution that boosted microbial diversification in the Neoproterozoic continental margins, where the Cambrian explosion of animals soon followed.

Association of coagulation markers with the severity of white matter hyperintensities in cerebral small vessel disease.

Background and purpose: This study aimed to explore the correlation and causal relationship between fibrinogen, D-dimer, and the severity of cerebral white matter hyperintensity (MMH). Methods: A retrospective analysis of 120 patients with cerebral small vessel disease (CSVD) confirmed by head MRI attending the Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine from August 2021 to February 2023 was performed. According to the Fazekas scale score, the patients were divided into 42 cases in the mild group, 44 cases in the moderate group, and 34 cases in the severe group. The levels of fibrinogen and D-dimer were compared among the three groups; the correlations between fibrinogen, D-dimer, and WMH severity were further analyzed; and independent risk factors for WMH severity were explored using the multivariate ordered logistic regression analysis. Furthermore, a two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of fibrinogen and D-dimer on WMH. Results: As the severity of WMH increased, the levels of D-dimer and fibrinogen also gradually increased, and the results showed a positive correlational association, with significant differences within the groups (all p < 0.05); the multivariate ordered logistic regression model showed that after adjusting for the relevant covariates, D-dimer (OR = 5.998, 95% CI 2.213-16.252, p < 0.001) and fibrinogen (OR = 9.074, 95% CI 4.054-20.311, p < 0.001) remained independent risk factors for the severity of WMH. In the MR study, the random-effect inverse variance weighted (IVW) model showed that increased levels of genetically predicted D-dimer (OR, 1.01; 95% confidence interval 0.95-1.06; p = 0.81) and fibrinogen (OR, 1.91; 95% confidence interval 0.97-3.78; p = 0.06) were not associated with increased risk of WMH. The authors did not obtain strong evidence of a direct causal relationship between D-dimer, fibrinogen, and WMH. Conclusion: In this retrospective-based study, the authors found possible associations between D-dimer, fibrinogen, and WMH, but there was no obvious causal evidence. Further efforts are still needed to investigate the pathophysiology between D-dimer, fibrinogen, and WMH.

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs.

Colorectal cancer is a common malignant tumor. A major factor in the high mortality rate of colorectal cancer is the emergence of multidrug resistance (MDR). Overexpression of the ABCG2 gene in cancer cells directly leads to MDR. Finding new inhibitors of ABCG2 may be an effective way to overcome drug resistance. We found that the compound GSK2606414 enhanced the sensitivity of the ABCG2 substrate to the chemotherapeutic drugs mitoxantrone and doxorubicin in ABCG2-overexpressing multidrug-resistant colorectal cancer cells by increasing their intracellular accumulation without affecting the protein expression of ABCG2. Molecular docking experiments predicted that GSK2606414 could stably bind in the drug-binding pocket of ABCG2. In conclusion, GSK2606414 can sensitize ABCG2-overexpressed multidrug-resistant colorectal cancer cells to chemotherapy drugs and can be used as a potential inhibitor of ABCG2.

BDH1-mediated ßOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway.

A ketogenic diet (KD) and ß-hydroxybutyrate (ßOHB) have been widely reported as effective therapies for metabolic diseases. ß-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated ßOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or ßOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated ßOHB metabolism activates NRF2 by enhancing the metabolic flux of ßOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either ßOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.

Multi-constraint point set registration with redundant point removal for the registration of coronary arteries.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death worldwide. The registration of the coronary artery at different phases can help radiologists explore the motion patterns of the coronary artery and assist in the diagnosis of CAD. However, there is no automatic and easy-to-execute method to solve the missing data problem that occurs at the endpoints of the coronary artery tree. This paper proposed a non-rigid multi-constraint point set registration with redundant point removal (MPSR-RPR) algorithm to tackle this challenge. METHODS: Firstly, the MPSR-RPR algorithm roughly registered two coronary artery point sets with the pre-set smoothness regularization parameter and Gaussian filter width value. The moving coherent, local feature, and the corresponding relationship between bifurcation point pairs were exploited as the constraints. Next, the spatial geometry information of the coronary artery was utilized to automatically recognize the vessel endpoints and to delete the redundant points of the coronary artery. Finally, the algorithm continued carrying out the multi-constraint registration with another group of the pre-set parameters to improve the alignment performance. RESULTS: The experimental results demonstrated that the MPSR-RPR algorithm achieved a significantly lower mean value of the modified Hausdorff distance (MHD) compared to the other state-of-the-art methods for addressing the serious missing data in the left and right coronary arteries. CONCLUSION: This study demonstrated the effectiveness of the proposed algorithm in aligning coronary arteries, providing significant value in assisting in the diagnosis of coronary artery and myocardial lesions.