Mingyang Du’s research while affiliated with Nanjing General Hospital and other places

Longer procedure time (PT) predicts worse prognosis after endovascular treatment (EVT) in acute vertebrobasilar artery occlusion (VBAO), but it remains unknown whether it is worth pursuing recanalization when the PT is obviously extended. Patients with acute VBAO who received EVT were retrospectively enrolled from 21 stroke centers in China from December 2015 to December 2018. Multivariable logistic analysis was performed to analyze the associations of PT with favorable outcome (defined as modified Rankin Scale score of 0 to 3) and mortality at 90 days. A total of 541 patients with median age of 64 years (IQR, 55–73) were included. The median baseline National institutes of Health stroke scale score was 23 (IQR, 14–28) and PT was 110 min (IQR, 74–156). The rate of favorable outcome was 36.5% in patients with PT 111–155 min (adjusted OR 0.51 [95% CI 0.28–0.92]) and 33.3% in patients with PT > 155 min (adjusted OR 0.52 [95% CI 0.29–0.93]) compared with 42.9% in patients with PT ≤ 75 min. Compared with the PT ≤ 75 min, PT of 111–155 min (adjusted OR 1.96 [95% CI 1.11–3.46]) and PT > 155 min (adjusted OR 2.10 [95% CI 1.21–3.66]) were associated with increased risks of mortality. Recanalization within four PT intervals were consistently associated with better outcomes compared with failure of recanalization (all P < 0.05). For acute VBAO patients treated with EVT, recanalization regardless of PT was associated with improved prognosis than failure of recanalization, supporting the continued pursuit of recanalization despite the PT being obviously extended. The findings need validation in randomized controlled trials. Graphical Abstract

Background The uric acid to high-density lipoprotein cholesterol ratio (UHR) is a novel marker of inflammation and metabolism. We aimed to explore the association of UHR with pneumonia after endovascular thrombectomy (EVT) in patients with vertebrobasilar artery occlusion (VBAO). Methods We retrospectively enrolled participants diagnosed with acute VBAO treated with EVT within 24 hours of estimated occlusion time from the multicenter PERSIST study. The primary outcome was pneumonia within 7 days after EVT according to the Pneumonia in Stroke Consensus Group recommendations. We utilized the restricted cubic spline curve to explore the dose–response relationship between UHR and pneumonia. We used multivariable logistic regression models to assess the association between UHR and the risk of pneumonia after EVT and verified the findings in subgroup analysis. Results Three hundred and seventy-eight patients were enrolled in this study, and 236 (62.4%) were diagnosed with pneumonia. In multivariable models, a higher UHR was associated with an increased risk of pneumonia after EVT (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01–1.10; P = 0.020; tertile 3 versus tertile 1: OR, 2.09; 95% CI, 1.15–3.82; P = 0.016). The dose–response relationship indicated that UHR was linearly associated with the risk of pneumonia (P = 0.888). The association between UHR and pneumonia remained significant in different subgroups. Conclusion This study demonstrated that a higher UHR was associated with an increased risk of pneumonia in VABO patients treated with EVT. Further studies were warranted to verify the prognostic values of UHR in pneumonia after EVT.

Clock genes regulate physiological and metabolic processes by responding to changes in environmental light and temperature, and genetic variations in these genes may facilitate environmental adaptation, offering opportunities for resilience to climate change. However, the genetic and molecular mechanisms remain unclear in marine organisms. In this study, we investigated the role of a key clock gene, the circadian locomotor output cycles kaput (Clock), in thermal adaptation using DNA affinity purification sequencing (DAP-Seq) and RNA interference (RNAi)-based transcriptome analysis. In cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata, Clock was subject to environmental selection and exhibited contrasting expression patterns. The transcriptome analysis revealed 2054 differentially expressed genes (DEGs) following the knockdown of the Clock expression, while DAP-Seq identified 150,807 genes regulated by Clock, including 5273 genes located in promoter regions. The combined analyses identified 201 overlapping genes between the two datasets, of which 98 were annotated in public databases. These 98 genes displayed distinct expression patterns in C. gigas and C. angulata under heat stress, which were potentially regulated by Clock, indicating its role in a molecular regulatory network that responds to heat stress. Notably, a heat-shock protein 70 family gene (Hsp12b) and a tripartite motif-containing protein (Trim3) were significantly upregulated in C. angulata but showed no significant changes in C. gigas, further highlighting their critical roles in thermal adaptation. This study preliminarily constructs a thermal regulatory network involving Clock, providing insights into the molecular mechanisms of clock genes in thermal adaptation.

Phenotypic plasticity plays an essential role in adaptive evolution. However, the molecular mechanisms of how genotype‐by‐environment interaction (G × E) effects shape phenotypic plasticity in marine organisms remain poorly understood. The crucial temperature‐responsive trait triacylglycerol (TAG) content and its major gene adipose triglyceride lipase ( Atgl ) expression have divergent plastic patterns in two congeneric oyster species ( Crassostrea gigas and Crassostrea angulata ) to adapt to relative‐cold/northern and relative‐warm/southern habitats, respectively. In this study, eight putative loci were identified in the Atgl promoter region ( cis ‐variations) between wild C. gigas and C. angulata that exhibited differential environmental responsiveness (G × E). The G and G × E effects of each locus were further dissected by measuring the Atgl gene expression of different genotypes in response to temperature changes at the cellular and organismal levels. Two transcription factors, non‐environmentally responsive non‐POU domain‐containing octamer‐binding protein ( Nono ) and environmentally responsive heterogeneous nuclear ribonucleoprotein K ( Hnrnpk ), were screened for binding to g.‐1804 (G locus) and g.‐1919 (G + G × E locus), respectively. The specificity of Nono binding to the C. angulata allele mediated the G effects of g.‐1804, and the lower environmental sensitivity of Hnrnpk in C. angulata mediated the G × E effects of g.‐1919, jointly regulating the trade‐offs between higher constitutive and lower plastic expression of Atgl gene expression in C. angulata . This study served as an experimental case to reveal how the genetic variations with G and (or) G × E effects propagate into the divergent pattern of plasticity in environmental adaptive traits, which provides new insights into predicting the adaptability of marine organisms to future climate changes.

Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it’s response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters’ major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-024-01923-0.

Cysteine-aspartic proteases (caspases) are critical drivers of apoptosis, exhibiting expansion and domain shuffling in mollusks. However, the functions and regulatory mechanisms of these caspases remain unclear. In this study, we identified a group of Caspase-3/6/7 in Bivalvia and Gastropoda with a long inter-subunit linker (IL) that inhibits cleavage activation. Within this region, we found that conserved phosphorylation at Thr260 in oysters, mediated by the PI3K-AKT pathway, suppresses heat-induced activation. This mechanism is involved in divergent temperature adaptation between two allopatric congeneric oyster species, the relatively cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. Our study elucidates the role of these effector caspase members and their long IL in bivalves, revealing that the PI3K-AKT pathway phosphorylates Thr260 on CgCASP3/6/7’s linker to inhibit heat-induced activation. These findings provide insights into the evolution and function of apoptotic regulatory mechanisms in bivalves.

Global warming drives adaptive evolution by influencing natural selection and exploiting temperature-related phenotypic plasticity. However, predicting how phenotypic plasticity will evolve under climate change remains a challenge, urging the need for understanding underlying genetic and molecular mechanisms. In this study, we focus on the expression plasticity divergence of heat shock protein 90 (Hsp90) which is heat responsive and exhibited strong selective sweep in the upstream noncoding region of two allopatric congeneric oyster species: cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. Functional characterization confirmed Hsp90 expression is an ideal proxy for thermotolerance. The expression divergence in constitutive and plastic expressions, represents adaption to the mean and variance of habitat temperature changes, respectively. By combining forward and reverse genetic approaches, four causative loci with G+G×E effects in the promoter region (cis-variations) of Hsp90 between C. gigas and C. angulata were identified. Moreover, the allele g.-2291G of the causative loci in C.angulata specifically binds to the positive transcription factor Purine Rich Element Binding Protein B (PURB), explaining the higher constitutive expression of Hsp90. Meanwhile the response of Purb to thermal stress affects the magnitude of plastic expression in C. angulata. This integrative study revealed that cis-variation interacts with trans-variation induced by environmental changes underlying the G×E effect, thereby mediating the divergence of plastic expression. Furthermore, we established a paradigm for studying genetic variants and their G×E effects at an unprecedented resolution at the single nucleotide level in non-model organisms. This study will deepen our understanding of the significant role of phenotypic plasticity in adaptive responses and promote predictions of adaptive potential in marine organisms under climate change.

Pyruvate kinase (PK), as a key rate-limiting enzyme in glycolysis, has been widely used to assess the stress tolerance and sensitivity of organisms. However, its phosphorylation regulatory mechanisms mainly focused on human cancer research, with no reports in marine organisms. In this study, we firstly reported a conserved PK Ser11 phosphorylation site in mollusks, which enhanced enzyme activity by promoting substrate binding, thereby regulating divergent thermal metabolism of two allopatric congeneric oyster species with differential habitat temperature. It was phosphorylated by ERK kinase, and regulated by the classical MAPK pathway. The MAPK/ERK-PK signaling cascade responded to increased environmental temperature and exhibited stronger activation pattern in the relatively thermotolerant species (Crassostrea angulata), indicating its involvement in shaping temperature adaptation. These findings highlight the presence of complex and unique phosphorylation-mediated signaling transduction mechanisms in marine organisms, and provide new insights into the evolution and function of the crosstalk between classical pathways.