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Background A possible relationship between periodontitis and Alzheimer’s disease (AD) has been reported. However, there is limited information on the association between the Porphyromonas gingivalis ( P. gingivalis ) periodontal infection and the pathological features of AD. The hypothesis that P. gingivalis periodontal infection may cause cognitive impairment via age-dependent neuroinflammation was tested. Results Thirty 4-week-old (young) female C57BL/6 J mice were randomly divided into two groups, the control group and the experimental group. Thirty 12-month-old (middle-aged) were grouped as above. The mouth of the mice in the experimental group was infected with P. gingivalis . Morris water maze(MWM) was performed to assess the learning and memory ability of mice after 6 weeks. Moreover, the expression levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the mice brain tissues were determined by Quantitative real-time polymerase chain reaction (qRT-PCR), Enzyme Linked Immunosorbent Assay(ELISA) and immunohistochemistry. Our results showed that the learning and memory abilities of the middle-aged P. gingivalis infected mice were impaired. Moreover, the expression levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the brain tissues of the middle-aged P. gingivalis infected mice were increased. Conclusions These results suggest that P. gingivalis periodontal infection may cause cognitive impairment via the release of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the brain tissues of middle-aged mice.

Microvesicles (MVs) are membrane vesicles secreted by cells and are present in the saliva of healthy individuals. It has various functions and has been reported to be a biomarker for malignant tumors. The changes in saliva levels of MVs associated with disease(s) is unclear. This study aimed to determine the proportion of salivary apoptotic MVs and their association with oral ulcer(s) in patients with non-healing oral ulcer(s) and reported oral cancer. Saliva (5 mL) was collected from patients with non-healing oral ulcer(s) and reported oral cancer (at the time of saliva collection, the participant have an oral ulcer(s) in the oral cavity and have an oral cancer lesion; n  = 73) and healthy volunteers with oral ulcer(s) ( n  = 62). A standard differential centrifugation protocol was used for the purification of MVs. Dynamic light scattering and transmission electron microscopy were used to characterize MVs. Flow cytometry was used to quantify salivary apoptotic MVs. Immunocytochemistry was performed according to a standard protocol. None of patients with oral cancer has smoking and drinking habit. The majority of saliva samples derived from patients with non-healing oral ulcer(s) and reported oral cancer were more positive for the fluorescent dye carboxyfluorescein succinimidyl ester than those of healthy volunteers with oral ulcer(s). Salivary fluid obtained from patients had membrane-limited vesicles that were round and/or slightly elongated in shape, with diameters of 100–1,000 nm. The number of salivary apoptotic MVs was higher in patients with non-healing oral ulcer(s) than in those derived from healthy volunteers with oral ulcer(s) ( p  < 0.001). There was an association between salivary apoptotic MVs in patients with non-healing oral ulcer(s) and the degree or severity of oral ulcers ( p  < 0.001). Levels of salivary apoptotic MVs are elevated in patients with non-healing oral ulcer(s) and confirmed oral cancer. Elevated levels of salivary apoptotic MVs are associated with clinicopathological data of patients with oral cancer. Evidence level: IV. Technical efficacy: stage 3.

Seed weight is a key component of crop yield. However, molecular mechanisms underlying soybean seed weight variation remain largely elusive. Here, we identify a major seed weight determining gene Glycine max SMALL SEED 6 ( GmSMS6 ) that encodes a 14-3-3 protein. GmSMS6 physically and genetically interacts with the transcription factor GmbZIP151 and the RING-type E3 ligase GmUBQ1. GmSMS6 acts as a regulatory hub switch that coordinates the transcriptional activation activity and GmUBQ1-mediated stability of GmbZIP151, primarily repressing cellular expansion of soybean cotyledons. Knocking out GmSMS6 increases seed weight and protein content but decreases oil accumulation in multiple soybean genetic backgrounds. A loss-of-function allele of GmSMS6 is absent in available soybean resources, while the weakly expressed haplotype associated with heavy seed weight has undergone selection in G. max . These results provide insights into mechanisms underlying soybean domestication and highlight the importance of gene loss for improving crop yield and quality. Molecular mechanisms determining soybean seed weights remain largely elusive. Here, the authors identify a 14-3-3 protein encoding gene GmSMS6 negatively regulates soybean seed weight and size via the possible interactions with the transcription factor GmbZIP151 and the RING-type E3 ligase GmUBQ1.

D-type cyclins (hereafter, cyclin D) are central regulators orchestrating G1/S cell cycle transition. Accordingly, aberrant expression of cyclin D is strongly correlated with proliferation-related diseases such as cancer. However, the mechanisms regulating cyclin D turnover are incompletely elucidated. Here we identify FBXO32, namely atrogin-1, as the E3 ubiquitin ligase that targets all three cyclin D for ubiquitination and stabilization. Specifically, FBXO32 catalyzes the lysine (Lys/K)27-linked polyubiquitination of cyclin D1 at the K58 site and subsequent stabilization. Moreover, GSK-3β inactivation-mediated dephosphorylation of cyclin D1 facilitates its interaction with FBXO32 and subsequent ubiquitination. Furthermore, FBXO32 exhibits tumor-promoting effect in mouse models and increased FBXO32 is associated with poor prognosis of cancer patients. Additionally, disrupting the FBXO32-cyclin D axis enhances the tumor-killing effect of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib. Collectively, these findings reveal that FBXO32 enhances the protein stability of cyclin D via K27-linked ubiquitination, and contributes to cancer progression and the limited response of cancer cells to CDK4/6 inhibitors. How D-type cyclins become dysregulated in cancer remains to be understood. Here, the authors identify that F-box protein FBXO32 catalyzes the K27-linked polyubiquitination and subsequent stabilization of D-type cyclins, contributing to cancer progression in both liver and pancreatic tumor models.

Astronauts consistently exhibit slower movements in microgravity, even during tasks requiring rapid responses. The sensorimotor mechanisms underlying this general slowing remain debated. Two hypotheses have been proposed: either the sensorimotor system adopts a conservative control strategy for safety and postural stability, or the system underestimates body mass due to reduced inputs from proprioceptive receptors. To dissociate these opinions, we studied 12 taikonauts aboard the China Space Station performing a classical hand-reaching task. Compared to their pre-flight performance and to an age-matched control group, participants showed increased movement durations and altered kinematic profiles in microgravity. Model-based analyses of motor control parameters revealed that these changes stemmed from reduced initial force generation in the feedforward control phase followed by compensatory feedback-based corrections. These findings provide support for the body mass underestimation hypothesis while being inconsistent with the strategic slowing hypothesis. Importantly, the sensory estimate of bodily property in microgravity is biased but immune from sensorimotor adaptation, calling for an extension of existing theories of motor learning.

Receptor-like proteins (RLPs) are crucial pattern-recognition receptors on the surface of plant cells, which are involved in almost all processes of the plant life cycle. Recently, the evolution of high-throughput sequencing technology has strengthened the appraisal and identification of increasing numbers of RLPs and has primarily improved our understanding of the roles of RLPs in various biological processes. Here, we review the classification and evolutionary characteristics of RLPs and their regulatory roles in pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). In particular, we summarize the ligands recognized by RLPs, their co-receptors, and downstream signalling cascades mediated by RLPs. To summarize, this review offers beneficial guidance for researchers in at-a-glance comprehension of the function of RLPs. It also puts forward the prospect of mining broad-spectrum candidate genes in light of the research on the disease resistance mechanism of RLPs and current challenges in disease resistance breeding.

Macrophages hold a critical position in maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated β-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-β release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p/TBP promotes β-TrCP/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.

The ATP-binding cassette (ABC) transporter family plays a critical role in plant growth, development, and disease resistance. However, the evolution and functional characteristics of the ABC gene family in Rosaceae species have not been fully studied. In this study, we performed the first whole-genome identification, as well as an evolutionary analysis and comparative analysis of ABC genes in Rosaceae plants. We identified 3037 ABC genes in 20 plant species, classifying them into eight subfamilies. Comparative analysis revealed significant variations in family size and expansion patterns among species, suggesting adaptive evolution. Tandem duplication (TD: where genes are duplicated in sequence) and whole-genome duplication (WGD: duplication of the entire genome) were identified as the primary drivers of ABC family expansion. In pears, gene pairs produced by WGD underwent purifying selection. Gene ontology (GO) enrichment analysis indicated the involvement of ABC proteins in transmembrane transport and signal transduction pathways. Under Valsa pyri infection, most ABC genes were upregulated in the early stages, highlighting the role of ABCG genes in pathogen response. A weighted gene co-expression network analysis (WGCNA) identified five key ABCG genes potentially involved in pathogen resistance regulation. Our findings provide insights into the evolutionary adaptability of the ABC gene family and their potential applications in plant disease defense.

Background Bone marrow mesenchymal stem cells (BMSCs) may be a promising target in the treatment of myocardial infarction (MI). However, the underlying molecular mechanisms of BMSC therapy remain unclear. Objective This study sought to evaluate the efficacy of direct intramyocardial transplantation of BMSCs in a mouse model of MI. Methods Mouse BMSCs were transfected with small interfering RNA or overexpression plasmid targeting TXNIP. The viability, proliferation, and apoptosis of BMSCs after hypoxia treatment were detected by MTT method, EdU analysis, and flow cytometry, respectively. A mouse model of MI was constructed, after which BSMCs were injected intramyocardially immediately. Cardiac ultrasound, HE staining, TUNEL staining and ELISA, IHC analysis, and Western blot were adopted to evaluate the effects of BSMC therapy on cardiac function, myocardial inflammation, and fibrosis in mice. Results In vitro experiments reported that ablating TXNIP increased viability and inhibited apoptosis of hypoxia-treated BMSCs while overexpressing TXNIP did the opposite. In vivo results stated that BSMCs improved cardiac function, myocardial inflammation, and fibrosis after MI, which was further improved by silencing TXNIP but reversed by overexpressing TXNIP. Meanwhile, in vivo cell tracking experiments showed that the retained BMSCs in the myocardium decreased after transplantation, and TXNIP depletion promoted the survival of BMSCs in MI mice, whereas TXNIP overexpression did the opposite. Conclusion In conclusion, BMSC transplantation improves cardiac function, myocardial inflammation, and fibrosis after MI by regulating the TXNIP/NLRP3 pathway.

Rhythmical oscillations of neural populations can reflect working memory performance. However, whether neuronal oscillations of the cerebral cortex change in extreme environments, especially in a space station, remains unclear. Here, we recorded electroencephalography (EEG) signals when volunteers and astronauts were executing a memory task in extreme working conditions. Our experiments showed that two extreme conditions affect neuronal oscillations of the cerebral cortex and manifest in different ways. Lengthy periods of mental work impairs the gating mechanism formed by theta-gamma phase-amplitude coupling of two cortical areas, and sleep deprivation disrupts synaptic homeostasis, as reflected by the substantial increase in theta wave activity in the cortical frontal-central area. In addition, we excluded the possibility that nutritional supply or psychological situations caused decoupled theta-gamma phase-amplitude coupling or an imbalance in theta wave activity increase. Therefore, we speculate that the decoupled theta-gamma phase-amplitude coupling detected in astronauts results from their lengthy periods of mental work in the China Space Station. Furthermore, comparing preflight and inflight experiments, we find that long-term spaceflight and other hazards in the space station could worsen this decoupling evolution. This particular neuronal oscillation mechanism in the cerebral cortex could guide countermeasures for the inadaptability of humans working in spaceflight. A detailed analysis of EEG data from astronauts and other participants under extreme conditions provides insight into the neural dynamics associated with heavy mental workloads, including theta-gamma phase amplitude decoupling.