Human odor perception depends on a repertoire of roughly 400 odorant receptors (ORs), a subfamily of G protein-coupled receptors (GPCRs) that detect volatile molecules through combinatorial activation. Intriguingly, even structurally similar odorants can evoke distinct perceptual qualities by selectively activating different ORs-a specificity that remains poorly understood and often eludes conventional docking-based predictions. Here, we explore the molecular basis of this selectivity using two structurally similar flavorants, furaneol and sotolone, which specifically activate OR5M3 and OR8D1, respectively. While docking and free energy analyses provided initial insights, they could not fully explain the observed selectivity. Therefore, extensive MD and metadynamics simulations were performed, revealing that odorant ligands modulate TM6 dynamics in ORs, whose motion may serve as a key gating event coupling extracellular closure for ligand binding with intracellular opening for G-protein engagement. In contrast, non-associated ligands could result in an outward displacement of the extracellular region of TM6, thereby promoting receptor inactivation through pocket opening and ligand release. Moreover, the simulations reveal that the negatively charged deprotonated state of both furaneol and sotolone drives the opening of the binding pockets in both OR5M3 and OR8D1, suggesting that these ORs are sensitive to ligand charge and protonation state. Together, these findings establish a molecular framework for predicting olfactory receptor ligand-binding modes in the early activation state and offer new insights into rational design in flavor chemistry and sensory neuroscience.

Alzheimer’s disease (AD) is a prevalent age-related neurodegenerative disorder caused by a multifactorial etiology, thus dietary intervention plays an important role in the prevention of AD at its early stage. Selenium (Se)-enriched green tea (Se-GT) exhibits benefits for reducing the risk of several diseases. However, few studies were reported on Se-GT in the intervention of AD and its associated mechanism. The current study was designed to investigate the Se-enriched green tea water extract (Se-TE) on the pathologies of triple transgenic AD mice and primary neurons, as well as its potential regulatory mechanism. Our results indicated that Se-TE supplement ameliorated learning and memory impairment of AD mice, and exerted neuroprotective effects, evidenced as by inhibiting β-amyloid generation via regulating the expression of insulin-degrading enzyme and proliferator-activated receptor γ reducing tau hyperphosphorylation via regulating glycogen synthase kinase 3β and protein phosphatase 2A, repairing neuronal injury and reducing neuronal apoptosis via inhibiting endoplasmic reticulum stress and oxidative stress. Our research findings illuminate the advantageous effects of Se-TE in both the prevention and alleviation of AD.

DDX3X, a DEAD-box RNA helicase, has been identified as a risk gene for autism spectrum disorder (ASD). To elucidate the role of DDX3X mutations in ASD pathogenesis, HT22 cell models and mouse models with Ddx3x knockdown specifically in the medial prefrontal cortex were established. Ddx3x knockdown in HT22 cells resulted in slower growth, while in mice, it induced autism-like behaviors. Proteomic analysis in cortex revealed that many down-regulated proteins were involved in synaptic plasticity. The differentially expressed proteins (DEPs) were associated with long-term potentiation, glutamatergic and GABAergic synapses, postsynaptic density, branched-chain amino acid degradation, and the oxytocin pathway. Integrating cellular and cortical omics studies revealed overlaps in the ubiquitin-proteasome system and the 'de novo' protein folding pathway. These pathways were inhibited in the cortex of the model mice. The expression of several important proteins was validated. Confocal microscopy and transmission electron microscopy demonstrated a significant reduction in dendritic spine density and postsynaptic density of mouse models. Electrophysiological experiments showed that the frequency of miniature excitatory postsynaptic currents was significantly reduced. These results suggest that DDX3X deficiency impairs synaptic function, thereby affecting neurodevelopment and social abilities. Abnormal synaptic plasticity may contribute to the pathogenesis of ASD with DDX3X gene mutations.

Euglena gracilis (E. gracilis) is a unicellular eukaryotic photosynthetic protist without cell wall. As a model organism, it has been extensively studied in endosymbiosis, chloroplast development, environmental bioremediation, and high-value product synthesis. Heavy metal pollution, such as cadmium (Cd) stress, is prevalent and induces high levels of reactive oxygen species (ROS) in microalgae, leading to oxidative stress, reduced photosynthetic efficiency, and inhibited growth. This study explored the application of gamma-aminobutyric acid (GABA), a plant hormone-like substance, to enhance heavy metal tolerance in E. gracilis under Cd stress, aiming to increase the accumulation of high-value by-products such as lipids. As previously studied, our findings also showed that Cd stress significantly inhibited E. gracilis growth and pigment accumulation. However, it is worth noting that our results showed that exogenous GABA addition improved cell counts, lipid content, protein content and pigment content. GABA also significantly increased glutathione (GSH) content. Notably, Metabolomic analysis revealed that Cd stress shifted E. gracilis energy storage from carbohydrates to lipids and proteins, and exogenous GABA addition further enhanced this trend. These results suggest that GABA play a significant role in increasing lipid accumulation and enhancing Cd tolerance in E. gracilis, providing an economical and eco-friendly strategy for lipid production and Cd adsorption.

Alzheimer's disease is a progressive neurodegenerative disorder with no cure, making preventive strategies crucial. Dietary interventions, particularly the Mediterranean (MeDi) and MIND diets, have been associated with reduced cognitive decline, but their long-term comparative effects remain underexplored. To compare the long-term neuroprotective effects of the Mediterranean and MIND diets in healthy individuals and AD patients, assess dietary adherence and cognitive function relationships, and investigate the impact of micronutrients on cognitive biomarkers. A 5-year prospective cohort study was conducted with 1500 participants (750 healthy controls, 750 AD patients). Dietary adherence was assessed using validated dietary screening tools. Cognitive function was evaluated via MMSE and MoCA scores, while biomarkers (amyloid-beta, tau, NfL, CRP, IL-6, TNF-α, polyphenols, omega-3, and B vitamins) were measured through blood and CSF samples. Machine learning techniques were utilized to analyze dietary patterns and predict cognitive trajectories. Higher adherence to both diets was associated with significantly better cognitive scores (p < 0.0001), lower amyloid-beta, tau, and NfL levels, and reduced inflammatory markers (CRP, IL-6, TNF-α). The MIND diet showed a slightly stronger association with cognitive protection than MeDi. Micronutrients such as polyphenols, omega-3, and B vitamins correlated with improved cognitive performance. Genetic analysis suggested that APOE-ε4 carriers may experience variable responses to dietary interventions. The Mediterranean and MIND diets provide significant neuroprotection against cognitive decline and AD progression. While both diets confer benefits, the MIND diet demonstrated a marginally greater impact on cognitive preservation. These findings underscore the importance of dietary interventions as non-pharmacological strategies for AD prevention and management. Further research is needed to optimize dietary recommendations based on genetic predisposition and metabolic factors.

Extracellular vesicles (EVs) are nanoscale particles with membrane structures secreted by cells, facilitating the transfer of proteins, lipids, small RNAs, lncRNAs, and DNAs. These vesicles have been extensively studied for their role in mediating cell-to-cell communication in mammalian systems and their potential applications in disease diagnosis and treatment. While extensively studied in mammalian systems, the functions of microalgal EVs, particularly their roles in environmental adaptation, remain underexplored. In this study, we identified EVs in four selected microalgal cultures, including Chlamydomonas, and we found EVs can transfer miRNAs and proteins between Chlamydomonas cells. Notably, miRNAs in EVs were selectively packaged and distinct from those in host cells, suggesting their role in stress signaling and cellular adaptation. Proteomic analyses identified stress-responsive proteins and potential biomarkers for nutrient depletion. These findings suggest that Chlamydomonas EVs play a significant role in nutrient sensing and information transfer between cells, especially under nutrient stress conditions. Our research highlights the critical role of EVs in nutrient sensing and intercellular communication in microalgae, offering insights into their adaptive strategies in dynamic aquatic ecosystems.

Blood-based biomarkers have become increasingly important for Alzheimer's disease (AD) diagnosis. However, due to individual variations, diagnostic accuracy using a single blood biomarker remains low, making it challenging to implement in large-scale AD screening efforts. Herein, we developed a multiplex fluorescent sensing platform for simultaneously measuring Aβ40, Aβ42, and P-tau181 in the blood, and constructed an artificial intelligence (AI) model. These three biomarkers were analyzed in 60 clinical samples: 15 healthy control, 15 subjective cognitive decline, 15 mild cognitive impairment, and 15 AD samples. The AI model based on these three biomarkers exhibited high predictive accuracy (91%), high positive predictive value (PPV) and low false rate (8.8%). The diagnostic accuracy and PPV of the AI model exceeded 90% for AD grading diagnosis in clinical samples. This study introduces a promising strategy for disease diagnosis and grading based on multi-biomarker analysis.

Despite advances in chemoradiotherapy and hematopoietic stem cell transplantation, the treatment of acute myeloid leukemia (AML) remains challenging due to significant side effects and poor prognosis. This study aimed to investigate the role of nuclear factor I-C (NFIC) in AML progression by evaluating whether NFIC exacerbates AML through the inhibition of SRY-box transcription factor 1 (SOX1) and activation of autophagy, thereby providing potential insights for clinical treatment. NFIC and SOX1 expression levels in AML and normal samples were analyzed using bioinformatics, ELISA, RT-qPCR, and western blotting, and the interaction between NFIC and SOX1 was assessed through RNA pull-down and RNA-binding protein immunoprecipitation assays. Moreover, CCK-8 assay, FITC/PI apoptosis detection, immunofluorescence staining, RT-qPCR, and western blotting were conducted to assess cell viability, apoptosis, and the expression of NFIC, SOX1, Bax, Bcl-2, LC3-I, LC3-II, p62, and Beclin-1 following gene transfection. NFIC expression was significantly upregulated in AML samples while SOX1 expression was downregulated compared to normal controls. High NFIC levels were associated with poor prognosis in AML patients, and it was found to regulate SOX1 expression in KG-1 and NB4 cells negatively. Silencing NFIC or overexpressing SOX1 resulted in reduced cell viability and autophagy, and increased apoptosis in KG-1 and NB4 cells. Importantly, NFIC knockdown did not affect apoptosis in bone marrow mononuclear cells. The adverse effects of NFIC overexpression were reversed by SOX1 overexpression, highlighting the interplay between these factors in AML. This study demonstrates that NFIC promotes AML progression by activating autophagy and suppressing apoptosis in KG-1 and NB4 cells by inhibiting SOX1, providing a potential basis for therapeutic strategies targeting NFIC and SOX1 in AML.

Microalgae are emerging as a key player in healthcare, functional foods, and sustainable biotech due to their capacity to produce bioactive compounds like β-glucans, omega-3 fatty acids, and antioxidants in an eco-friendly manner. This review comprehensively discusses the role of microalgae in healthcare and functional foods, focusing particularly on β-glucan therapeutics, drug delivery innovations, and synthetic biology applications. In healthcare, microalgae-derived compounds show immense promise for treating diseases, boosting immunity, and tackling oxidative stress. Euglena-derived paramylon, a type of β-glucan, has shown potential in various medical applications, including immunomodulation and anticancer therapy. Synthetic biology and bioprocess engineering are enhancing microalgae’s therapeutic and nutritional value, with applications in drug delivery and personalized medicine. To maximize the potential of microalgae, further research and development are needed to address scalability, regulatory alignment, and consumer acceptance, with a focus on interdisciplinary collaboration and sustainable practices to align healthcare innovation with environmental conservation.

Background Alzheimer's disease (AD) is a neurodegenerative disorder with a very long duration, posing a serious threat to people's life and health. To date, no medicine that can cure or reverse the disease has been developed or reported, so early diagnosis and timely intervention are essential. The concentration of Phosphorylated tau181 (P-tau181) in blood has been approved by FDA as a standard for assisting clinical diagnosis of AD. Results In this study, a fluorescence biosensor based on vertical graphene-modified nano-gold film (VG@nAu) was developed for the grading of AD diagnosis by detecting P-tau181 protein in the blood. The VG@nAu substrate that produces hundreds of times IR800 molecular compared with a glass substrate, which is prepared by sputtering nano-gold onto vertical graphene surface. The detection limit of this fluorescence biosensor for P-tau181 is 0.82 pg/mL. The sensor also shows excellent selectivity and stability. Moreover, we analyzed the levels of P-tau181 in 16 clinical samples divided into four groups (HC group, SCD group, MCI group, and AD group) and found significant differences in P-tau181 levels. The grouping result based on the detection results using this biosensor is consistent with the grouping results of the clinical doctors. Significance This study achieves ultrasensitive detection of P-tau181 protein by constructing a fluorescent biosensor, which validates the feasibility of the VG@nAu-based fluorescence biosensor for the grading of AD diagnosis. This research provides a promising tool for ultrasensitive detecting biomarkers in clinical samples, indicating significant potential for its use in related diagnosing disease.

Astrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear. We investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice. Here, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice. Our findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies.

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tauopathies. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice, murine tau KO mice, and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK3β mediated tau phosphorylation. Moreover, Akt, the inhibitory kinase upstream of GSK3β, was activated in a tau-dependent manner. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation but inhibited 4E-BP1 phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. By comparing the hippocampal membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to C57 and Tau KO mice, the membrane association of oxidative phosphorylation-related proteins was impeded by human tau in the hippocampus. In vitro study consistently showed that aerobic glycolysis was promoted in the presence of human tau under high glucose conditions, which maintained the ratio of NAD+/NADH. On the other hand, human tau restricted the level of oxidative phosphorylation, modulated the activity of SDH, and reduced ROS production upon high glucose challenging. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute hyperglycemia conditions, which is similar with the Warburg effect, through influencing the homeostasis of protein-membrane association.

The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ1-42 oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ1-42. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ1-42 inhibits its oligomerization. Aβ1-42 treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ1-42 exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ1-42 oligomer developed cognitive impairment in behavioral tests. Aβ1-42 oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ1-42 also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tau-related neurodegenerative disease, including Alzheimer’s disease, tau related FTDP-17, Pick’s disease, et al. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice in which murine tau has been deleted simultaneously, murine tau knockout (Tau KO) mice and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK-3β mediated tau phosphorylation. Moreover, Akt, the upstream GSK-3β inhibitory kinase, was activated in a tau dependent manner. By comparing the membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to WT and Tau KO mice, the membrane-association of Krts, TFAM, TRAP1, mTOR et al, were strengthened by human tau. Whereas, the membrane-association of ribosomal proteins Rpls, proteasome proteins Psmds, and mitochondrial proteins, such as COXs, Ndufa1, Mtnt4, et al, were impeded by human tau. In vitro study showed that aerobic glycolysis was promoted in the presence of human tau, which maintained NAD+/NADH ratio. On the other hand, it restricted oxidative phosphorylation level, modulated the activity of SDH, and reduced ROS production upon challenging by high glucose. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation, but inhibited 4EBP phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute high hyperglycemia conditions, which is similar with the Warburg-effect, through influencing the homeostasis of protein-membrane association. ### Competing Interest Statement The authors have declared no competing interest.