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Functional disability is a rising global concern in aging societies, yet little is known about how co-occurring symptoms such as pain, sleep disturbances, and depressive mood jointly contribute to its development across diverse populations. This study aimed to examine the longitudinal associations between multimodal symptom clusters and incident functional disability using harmonized data from three culturally distinct cohorts in Europe (SHARE, ELSA) and East Asia (KLoSA). We analyzed harmonized data from 33,766 functionally independent adults aged 50 years from the SHARE, ELSA, and KLoSA. Symptom clusters were defined as baseline pain, sleep disturbance, and depressive moods. Cox models estimated disability risk, Sankey plots visualized symptom-function transitions, and mediation analyses explored indirect pathways. Multi-symptom clusters showed a graded dose–response association with functional decline, with triple-symptom groups conferring the highest risk (HR=2.36). Pain and sleep disturbance were the strongest predictors. Longitudinally, symptom clusters exhibited dynamic yet patterned trajectories–including persistence, progression, and partial reversal–highlighting early windows for intervention. Mediation analyses revealed reciprocal indirect effects between pain and sleep, whereas joint exposure resulted in pathway suppression. This is the first multinational study to systematically examine symptom cluster–disability pathways across culturally distinct cohorts. These findings underscore the predictive value and temporal dynamics of symptom combinations and support their use in global aging surveillance and targeted geriatric prevention strategies.

Potato-based reconstituted rice represents an innovative staple food solution that addresses nutritional and economic challenges. Using fresh potatoes instead of potato flour eliminates nutrient loss and reduces energy costs associated with traditional processing methods. This study examined reconstituted rice produced from the yellow-fleshed ‘Dianshu 1428’ and purple-fleshed ‘Diancaishu 101’ potato varieties, comparing their nutritional and aromatic profiles with commercial rice-based alternatives. The results demonstrated significant nutritional advantages: potato-based reconstituted rice contains 3 g/100 g dietary fiber, a five-fold higher potassium content, and 11–12 times more iron than conventional rice-based reconstituted rice. Unique aroma compounds, including methional, 2-ethyl-3,5-dimethylpyrazine, α-ionone, and (E,E)-2,6-nonadienal, impart distinctive potato, nutty, fruity, and fatty flavors. Yellow-fleshed varieties contributed 14.1 μg/100 g carotenoids, while purple-fleshed varieties provided 45 mg/100 g anthocyanins. These findings establish that potato-based reconstituted rice offers a superior nutritional composition and unique sensory characteristics compared to traditional alternatives, providing scientific guidance for the selection of the potato variety and product optimization in developing nutritionally enhanced potato staple foods with specific functional and sensory attributes.

As a central part of the mammalian brain, the prefrontal cortex (PFC) has been implicated in regulating cocaine-induced behaviors including compulsive seeking and reinstatement. Although dysfunction of the PFC has been reported in animal and human users with chronic cocaine abuse, less is known about how the PFC is involved in cocaine-induced behaviors. By using two-photon Ca 2+ imaging to simultaneously record tens of intact individual networking neurons in the frontal association cortex (FrA) in awake male mice, here we report that a systematic acute cocaine exposure decreased the FrA neural activity in mice, while the chemogenetic intervention blocked the cocaine-induced locomotor sensitization. The hypoactivity of FrA neurons was critically dependent on both dopamine transporters and dopamine transmission in the ventromedial PFC (vmPFC). Both dopamine D1R and D2R neurons in the vmPFC projected to and innervated FrA neurons, the manipulation of which changed the cocaine-induced hypoactivity of the FrA and locomotor sensitization. Together, this work demonstrates acute cocaine-induced hypoactivity of FrA neurons in awake mice, which defines a cortico-cortical projection bridging dopamine transmission and cocaine sensitization. The prefrontal cortex is involved in cocaine abuse disorders. Here, the authors show that cocaine suppresses frontal association cortex (FrA) in awake mice and induces locomotor sensitization through a dopamine dependent VTA-vmPFC-FrA pathway.

Despite the important role the circadian clock plays in numerous critical physiological responses in plants, such as hypocotyl elongation, leaf movement, stomatal opening, flowering, and stress responses, there have been no investigations into the effect of the circadian clock on physiological and transcriptional networks under salt stress. Ulmus pumila L. has been reported to tolerate 100–150 mM NaCl treatment. We measured the diurnal variation in photosynthesis and chlorophyll fluorescence parameters and performed a time-course transcriptome analysis of 2-years-old U. pumila seedlings under salt treatment to dissect the physiological regulation and potential relationship between the circadian network and the salt stress response. Seedlings in 150 mM NaCl treatment exhibited salt-induced physiological enhancement compared to the control group. A total of 7009 differentially expressed unigenes (DEGs) were identified under salt stress, of which 16 DEGs were identified as circadian rhythm-related DEGs (crDEGs). Further analysis of dynamic expression changes revealed that DEGs involved in four crucial pathways—photosynthesis, thiamine metabolism, abscisic acid synthesis and metabolism, and the hormone-MAPK signal crosstalk pathway—are closely related to the circadian clock. Finally, we constructed a co-expression network between the circadian clock and these four crucial pathways. Our results help shed light on the molecular link between the circadian network and salt stress tolerance in U. pumila.

The activation of the stimulating factor of the interferon gene (STING) pathway can enhance the immune response within the tumor. Cyclic diguanylate monophosphate (c-di-GMP) is a negatively charged, hydrophilic STING agonist, however, its effectiveness is limited due to the poor membrane permeability and low bioavailability. Herein, we introduced KL-7 peptide derived from Aβ amyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP, which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust “ in situ immunity” to kill melanoma cells. KL-7 peptide nanotube, also called PNT, was loaded with negatively charged c-di-GMP via electrostatic interaction, which prepared a nanocomposite named c-di-GMP-PNT. Treatment of RAW 264.7 cells (leukemia cells in mouse macrophage) with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-β along with phospho-STING (Ser365) protein expression, indicating the activation of the STING pathway. In the unilateral flank B16-F10 (murine melanoma cells) tumor-bearing mouse model, compared to PNT and c-di-GMP, c-di-GMP-PNT can promote the expression of INF-β, TNF-α, IL-6, and IL-1β. At the same time, up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues, resulting in significant inhibition of tumor growth in tumor-bearing mice. More importantly, in a bilateral flank B16-F10 tumor model, both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT. Moreover, c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs (heart, liver, spleen, lung, and kidney) and biochemical indexes of mice. In summary, our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity.

Ulmus pumila L. is an excellent afforestation and biofuel tree that produces high-quality wood, rich in starch. In addition, U. pumila is highly adaptable to adverse environmental conditions, which is conducive to its utilization for vegetating saline soils. However, little is known about the physiological responses and transcriptional regulatory network of U. pumila under salt stress. In this study, we exposed five main cultivars in saline–alkali land (Upu2, 5, 8, 11, and 12) to NaCl stress. Of the five cultivars assessed, Upu11 exhibited the highest salt resistance. Growth and biomass accumulation in Upu11 were promoted under low salt concentrations (<150 mM). However, after 3 months of continuous treatment with 150 mM NaCl, growth was inhibited, and photosynthesis declined. A transcriptome analysis conducted after 3 months of treatment detected 7009 differentially expressed unigenes (DEGs). The gene annotation indicated that these DEGs were mainly related to photosynthesis and carbon metabolism. Furthermore, PHOTOSYNTHETIC ELECTRON TRANSFERH (UpPETH), an important electron transporter in the photosynthetic electron transport chain, and UpWAXY, a key gene controlling amylose synthesis in the starch synthesis pathway, were identified as hub genes in the gene coexpression network. We identified 25 and 62 unigenes that may interact with PETH and WAXY, respectively. Overexpression of UpPETH and UpWAXY significantly increased the survival rates, net photosynthetic rates, biomass, and starch content of transgenic Arabidopsis plants under salt stress. Our findings clarify the physiological and transcriptional regulators that promote or inhibit growth under environmental stress. The identification of salt-responsive hub genes directly responsible for photosynthesis and starch synthesis or metabolism will provide targets for future genetic improvements.

Current models emphasize thatmembrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G protein Giβγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm dependence of QS for tuning autoinhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm → P2Y12(D76/D127) → Giβγ → QS → myocyte contractility, offering a universal Vm-GPCR signaling pathway for its functions in the nervous system and other systems containing GPCRs.

Large dense‐core vesicles (LDCVs) are larger in volume than synaptic vesicles, and are filled with multiple neuropeptides, hormones, and neurotransmitters that participate in various physiological processes. However, little is known about the mechanism determining the size of LDCVs. Here, it is reported that secretogranin II (SgII), a vesicle matrix protein, contributes to LDCV size regulation through its liquid–liquid phase separation in neuroendocrine cells. First, SgII undergoes pH‐dependent polymerization and the polymerized SgII forms phase droplets with Ca2+ in vitro and in vivo. Further, the Ca2+‐induced SgII droplets recruit reconstituted bio‐lipids, mimicking the LDCVs biogenesis. In addition, SgII knockdown leads to significant decrease of the quantal neurotransmitter release by affecting LDCV size, which is differently rescued by SgII truncations with different degrees of phase separation. In conclusion, it is shown that SgII is a unique intravesicular matrix protein undergoing liquid–liquid phase separation, and present novel insights into how SgII determines LDCV size and the quantal neurotransmitter release. The mystery of what fundamentally determines the size of large dense‐core vesicles (LDCVs) in neuroendocrine cells is uncovered. Secretogranin II, an intravesicular matrix protein, undergoes liquid–liquid phase separation in vitro and in vivo to determine the size/volume of LDCVs, thus tuning the quantal neurotransmitters release.

Aims/hypothesis Insulin is a key metabolic regulator in health and diabetes. In pancreatic beta cells, insulin release is regulated by the major second messengers Ca 2+ and cAMP: exocytosis is triggered by Ca 2+ and mediated by the cAMP/protein kinase A (PKA) signalling pathway. However, the causal link between these two processes in primary beta cells remains undefined. Methods Time-resolved confocal imaging of fluorescence resonance energy transfer signals was performed to visualise PKA activity, and combined membrane capacitance recordings were used to monitor insulin secretion from patch-clamped rat beta cells. Results Membrane depolarisation-induced Ca 2+ influx caused an increase in cytosolic PKA activity via activating a Ca 2+ -sensitive adenylyl cyclase 8 (ADCY8) subpool. Glucose stimulation triggered coupled Ca 2+ oscillations and PKA activation. ADCY8 knockdown significantly reduced the level of depolarisation-evoked PKA activation and impaired replenishment of the readily releasable vesicle pool. Pharmacological inhibition of PKA by two inhibitors reduced depolarisation-induced PKA activation to a similar extent and reduced the capacity for sustained vesicle exocytosis and insulin release. Conclusions/interpretation Our findings suggest that depolarisation-induced Ca 2+ influx plays dual roles in regulating exocytosis in rat pancreatic beta cells by triggering vesicle fusion and replenishing the vesicle pool to support sustained insulin release. Therefore, Ca 2+ influx may be important for glucose-stimulated insulin secretion.