Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice.

BACKGROUND: Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known. METHODS: Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. RESULTS: CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect. CONCLUSIONS: Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression.

MXene-Based Pressure Sensor with a Self-Healing Property for Joule Heating and Friction Sliding.

As a kind of flexible electronic device, flexible pressure sensor has attracted wide attention in medical monitoring and human-machine interaction. With the continuous deepening of research, high-sensitivity sensor is developing from single function to multi-function. However, Current multifunctional sensors lack the ability to integrate joule heating, detect sliding friction, and self-healing. Herein, a MXene/polyurethane (PU) flexible pressure sensor with a self-healing property for joule heating and friction sliding is fabricated. The MXene/PU sensitive layer with special spinosum structure is prepared by a simple spraying method. After face-to-face assembly of the sensitive layers, the MXene/PU flexible pressure sensor is obtained and showed excellent sensitivity (150.65 kPa-1), fast response/recovery speed (75.5/63.9 ms), and good stability (10 000 cycles). Based on the self-healing property of PU, the sensor also has the ability to heal after mechanical damage. In addition, the sensor realizes the joule heating function under low voltage, and has the real-time monitoring ability of sliding objects. Combined with low cost and simple manufacturing method, the multi-functional MXene/PU flexible sensor shows a wide range of application potential in human activity monitoring, thermal management, and slip recognition.

Transformational Modulation of Fluorescence to Room Temperature Phosphorescence in Metal-Organic Frameworks with Flexible C-S-C Bonds.

Photoluminescent metal-organic frameworks (MOFs) have been a subject of considerable interest for many years. However, the regulation of excited states of MOFs at the single crystal level remains restricted due to a lack of control methods. The singlet-triplet emissive property can be significantly influenced by crystal conformational distortions. This review introduces an intelligent responsive MOF material, denoted as LIFM-SHL-3a, characterized by flexible C-S-C bonds. LIFM-SHL-3a integrates elastic structural dynamics with fluorescence and room temperature phosphorescence (RTP) modulation under heating conditions. The deformable carbon-sulfur bond essentially propels the distortion of molecular conformation and alters the stacking mode, as illustrated by single-crystal-to-single-crystal transformation detection. The deformation of flexible C-S-C bonds leads to different noncovalent interactions in the crystal system, thereby achieving modulation of the fluorescence (F) and RTP bands. In the final state structure, the ratio of fluorescence is 66.7%, and the ratio of RTP is 32.6%. This stands as a successful demonstration of modulating F/RTP within the dynamic MOF, unlocking potential applications in optical sensing and beyond. Especially, a PL thermometer with a relative sensitivity of 0.096-0.104%·K-1 in the range of 300-380 K and a H2S probe with a remarkably low LOD of 125.80 nM can be obtained using this responsive MOF material of LIFM-SHL-3a.

[High-temperature adaptation mechanisms and biotechnological potentials of thermophilic cyanobacteria].

Thermophilic cyanobacteria are prokaryotic organisms that possess exceptional heat-resistant characteristics. This group serves as an excellent model for investigating the heat tolerance of higher photosynthetic organisms, including higher plants, some protists (such as algae and euglena), and bacteria. Analyzing the mechanisms of high-temperature adaptation in thermophilic cyanobacteria can enhance our understanding of how photosynthetic organisms and microorganisms tolerate high temperatures at the molecular level. Additionally, these thermotolerant cyanobacteria have the potential to contribute to breeding heat-tolerant plants and developing microbial cell factories. This review summarizes current research on thermophilic cyanobacteria, focusing on their ecology, morphology, omics studies, and mechanisms of high-temperature tolerance. It offers insight into the potential biotechnological applications of thermophilic cyanobacteria and highlights future research opportunities. Specifically, attention is given to the photosynthetic physiology and metabolism of cyanobacteria, and the molecular basis of heat-tolerance mechanisms in thermophilic cyanobacteria is explored.

Brain age prediction and deviations from normative trajectories in the neonatal connectome.

Structural and functional connectomes undergo rapid changes during the third trimester and the first month of postnatal life. Despite progress, our understanding of the developmental trajectories of the connectome in the perinatal period remains incomplete. Brain age prediction uses machine learning to estimate the brain's maturity relative to normative data. The difference between the individual's predicted and chronological age-or brain age gap (BAG)-represents the deviation from these normative trajectories. Here, we assess brain age prediction and BAGs using structural and functional connectomes for infants in the first month of life. We used resting-state fMRI and DTI data from 611 infants (174 preterm; 437 term) from the Developing Human Connectome Project (dHCP) and connectome-based predictive modeling to predict postmenstrual age (PMA). Structural and functional connectomes accurately predicted PMA for term and preterm infants. Predicted ages from each modality were correlated. At the network level, nearly all canonical brain networks-even putatively later developing ones-generated accurate PMA prediction. Additionally, BAGs were associated with perinatal exposures and toddler behavioral outcomes. Overall, our results underscore the importance of normative modeling and deviations from these models during the perinatal period.

Thermal control over phosphorescence or thermally activated delayed fluorescence in a metal-organic framework.

By integrating a tailor-made donor-acceptor (D-A) ligand in a metal-organic framework (MOF), a material with unprecedented features emerges. The ligand combines a pair of cyano groups as acceptors with four sulfanylphenyls as donors, which expose each a carboxylic acid as coordination sites. Upon treatment with zinc nitrate in a solvothermal synthesis, the MOF is obtained. The new material combines temperature-assisted reverse intersystem crossing (RISC) and intersystem crossing (ISC). As these two mechanisms are active in different temperature windows, thermal switching between their characteristic emission wavelengths is observed for this material. The two mechanisms can be activated by both, one-photon absorption (OPA) and two-photon absorption (TPA) resulting in a large excitement window ranging from ultraviolet (UV) over visible light (VL) to near infrared (NIR). Furthermore, the emission features of the material are pH sensitive, such that its application potential is demonstrated in a first ammonia sensor.

Artemether regulates liver glycogen and lipid utilization through mitochondrial pyruvate oxidation in db/db mice.

OBJECTIVES: Diabetes is an important global health problem. The occurrence and development of type 2 diabetes (T2D) involves multiple organs, among which the liver is an important organ. Artemether is a methyl ether derivative of artemisinin and has displayed significant antidiabetic effects. However, its regulation of glucose metabolism is not clearly elucidated. This study explored the effect of artemether on liver mitochondrial pyruvate metabolism. METHODS: T2D db/db mice were used and grouped into db/db and db/db+Art groups. Lean wild type mice served as control. After artemether intervention for 12 weeks, the respiratory exchange ratio (RER), redox state, relevant serum lipid content, liver glycogen and lipid content, liver insulin and insulin-like growth factor 1 (IGF-1) signal transduction, mitochondrial pyruvate oxidation pathway, fatty acid and glycogen metabolic pathways were evaluated. RESULTS: This experiment demonstrated that artemether raised RER and enhanced liver mitochondrial pyruvate metabolism in db/db mice. Artemether also reduced serum and urinary lipid peroxidation products and regulated the redox status in liver. The accumulation of liver glycogen in diabetic mice was attenuated, the proportion of lipid content in serum and liver was changed by artemether. The signal pathway associated with liver glycogen metabolism was also regulated by artemether. In addition, artemether increased serum insulin and regulated insulin/IGF-1 signal pathway in liver. CONCLUSIONS: The present study confirmed that artemether can regulate liver glycogen and lipid utilization in T2D mice, its biological mechanisms were associated with mitochondrial pyruvate oxidation in the liver.

Power and reproducibility in the external validation of brain-phenotype predictions.

Brain-phenotype predictive models seek to identify reproducible and generalizable brain-phenotype associations. External validation, or the evaluation of a model in external datasets, is the gold standard in evaluating the generalizability of models in neuroimaging. Unlike typical studies, external validation involves two sample sizes: the training and the external sample sizes. Thus, traditional power calculations may not be appropriate. Here we ran over 900 million resampling-based simulations in functional and structural connectivity data to investigate the relationship between training sample size, external sample size, phenotype effect size, theoretical power and simulated power. Our analysis included a wide range of datasets: the Healthy Brain Network, the Adolescent Brain Cognitive Development Study, the Human Connectome Project (Development and Young Adult), the Philadelphia Neurodevelopmental Cohort, the Queensland Twin Adolescent Brain Project, and the Chinese Human Connectome Project; and phenotypes: age, body mass index, matrix reasoning, working memory, attention problems, anxiety/depression symptoms and relational processing. High effect size predictions achieved adequate power with training and external sample sizes of a few hundred individuals, whereas low and medium effect size predictions required hundreds to thousands of training and external samples. In addition, most previous external validation studies used sample sizes prone to low power, and theoretical power curves should be adjusted for the training sample size. Furthermore, model performance in internal validation often informed subsequent external validation performance (Pearson's r difference <0.2), particularly for well-harmonized datasets. These results could help decide how to power future external validation studies.

Structural insight into the functional regulation of Elongation factor Tu by reactive oxygen species in Synechococcus elongatus PCC 7942.

In cyanobacteria, Elongation factor Tu (EF-Tu) plays a crucial role in the repair of photosystem II (PSII), which is highly susceptible to oxidative stress induced by light exposure and regulated by reactive oxygen species (ROS). However, the specific molecular mechanism governing the functional regulation of EF-Tu by ROS remains unclear. Previous research has shown that a mutated EF-Tu, where C82 is substituted with a Ser residue, can alleviate photoinhibition, highlighting the important role of C82 in EF-Tu photosensitivity. In this study, we elucidated how ROS deactivate EF-Tu by examining the crystal structures of EF-Tu in both wild-type and mutated form (C82S) individually at resolutions of 1.7 Šand 2.0 Šin Synechococcus elongatus PCC 7942 complexed with GDP. Specifically, the GDP-bound form of EF-Tu adopts an open conformation with C82 located internally, making it resistant to oxidation. Coordinated conformational changes in switches I and II create a tunnel that positions C82 for ROS interaction, revealing the vulnerability of the closed conformation of EF-Tu to oxidation. An analysis of these two structures reveals that the precise spatial arrangement of C82 plays a crucial role in modulating EF-Tu's response to ROS, serving as a regulatory element that governs photosynthetic biosynthesis.