Orexin increases the neuronal excitability of several brain areas associated with maintaining of arousal.

Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.

Dual response signal CdTe QDs@ZIF-8 with butterfly spectrum for dual-mode fluorescence/colorimetric detection of tetracycline in animal feeds.

In this study, a ratiometric fluorescent sensor CdTe QDs@ZIF-8 with butterfly spectra is successfully constructed by in situ encapsulating mercaptopropionic acid-modified CdTe quantum dots in zeolitic imidazolate framework-8 (ZIF-8) with a simple strategy, and used for the detection of tetracycline in fluorescence/smartphone colorimetry dual-mode. ZIF-8 not only reduces the agglomeration of the quantum dots but also surprisingly generates a new green fluorescence signal at 524 nm while the red fluorescence of the CdTe quantum dots at 650 nm quenches when tetracycline is added. The two opposing fluorescence signals create a butterfly-shaped fluorescence spectrum, allowing the sensor to detect tetracycline over a linear range of 0-70 µM with the detection limit (LOD) of 0.0155 µM by using a ratiometric fluorescence technique. What is more, based on the obvious color change of the fluorescent sensor gradually from red to green under UV light, a highly stable point-of-care testing sensor has been developed for on-site detection of tetracycline through color recognition by smartphones, which can be used for real-time detection of this antibiotic in the range of 0-1000 µM with the LOD of 0.0249 µM. This work provides a simple and efficient method for the on-site detection of tetracycline.

Phytocannabinoid-like meroterpenoids from twigs and leaves of Rhododendron spinuliferum.

Six pairs of previously undescribed enantiomeric phytocannabinoid-like meroterpenoids, (±)-spinulinoids A‒F, and two naturally occurring compounds, (+)-rhododaurichromanic acid A and (E)-4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)benzoic acid, together with one known congener, (-)-rhododaurichromanic acid A, were obtained from the twigs and leaves of Rhododendron spinuliferum. Their structures were established by their extensive spectral data (NMR and HRESIMS), ECD calculations, and single-crystal X-ray diffraction data. Spinulinoids A and B are unprecedented phytocannabinoid-like meroterpenoids constructed by the resorcinol moiety and a ß-bisabolene unit, whereas spinulinoid C represents a rare adduct of quinone and ß-bisabolene with a tricyclic 6/6/6 ring system.

Carbon dots for efficient detection of water content in organic solvents.

The trace amount of water in organic solvents can affect the progress of chemical reactions, which will adversely affect chemical production in many industries, resulting in a doubling of costs. In this work, carbon dots (CDs) with abundant polar groups were synthesized by a simple one-step hydrothermal method. The prepared CDs showed superior dispersibility and fluorescence performance compared to the CDs that have been reported for the detection of water content in organic solvents. It can realize the fluorescence detection of trace water in several water-soluble organic solvents such as N,N-dimethylformamide, ethanol and methanol with wide linear range (0 %-100 %) and high sensitivity. This will provide a powerful tool for the rapid detection of water content in organic solvents in chemical production.

A Novel Function of GW5 on Controlling the Early Growth Vigor and its Haplotype Effect on Shoot Dry Weight and Grain Size in Rice (Oryza sativa L.).

Strong early growth vigor is an essential target in both direct seeded rice breeding and high-yielding rice breeding for rice varieties with relatively short growth duration in the double-cropping region. Shoot dry weight (SDW) is one of the important traits associated with early growth vigor, and breeders have been working to improve this trait. Finding stable QTLs or functional genes for SDW is crucial for improving the early growth vigor by implementing molecular breeding in rice. Here, a genome-wide association analysis revealed that the QTL for SDW, qSDW-5, was stably detected in the three cultivation methods commonly used in production practice. Through gene-based haplotype analysis of the annotated genes within the putative region of qSDW-5, and validated by gene expression and knockout transgenic experiments, LOC_Os05g09520, which is identical to the reported GW5/GSE5 controlling grain width (GW) and thousand grain weight (TGW) was identified as the causal gene for qSDW-5. Five main haplotypes of LOC_Os05g09520 were identified in the diverse international rice collection used in this study and their effects on SDW, GW and TGW were analyzed. Phenotypic comparisons of the major haplotypes of LOC_Os05g09520 in the three subpopulations (indica, japonica and aus) revealed the same patterns of wider GW and higher TGW along with higher SDW. Furtherly, the haplotype analysis of 138 rice varieties/lines widely used in southern China showed that 97.8% of the cultivars/lines carry Hap2LOC_Os05g09520. These results not only provide a promising gene source for the molecular breeding of rice varieties with strong early growth vigor, but also elucidate the effect of the LOC_Os05g09520 haplotypes on SDW, GW, and TGW in rice. Importantly, this study provides direct genetic evidence that these three traits are significantly correlated, and suggests a breeding strategy for developing high-yielding and slender grain-shaped indica cultivars with strong early growth vigor.

Prediction and practical application of bauxite mineralization in Wuzhengdao area, Guizhou, China.

Wu-Zheng-Dao District in China is the world's most famous mining areas. It hosts several world-class deposits, such as Xinming, Datang and Luolong bauxite deposits. Although this area still has significant potential for the discovery of new deposits, mineral prediction has become increasingly diffcult as the number of shallow deposits diminishes. Therefore, it is necessary to explore new and effective metallogenic prediction methods.Weights of evidence and machine-learning algorithms were used for mineral prospecting in this study. This study used a confusion matrix, receiver operating characteristic (ROC) curve,and prediction efficiency curve to evaluate the prediction results of each machine algorithm. The results showed that 95.9% of the deposits were located in high and distant scenic areas, accounting for 10% of the total area.The prospectivity map of the Wu-Zheng-Dao district shows that the high prospective areas are generally confined to the claystone and carbonatite rocks of the Eastern region, in particular, of the clay layers, and several areas of high prospectivity also occur in the Southern Cross Domain. According to the predicted results, after on-site exploration, design, and construction, Yanfengqian bauxite deposit was discovered, with an average thickness of 1.82 meters; The average content of Al2O3 is 61.24%; The resource amount is 28.9503 million tons.

Design, Synthesis, and Biological Activity of Silicon-Containing Carboxamide Fungicides.

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

Covalent post-synthetic modification of MOFs as a fluorescent sensor for the efficient detection of the biomarker of cystinuria.

Cystinuria is a genetic disorder, and in severe cases, it might lead to kidney failure. As an important biomarker for cystinuria, the level of arginine (Arg) in urine is a vital indicator for cystinuria screening. Therefore, it is urgently needed to detect Arg with high selectivity and sensitivity. In this work, a boric acid functionalized Zr-based metal-organic framework UiO-PhbA is prepared by grafting phenylboronic acid on UiO-66-NH2 through a Schiff base reaction using a covalent post-synthesis modification (CPSM) strategy. The prepared UiO-PhbA exhibits a sensitive and specific fluorescence "turn-on" response to Arg and can be exploited to detect Arg in human serum and urine samples with a broad linear range of 0.6-350 µM and low limit of detection (LOD) of 18.45 nM. This study provides a new and reliable rapid screening protocol for sulfite oxidase deficiency-related diseases.

Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

N-acetylglucosamine kinase (BbHxk1) has pleiotropic effects on vegetative growth, cell wall integrity, morphological transition, cuticle infection, and metabolic modulation in the biological pesticide Beauveria bassiana.

Beauveria bassiana is a popular and eco-friendly biopesticide. During its pathogen-pest interaction, both N-acetylglucosamine (GlcNAc) catabolism and anabolism are crucial for nutrient supply and cell-wall construction. The initiation of GlcNAc metabolism relies on the catalysis of GlcNAc kinase, which has been extensively studied in the human pathogen Candida albicans. However, the physiological function of GlcNAc kinase remains poorly understood in entomopathogenic fungi. In the present study, a GlcNAc kinase homolog was identified and designated as BbHxk1 in B. bassiana. Deletion of BbHxk1 resulted in viable but reduced vegetative growth on various carbon sources. ΔBbHxk1 mutants displayed severe defects in cell wall integrity, making them more susceptible to cell wall stress cues. Furthermore, the absence of BbHxk1 resulted in an increase in conidial yield and blastospore production, and a faster rate of germination and filamentation, potentially attributed to higher intracellular ATP levels. BbHxk1 deficiency led to a reduction in the activities of cuticle-degrading enzymes, which might contribute to the attenuated pathogenicity specifically through cuticle penetration rather than hemocoel infection towards Galleria mellonella larvae. Being different from C. albicans Hxk1, which facultatively acts as a catalyzing enzyme and transcriptional regulator, BbHxk1 primarily acts as a catalyzing enzyme and metabolic regulator. The altered metabolomic profiling correlated with the phenotypic defects in ΔBbHxk1 mutants, further implicating a potential metabolism-dependent mechanism of BbHxk1 in mediating physiologies of B. bassiana. These findings not only unveil a novel role for GlcNAc kinase in B. bassiana, but also provide a solid theoretical basis to guide metabolic reprogramming in order to maintain or even enhance the efficiency of fungi for practical applications.

Endoplasmic reticulum stress response modulator OsbZIP39 regulates cadmium accumulation via activating the expression of defensin-like gene OsCAL2 in rice.

Accumulation of cadmium (Cd) in rice is not only harmful to the growth of plants but also poses a threat to human health. Exposure to Cd triggers unfolded protein response (UPR) within cells, a process that is still not completely understood. The study demonstrated that the lack of OsbZIP39, an essential endoplasmic reticulum (ER)-resident regulator of the UPR, resulted in decreased Cd intake and reduced Cd levels in the roots, stems, and grains of rice. Upon exposure to Cd stress, GFP-OsbZIP39 translocated from ER to nucleus, initiating UPR. Further investigation revealed that Cd treatment caused changes in sphingolipid levels in the membrane, influencing the localization and activation of OsbZIP39. Yeast one-hybrid and dual-LUC assays were conducted to validate the interaction between activated OsbZIP39 and the promoter of the defensin-like gene OsCAL2, resulting in an increase in its expression. Different variations were identified in the coding region of OsbZIP39, which may explain the varying levels of Cd accumulation observed in the indica and japonica subspecies. Under Cd treatment, OsbZIP39ind exhibited a more significant enhancement in the transcription of OsCAL2 compared to OsbZIP39jap. Our data suggest that OsbZIP39 positively regulates Cd uptake in rice, offering an encouraging objective for the cultivation of low-Cd rice.

Carbon peaking prediction scenarios based on different neural network models: A case study of Guizhou Province.

Global warming, caused by greenhouse gas emissions, is a major challenge for all human societies. To ensure that ambitious carbon neutrality and sustainable economic development goals are met, regional human activities and their impacts on carbon emissions must be studied. Guizhou Province is a typical karst area in China that predominantly uses fossil fuels. In this study, a backpropagation (BP) neural network and extreme learning machine (ELM) model, which is advantageous due to its nonlinear processing, were used to predict carbon emissions from 2020 to 2040 in Guizhou Province. The carbon emissions were calculated using conversion and inventory compilation methods with energy consumption data and the results showed an "S" growth trend. Twelve influencing factors were selected, however, five with larger correlations were screened out using a grey correlation analysis method. A prediction model for carbon emissions from Guizhou Province was established. The prediction performance of a whale optimization algorithm (WOA)-ELM model was found to be higher than the BP neural network and ELM models. Baseline, high-speed, and low-carbon scenarios were analyzed and the size and time of peak carbon emissions in Liaoning Province from 2020 to 2040 were predicted using the WOA-ELM model.

Scavenging and release of REE and HFSE by Na-metasomatism in magmatic-hydrothermal systems.

Exploitable or potentially exploitable deposits of critical metals, such as rare-earth (REE) and high-field-strength elements (HFSE), are commonly associated with alkaline or peralkaline igneous rocks. However, the origin, transport and concentration of these metals in peralkaline systems remains poorly understood. This study presents the results of a mineralogical and geochemical investigation of the Na-metasomatism of alkali amphiboles and clinopyroxenes from a barren peralkaline granite pluton in NE China, to assess the remobilization and redistribution of REE and HFSE during magmatic-hydrothermal evolution. Alkali amphiboles and aegirine-augites from the peralkaline granites show evolutionary trends from sodic-calcic to sodic compositions, with increasing REE and HFSE concentrations as a function of increasing Na-index [Na#, defined as molar Na/(Na+Ca) ratios]. The Na-amphiboles (i.e., arfvedsonite) and aegirine-augites can be subsequently altered, or breakdown, to form hydrothermal aegirine during late- or post-magmatic alteration. Representative compositions analyzed by in-situ LA-ICPMS show that the primary aegirine-augites have high and variable REE (2194-3627 ppm) and HFSE (4194-16,862 ppm) contents, suggesting that these critical metals can be scavenged by alkali amphiboles and aegirine-augites. Compared to the primary aegirine-augites, the presentative early replacement aegirine (Aeg-I, Na# = 0.91-0.94) has notably lower REE (1484-1972) and HFSE (4351-5621) contents. In contrast, the late hydrothermal aegirine (Aeg-II, Na# = 0.92-0.96) has significantly lower REE (317-456 ppm) and HFSE (6.44-72.2 ppm) contents. Given that the increasing Na# from aegirine-augites to hydrothermal aegirines likely resulted from Na-metasomatism, a scavenging-release model can explain the remobilization of REE and HFSE in peralkaline granitic systems. The scavenging and release of REE and HFSE by Na-metasomatism provides key insights into the genesis of globally significant REE and HFSE deposits. The high Na-index of the hydrothermal aegirine might be useful as a geochemical indicator in the exploration for these critical-metals.

GWAS and Transcriptomic Analysis Identify OsRING315 as a New Candidate Gene Controlling Amylose Content and Gel Consistency in Rice.

Cooking quality is the main factor determining the market value of rice. Although several major genes and a certain number of QTLs controlling cooking quality have been identified, the genetic complexity and environmental susceptibility limit the further improvement for cooking quality by molecular breeding. This research conducted a genome-wide association study to elucidate the QTLs related to cooking quality including amylose content (AC), gel consistency (GC) and alkali spreading value (ASV) by using 450 rice accessions consisting of 300 indica and 150 japonica accessions in two distinct environments. A total of 54 QTLs were identified, including 25 QTLs for AC, 12 QTLs for GC and 17 QTLs for ASV. Among them, 10 QTLs were consistently observed by the same population in both environments. Six QTLs were co-localized with the reported QTLs or cloned genes. The Wx gene for AC and GC, and the ALK gene for ASV were identified in every population across the two environments. The qAC9-2 for AC and the qGC9-2 for GC were defined to the same interval. The OsRING315 gene, encoding an E3 ubiquitin ligase, was considered as the candidate gene for both qAC9-2 and qGC9-2. The higher expression of OsRING315 corresponded to the lower AC and higher GC. Three haplotypes of OsRING315 were identified. The Hap 1 mainly existed in the japonica accessions and had lower AC. The Hap 2 and Hap 3 were predominantly present in the indica accessions, associated with higher AC. Meanwhile, the GC of accessions harboring Hap 1 was higher than that of accessions harboring Hap 3. In addition, the distribution of the three haplotypes in several rice-growing regions was unbalanced. The three traits of cooking quality are controlled by both major and minor genes and susceptible to environmental factors. The expression level of OsRING315 is related to both AC and GC, and this gene can be a promising target in quality improvement by using the gene editing method. Moreover, the haplotypes of OsRING315 differentiate between indica and japonica, and reveal the differences in GC and AC between indica and japonica rice.

Brønsted acid catalyzed [4 + 2] cycloaddition for the synthesis of bisbenzannulated spiroketals with antifungal activities.

The intermolecular [4 + 2] cycloaddition of o-hydroxy benzyl alcohols with isochroman ketals was realized by CF3CO2H catalysis. A broad range of bisbenzannulated [6,6]-spiroketals were formed under the metal-free mild conditions in moderate to excellent yields (45-98%) with mostly excellent diastereoselectivities (up to >20 : 1 dr). Furthermore, the enantioselective version was also preliminarily investigated and the bisbenzannulated [6,6]-spiroketal was obtained with 61% ee in the presence of Sc(OTf)3/Feng's chiral N,N'-dioxide ligand. Some of the bisbenzannulated [6,6]-spiroketal products showed good in vitro antifungal activities against Sclerotinia sclerotiorum and Rhizoctonia solani.

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

Pangenome-Wide Association Study and Transcriptome Analysis Reveal a Novel QTL and Candidate Genes Controlling both Panicle and Leaf Blast Resistance in Rice.

Cultivating rice varieties with robust blast resistance is the most effective and economical way to manage the rice blast disease. However, rice blast disease comprises leaf and panicle blast, which are different in terms of resistance mechanisms. While many blast resistant rice cultivars were bred using genes conferring resistance to only leaf or panicle blast, mining durable and effective quantitative trait loci (QTLs) for both panicle and leaf blast resistance is of paramount importance. In this study, we conducted a pangenome-wide association study (panGWAS) on 9 blast resistance related phenotypes using 414 international diverse rice accessions from an international rice panel. This approach led to the identification of 74 QTLs associated with rice blast resistance. One notable locus, qPBR1, validated in a F4:5 population and fine-mapped in a Heterogeneous Inbred Family (HIF), exhibited broad-spectrum, major and durable blast resistance throughout the growth period. Furthermore, we performed transcriptomic analysis of 3 resistant and 3 sensitive accessions at different time points after infection, revealing 3,311 differentially expressed genes (DEGs) potentially involved in blast resistance. Integration of the above results identified 6 candidate genes within the qPBR1 locus, with no significant negative effect on yield. The results of this study provide valuable germplasm resources, QTLs, blast response genes and candidate functional genes for developing rice varieties with enduring and broad-spectrum blast resistance. The qPBR1, in particular, holds significant potential for breeding new rice varieties with comprehensive and durable resistance throughout their growth period.

Mechanism of soot and particulate matter formation during high temperature pyrolysis and gasification of waste derived from MSW.

This research investigates the formation mechanism of soot and particulate matter during the pyrolysis and gasification of waste derived from Municipal Solid Waste (MSW) in a laboratory scale drop tube furnace. Compared with CO2 gasification atmosphere, more ultrafine particles (PM0.2, aerodynamic diameter less than 0.2 µm) were generated in N2 atmosphere at 1200℃, which were mainly composed of polycyclic aromatic hydrocarbons (PAHs), graphitic carbonaceous soot and volatile alkali salts. High reaction temperatures promote the formation of hydrocarbon gaseous products and their conversion to PAHs, which ultimately leads to the formation of soot particles. The soot particles generated by waste derived from MSW pyrolysis and gasification both have high specific surface area and well-developed pore structure. Compared with pyrolysis, the soot generated by gasification of waste derived from MSW had smaller size and higher proportion of inorganic components. The higher pyrolysis temperature led to the collapse of the mesoporous structure of submicron particles, resulting in a decrease in total pore volume and an increase in specific surface area. Innovatively, this research provides an explanation for the effect of reaction temperature/ CO2 on the formation pathways and physicochemical properties of soot and fine particulate matter.

Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.

Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice.

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.