Integrative analysis of metabolomics and proteomics unravels purine metabolism dysregulation in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites' levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, we discovered that fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one­carbon metabolism were also significantly altered in this disease. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.

Comparison on distribution and sources of typical major and toxic trace elements in various glacial watersheds of the northeast Tibetan Plateau.

Toxic and major elements, such as As and Fe, in watersheds can significantly impact the surrounding water environment and ecosystem. Thus, in this study, we conducted an investigation into the origins and spatial distribution of typical toxic trace elements (As and Mn) and crustal major elements (Al, Fe, and Ti) in suspended particulate matter (SPM) across various glacial watersheds located at different elevations in the northeastern Tibetan Plateau (NETP) from June to July in 2017. The results revealed that the mean value of each element followed the order of abundance in the samples, with Al having the highest mean value at 21307 µg/L, followed by Fe at 13366 µg/L, Ti at 1520 µg/L, Mn at 245 µg/L, and As at 66.6 µg/L. Moreover, our study identified high content of these elements from the Dabanshan Snowpack, Laohugou Glacier No.12, and Yuzhufeng Glacier in the upper reaches of the basin, which were found to be 9.9, 10.2, and 19.4 times higher, respectively, than that of the upper reaches of the Heihe River. We found that As and Mn exhibited clear indications of anthropogenic influence on a local and regional scale. The calculated enrichment factor (EF) demonstrated a significant As enrichment (EF>100) in the Qiyi and Lenglongling Glaciers, possibly resulting in the release of upstream glacier melt and anthropogenic-derived As deposition. Our findings suggested that the upstream region was primarily linked to glacier meltwater discharge. In contrast, the middle and lower reaches of the basin exhibited a more pronounced influence from local human activities. Based on the findings, the water environment of the glacier watershed appears to be in good condition overall. However, the presence of elevated levels of As element in the water system can be traced back to both anthropogenic and natural factors. As a result, ensuring the safety of the water supply for nearby residents is a matter of utmost concern. This study provides a comprehensive examination of hydrochemical variations and the overall water environment of high-altitude glacier basins in the NETP, offering valuable insights into the topic.

Catalytic Enantioselective Steglich-Type Rearrangement of Enol Lactones: Asymmetric Synthesis of Spirocyclic 1,3-Diketones.

An example of asymmetric Steglich-type rearrangement of enol lactones is reported. This highly enantioselective acyl transfer reaction is catalyzed by chiral isothiourea at ambient temperature and provides a useful synthetic approach to access enantioenriched spirotricyclic ß,ß'-diketones from a broad range of indanone or tetralone-derived lactones. Preliminary mechanistic studies suggest the initial formation of an N-acylated iminium cation intermediate that induces a following facial selective condensation.

Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer.

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer.

Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0-10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia.

Simultaneous determination of eight bioactive components of Qishen Yiqi dripping pills in rat plasma using UFLC-MS/MS and its application to a pharmacokinetic study.

In this study, a rapid and reliable ultra-fast liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of eight active ingredients, including astragaloside IV, ononin, tanshinol, protocatechualdehyde, protocatechuic acid, salvianolic acid D, rosmarinic acid and ginsenoside Rg1 , in rat plasma. The plasma samples were pretreated by protein precipitation with acetonitrile. Chromatographic separation was performed on a Waters Acquity UPLC® BEH C18 column (1.7 µm particles, 2.1 × 100 mm). The mobile phase consisted of 0.1% aqueous formic acid (A)-acetonitrile with 0.1% formic acid (B) at a flow rate of 0.4 mL/min. Quantification was performed on a triple quadruple tandem mass spectrometry with electrospray ionization by multiple reaction monitoring both in the negative and in the positive ion mode. The lower limit of quantification of tanshinol was 2.0 ng/mL and the others were 5.0 ng/mL. The extraction recoveries, matrix effects, intra- and inter-day precision and accuracy of eight tested components were all within acceptable limits. The validated method was successfully applied to the pharmacokinetic study of the eight active constituents after intragastric administration of three doses (1.0, 3.0, 6.0 g/kg body weight) of Qishen Yiqi Dripping Pills to rats.

Development of urinary pseudotargeted LC-MS-based metabolomics method and its application in hepatocellular carcinoma biomarker discovery.

Hepatocellular carcinoma (HCC) is one of the pestilent malignancies leading to cancer-related death. Discovering effective biomarkers for HCC diagnosis is an urgent demand. To identify potential metabolite biomarkers, we developed a urinary pseudotargeted method based on liquid chromatography-hybrid triple quadrupole linear ion trap mass spectrometry (LC-QTRAP MS). Compared with nontargeted method, the pseudotargeted method can achieve better data quality, which benefits differential metabolites discovery. The established method was applied to cirrhosis (CIR) and HCC investigation. It was found that urinary nucleosides, bile acids, citric acid, and several amino acids were significantly changed in liver disease groups compared with the controls, featuring the dysregulation of purine metabolism, energy metabolism, and amino metabolism in liver diseases. Furthermore, some metabolites such as cyclic adenosine monophosphate, glutamine, and short- and medium-chain acylcarnitines were the differential metabolites of HCC and CIR. On the basis of binary logistic regression, butyrylcarnitine (carnitine C4:0) and hydantoin-5-propionic acid were defined as combinational markers to distinguish HCC from CIR. The area under curve was 0.786 and 0.773 for discovery stage and validation stage samples, respectively. These data show that the established pseudotargeted method is a complementary one of targeted and nontargeted methods for metabolomics study.

Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. In the study, ultra high performance liquid chromatography-mass spectrometry was used to investigate serum metabolic abnormalities of AD children. Two batch fasting sera were collected from AD children and healthy control; one of them was for nontargeted metabolomics analysis, the other for targeted eicosanoids analysis. AD children were divided into high immunoglobulin E (IgE) group and normal IgE group. On the basis of the two analysis approaches, it was found that the differential metabolites of AD, leukotriene B4, prostaglandins, conjugated bile acids, etc., were associated with inflammatory response and bile acids metabolism. Carnitines, free fatty acids, lactic acid, etc., increased in the AD group with high IgE, which revealed energy metabolism disorder. Amino acid metabolic abnormalities and increased levels of Cytochrome P450 epoxygenase metabolites were found in the AD group with normal IgE. The results provided a new perspective to understand the mechanism and find potential biomarkers of AD and may provide a new reference for personalized treatment.

Composition and constraints of lithium isotopes in cryoconite from various remote glacier areas of the Tibetan Plateau.

Lithium isotope is one of the most promising indicators for the study of continental silicate weathering, and lithium concentrations and its isotopic compositions in earth surface can provide a better understanding of the geochemical behavior and isotopic fractionation during weathering and erosion. This work focused on the composition and distribution of Li isotope in cryoconite deposited on various glacier areas in a large range of the Tibetan Plateau and surroundings, as well as its implications for cryoconite dust provenances. Results showed that δ7Li in cryoconite varied within the same order of magnitude (-2.14 ‰-7.74 ‰), which is characterized by geographic distribution of higher δ7Li value of cryoconite in northern glaciers (e.g. Yuzhufeng Glacier), and lower δ7Li value in southern glaciers. In comparison with other global materials, the cryoconite dust shows a lighter δ7Li isotopic composition due to constraints of climatic conditions and land surface weathering intensity. Compared with dust materials in the surrounding Asian dust sources (e.g. large deserts and Gobi), we find that, the primary sources of Li isotope in cryoconite of the northern locations were from both local dust/soils of the TP surface and the surrounding large deserts. Moreover, the products of anthropogenic activities (e.g. coal-burning) may also influence the isotopic composition of the cryoconite dust, and Li isotope may serve as potential tracers of anthropogenic source activities. Therefore, this work provides a complete view of the composition and distribution of Lithium isotopes in cryoconite from various glacier areas of the Tibetan Plateau, and the research significance of its transport processes and source constraints of Li isotopes in cryoconite is proposed.

Reconstruction of human dispersal during Aurignacian on pan-European scale.

The Aurignacian is the first techno-complex related with certainty to Anatomically Modern Humans in Europe. Studies show that they appeared around 43-42 kyr cal BP and dispersed rapidly in Europe during the Upper Palaeolithic. However, human dispersal is a highly convoluted process which is until today not well understood. Here, we provide a reconstruction of the human dispersal during the Aurignacian on the pan-European scale using a human dispersal model, the Our Way Model, which combines archaeological with paleoclimate data and uses the human existence potential as a unifying driver of human population dynamics. Based on the reconstruction, we identify the different stages of the human dispersal and analyse how human demographic processes are influenced by climate change and topography. A chronology of the Aurignacian human groups in Europe is provided, which is verified for locations where archaeological dating records are available. Insights into highly debated hypotheses, such as human dispersal routes, are provided.

Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study.

JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.

Distribution and source of heavy metals in Tibetan Plateau topsoil: New insight into the influence of long-range transported sources to the surrounding glaciers.

Heavy metals present a substantial threat to both the environment and human health. Considering the delicate ecological equilibrium of the Tibetan Plateau (TP) and its heightened susceptibility to anthropogenic impacts, scholarly attention has progressively turned toward the examination of heavy metal pollution within the plateau's environment. In this study, we conducted a comprehensive analysis of various heavy metals (As, Cr, Co, Ni, Cu, Mo, Cd, Pb, and Sb), utilizing topsoil samples collected from the TP during the period of 2018-2021. Additionally, snow and cryoconite samples obtained from TP glaciers during the same timeframe were also subjected to analysis. The results indicate elevated concentrations of total heavy metals in the eastern and western TP (328.7 µg/g), as opposed to the central and southern TP (145.7 µg/g). Most heavy metals exhibit a consistent spatial distribution pattern. High Enrichment Factors (EFs) and Geoaccumulation Index (Igeo) values for As and Cd suggest their enrichment in TP topsoil. Receptor modeling identified three primary sources of heavy metals within the topsoil: industrial sources (42.3%), inherent natural sources within the surface soil (20.6%), and vehicular emissions (14.2%). Substantial differences in heavy metal concentrations and spatial distribution were observed between the topsoil and the glacial snow-cryoconite matrix. The prominent presence of Sb in the snow-cryoconite matrix, in contrast to its low abundance in the topsoil, indicates distinct source influences of long-range transported materials between the two environments. Our inference suggests that the influence of heavy metals from distant pollutants undergo mixing and dilution in the topsoil due to the presence of local indigenous heavy metals, although such influence is notably observed on the glacier surface of the TP. Consequently, this underscores the significant impact of long-range transported sources on heavy metals, surpassing the influence of local TP soils, to the alpine glaciers and even other atmospheric sediments in Tibetan Plateau.

Nanotube ferroelectric tunnel junctions with an ultrahigh tunneling electroresistance ratio.

Low-dimensional ferroelectric tunnel junctions are appealing for the realization of nanoscale nonvolatile memory devices due to their inherent advantages of device miniaturization. Those based on current mechanisms have limitations, including low tunneling electroresistance (TER) effects and complex heterostructures. Here, we introduce an entirely new TER mechanism to construct a nanotube ferroelectric tunnel junction with ferroelectric nanotubes as the tunneling region. When rolling a ferroelectric monolayer into a nanotube, due to the coexistence of its intrinsic ferroelectric polarization with the flexoelectric polarization induced by bending, a metal-insulator transition occurs depending on the radiative polarization states. For the pristine monolayer, its out-of-plane polarization is tunable by an in-plane electric field, and the conducting states of the ferroelectric nanotube can thus be tuned between metallic and insulating states via axial electric means. Using α-In2Se3 as an example, our first-principles density functional theory calculations and nonequilibrium Green's function formalism confirm the feasibility of the TER mechanism and indicate an ultrahigh TER ratio that exceeds 9.9 × 1010% of the proposed nanotube ferroelectric tunnel junctions. Our findings provide a promising approach based on simple homogeneous structures for high density ferroelectric microelectric devices with excellent ON/OFF performance.

Fecal microbiota from patients with Parkinson's disease intensifies inflammation and neurodegeneration in A53T mice.

AIMS: We evaluated the potential of Parkinson's disease (PD) fecal microbiota transplantation to initiate or exacerbate PD pathologies and investigated the underlying mechanisms. METHODS: We transplanted the fecal microbiota from PD patients into mice by oral gavage and assessed the motor and intestinal functions, as well as the inflammatory and pathological changes in the colon and brain. Furthermore, 16S rRNA gene sequencing combined with metabolomics analysis was conducted to assess the impacts of fecal delivery on the fecal microbiota and metabolism in recipient mice. RESULTS: The fecal microbiota from PD patients increased intestinal inflammation, deteriorated intestinal barrier function, intensified microglia and astrocyte activation, abnormal deposition of α-Synuclein, and dopaminergic neuronal loss in the brains of A53T mice. A mechanistic study revealed that the fecal microbiota of PD patients stimulated the TLR4/NF-κB/NLRP3 pathway in both the brain and colon. Additionally, multiomics analysis found that transplantation of fecal microbiota from PD patients not only altered the composition of the gut microbiota but also influenced the fecal metabolic profile of the recipient mice. CONCLUSION: The fecal microbiota from PD patients intensifies inflammation and neurodegeneration in A53T mice. Our findings demonstrate that imbalance and dysfunction in the gut microbiome play significant roles in the development and advancement of PD.

Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

BACKGROUND: Although WD repeat domain 45 (WDR45) mutations have been linked to ß -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system. METHODS: To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration. RESULTS: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits. CONCLUSIONS: In this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases.

Assessing climatic impact on transition from Neanderthal to anatomically modern human population on Iberian Peninsula: a macroscopic perspective.

The Iberian Peninsula is of particular interest for the research on the Neanderthal (NEA) to anatomically modern human (AMH) population transition. The AMHs arrived in Iberia last from Eastern Europe and thus any possible contacts between the two populations occurred here later than elsewhere. The transition process took place in the earlier part of the Marine Isotope Stage 3 (∼60-27 cal ka BP) as repeated and profound climate changes challenged the population stability. To investigate how climate change and population interactions influenced the transition, we combine climate data with archaeological-site data to reconstruct the Human Existence Potential, a measure of the probability of human existence, for both the NEA and AMH populations in the Greenland Interstadial 11-10 (GI11-10) and Stadial 10-9/Heinrich event 4 (GS10-9/HE4) times. It is found that during GS10-9/HE4, large parts of the peninsula became unsuitable for NEA human existence and the NEA settlement areas contracted to isolated coastal hot spots. As a consequence, the NEA networks became highly unstable, triggering the final collapse of the population. The AMHs arrived in Iberia in GI10 but were confined to patches in the northern most strip of the peninsula. They were soon facing the much colder climate of GS10-9/HE4, which prevented their further expansion or even caused a contraction of their settlement areas. Thus, due to the constellation of climate change and the dispersal of the two populations into different regions of the peninsula, it is unlikely that the NEAs and AMHs coexisted in extensive areas and the AMHs had a significant influence on the demography of the NEAs.

A metabolome atlas of mouse brain on the global metabolic signature dynamics following short-term fasting.

Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Drivers of recent decline in dust activity over East Asia.

It is essential to understand the factors driving the recent decline of dust activity in East Asia for future dust projections. Using a physically-based dust emission model, here we show that the weakening of surface wind and the increasing of vegetation cover and soil moisture have all contributed to the decline in dust activity during 2001 to 2017. The relative contributions of these three factors to the dust emission reduction during 2010-2017 relative to 2001 are 46%, 30%, and 24%, respectively. Much (78%) of the dust emission reduction is from barren lands, and a small fraction (4.6%) of the reduction is attributed to grassland vegetation increase that is partly ascribed to the ecological restoration. This suggests that the ecological restoration plays a minor role in the decline of dust activity. Rather, the decline is mainly driven by climatic factors, with the weakening of surface wind playing the dominant role.

Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons.

Background: The classical motor symptoms of Parkinson's disease (PD) are tightly linked to the gradual loss of dopamine within the striatum. Concomitantly, medium spiny neurons (MSNs) also experience morphological changes, such as reduced dendritic complexity and spine density, which may be potentially associated with motor dysfunction as well. Thus, MSNs may serve as the emerging targets for PD therapy besides the midbrain dopaminergic neurons. Results: To comprehensively examine pathological alterations of MSNs longitudinally, we established a TH Cre/ Pitx3 fl/fl (Pitx3cKO ) mouse model that developed canonical PD features, including a significant loss of SNc DAergic neurons and motor deficits. During aging, the targeted neurotransmitter, MSNs morphology and DNA methylation profile were significantly altered upon Pitx3 deficiency. Specifically, dopamine, GABA and glutamate decreased in the model at the early stage. While nuclear, soma and dendritic atrophy, as well as nuclear invaginations increased in the aged MSNs of Pitx3cko mice. Furthermore, more nuclear DNA damages were characterized in MSNs during aging, and Pitx3 deficiency aggravated this phenomenon, together with alterations of DNA methylation profiling associated with lipoprotein and nucleus pathway at the late stage. Conclusion: The early perturbations of the neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology and epigenetics within the striatum at the late stage, which may provide new perspectives on the diagnosis and pathogenesis of PD.

Cu(ii)/SPDO complex catalyzed asymmetric Baeyer-Villiger oxidation of 2-arylcyclobutanones and its application for the total synthesis of eupomatilones 5 and 6.

A novel classical kinetic resolution of 2-aryl-substituted or 2,3-disubstituted cyclobutanones of Baeyer-Villiger oxidation catalyzed by a Cu(ii)/SPDO complex is reported for the first time, producing normal lactones in excellent enantioselectivities (up to 96% ee) and regioselectivities (up to >20/1), along with unreacted ketones in excellent enantioselectivities (up to 99% ee). The current transformation features a wide substrate scope. Moreover, catalytic asymmetric total syntheses of natural eupomatilones 5 and 6 are achieved in nine steps from commercially available 3-methylcyclobutan-1-one.