Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease.

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.

MRMQuant: Automated MRM Data Quantitation for Large-Scale Targeted Metabolomics Analysis.

Multiple reaction monitoring (MRM) is a powerful and popular technique used for metabolite quantification in targeted metabolomics. Accurate and consistent quantitation of metabolites from the MRM data is essential for subsequent analyses. Here, we developed an automated tool, MRMQuant, for targeted metabolomic quantitation using high-throughput liquid chromatography-tandem mass spectrometry MRM data to provide users with an easy-to-use tool for accurate MRM data quantitation with minimal human intervention. This tool has many user-friendly functions and features to inspect and correct the quantitation results as required. MRMQuant possesses the following features to ensure accurate quantitation: (1) dynamic signal smoothing, (2) automatic deconvolution of coeluted peaks, (3) absolute quantitation via standard curves and/or internal standards, (4) visualized inspection and correction, (5) corrections applicable to multiple samples, and (6) batch-effect correction.

Endometrial cancer risk stratification using MRI radiomics: corroborating with choline metabolism.

BACKGROUND AND PURPOSE: Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism. MATERIALS AND METHODS: From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance. RESULTS: Rad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO's 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019). CONCLUSIONS: Development of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov on 2015-08-01 with Identifier NCT02528864.

Diagnostic Potential of Alternations of Bile Acid Profiles in the Plasma of Patients with Huntington's Disease.

Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.

Identification of neutralizing antibodies against monkeypox virus using high-throughput sequencing of A35+H3L+B cells from patients with convalescent monkeypox.

The global monkeypox virus (MPXV) outbreak in 2022 emphasizes the urgent need for effective and accessible new-generation vaccines and neutralizing antibodies. Herein, we identified MPXV-neutralizing antibodies using high-throughput single-cell RNA and V(D)J sequencing of antigen-sorted B cells from patients with convalescent monkeypox. IgG1-expressing B cells were obtained from 34 paired heavy- and light-chain B cell receptor sequences. Subsequently, three potent neutralizing antibodies, MV127, MV128, and MV129, were identified and reacted with the MPXV A35 protein. Among these, MV129, which has a half-maximal inhibitory concentration of 2.68µg/mL against authentic MPXV, was considered to be the putative candidates for MPXV neutralization in response to monkeypox disease.

Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II HCC undergoing surgery? An observational cohort study.

INTRODUCTION: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed. METHODS: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis. RESULTS: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid ß-oxidation was enhanced in with low PMI or high SAT index. CONCLUSION: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.

Combined Plasma DHA-Containing Phosphatidylcholine PCaa C38:6 and Tetradecanoyl-Carnitine as an Early Biomarker for Assessing the Mortality Risk among Sarcopenic Patients.

The coming of the hyper-aged society in Taiwan prompts us to investigate the relationship between the metabolic status of sarcopenic patients and their most adverse outcome-death. We studied the association between any plasma metabolites and the risk for mortality among older Taiwanese sarcopenic patients. We applied a targeted metabolomic approach to study the plasma metabolites of adults aged ≥65 years, and identified the metabolic signature predictive of the mortality of sarcopenic patients who died within a 5.5-year follow-up period. Thirty-five sarcopenic patients who died within the follow-up period (Dead cohort) had shown a specific plasma metabolic signature, as compared with 54 patients who were alive (Alive cohort). Only 10 of 116 non-sarcopenic individuals died during the same period. After multivariable adjustment, we found that sex, hypertension, tetradecanoyl-carnitine (C14-carnitine), and docosahexaenoic acid (DHA)-containing phosphatidylcholine diacyl (PCaa) C38:6 and C40:6 were important risk factors for the mortality of sarcopenic patients. Low PCaa C38:6 levels and high C14-carnitine levels correlated with an increased mortality risk; this was even the same for those patients with hypertension (HTN). Our findings suggest that plasma PCaa C38:6 and acylcarnitine C14-carnitine, when combined, can be a better early biomarker for evaluating the mortality risk of sarcopenia patients.

Rapid and Direct Detection of Trimethylamine N-oxide Using an Off-Chip Capacitance Biosensor with Readout SoC for Early-Stage Thrombosis and Cardiovascular Disease.

A demonstration of an off-chip capacitance array sensor with a limit of detection of 1 µM trimethylamine N-oxide (TMAO) to diagnose a chronic metabolism disease in urine is presented. The improved Cole-Cole model is employed to determine the parameters of R_catalyzed, C_catalyzed, and Rp_catalyzed, enabling the prediction of the catalytic resistance of enzyme, reduction effects of the analyte, and characterize the small signal alternating current properties of ionic strength caused by catalysis. Based on the standard solutions, we investigate the effects of pixel geometry parameters, driving electrode width, and sensing electrode width on the electrical field change of the off-chip capacitance sensor; the proposed off-chip sensor with readout system-on-chip exhibits a high sensitivity of 21 analog-to-digital converter counts/µM TMAO (or 2.5 mV/µM TMAO), response time of 1 s, repetition of 98.9%, and drift over time of 0.5 mV. The proposed off-chip sensor effectively discriminates TMAO in a phosphate-buffered saline solution based on minute changes in capacitance induced by the TorA enzyme, resulting in a discernible 2.15% distinction. These measurements have been successfully corroborated using the conventional cyclic voltammetry method, demonstrating a mere 0.024% variance. The off-chip sensor is crafted with a specific focus on detecting TMAO, achieved by excluding any reduction reactions between the TMAO-specific enzyme TorA and the compounds creatine and creatinine present in urine. This deliberate omission ensures that the sensor's attention remains solely on TMAO, thereby enhancing its precision in achieving accurate and reliable TMAO detection.

Oral fecal transplantation enriches Lachnospiraceae and butyrate to mitigate acute liver injury.

While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury.

Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR-122.

Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA-122 (miR-122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR-122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV-transgenic mice with miR-122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early-onset hepatic steatosis, progressive liver fibrosis, and impaired late-phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30-35% compared to untreated mice. This effect was linked to the activation of ER stress-responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP-mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR-122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above-mentioned pathogenesis through HBV suppression.

Long-Wavelength Illumination-Induced Photocurrent Enhancement of a ZnPc Photocathodic Material for Bioanalytical Applications.

Herein, a novel photocathodic nanocomposite poly{4,8-bis[5-(2-ethylhexyl)-thiophen-2-yl] benzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt-3-fluoro-2-[(2-ethylhexyl)-carbonyl]thieno[3,4-b]thiophene-4,6-diyl}/phthalocyanine zinc (PTB7-Th/ZnPc) with high photoelectric conversion efficiency under long-wavelength illumination was prepared to construct an ultrasensitive biosensor for the detection of microRNA-21 (miRNA-21), accompanied by a prominent anti-interference capability toward reductive substances. Impressively, the new heterojunction PTB7-Th/ZnPc nanocomposite could not only generate a strong cathodic photocurrent to improve the detection sensitivity under long-wavelength illumination (660 nm) but also effectively avoid the high damage of biological activity caused by short-wavelength light stimulation. Accordingly, by coupling with rolling circle amplification (RCA)-triggered DNA amplification to form functional biquencher nanospheres, a PEC biosensor was fabricated to realize the ultrasensitive analysis of miRNA-21 in the concentration range of 0.1 fM to 10 nM with a detection limit as low as 32 aM. This strategy provided a novel long-wavelength illumination-induced photocurrent enhancement photoactive material for a sensitive and low-damage anti-interference bioassay and early clinical disease diagnosis.

Lack of incremental value of three-dimensional measurement in assessing invasiveness for lung cancer.

OBJECTIVES: The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS: A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS: A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P = 0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P < 0.000 vs P < 0.000) and overall survival (P = 0.003 vs P = 0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P = 0.189). CONCLUSIONS: Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional.

Metabolomics Assessment of Volume Overload-Induced Heart Failure and Oxidative Stress in the Kidney.

The incidence of heart failure (HF) is increasing and is associated with a poor prognosis. Moreover, HF often coexists with renal dysfunction and is associated with a worsened outcome. In many experimental studies on cardiac dysfunction, the function of other organs was either not addressed or did not show any decline. Until now, the exact mechanisms for initiating and sustaining this interaction are still unknown. The objective of this study is to use volume overload to induce cardiac hypertrophy and HF in aortocaval fistula (ACF) rat models, and to elucidate how volume overload affects metabolic changes in the kidney, even with normal renal function, in HF. The results showed the metabolic changes between control and ACF rats, including taurine metabolism; purine metabolism; glycine, serine, and threonine metabolism; glycerophospholipid metabolism; and histidine metabolism. Increasing the downstream purine metabolism from inosine to uric acid in the kidneys of ACF rats induced oxidative stress through xanthine oxidase. This result was consistent with HK-2 cells treated with xanthine and xanthine oxidase. Under oxidative stress, taurine accumulation was observed in ACF rats, indicating increased activity of the hypotaurine-taurine pathway as a defense mechanism against oxidative stress in the kidney. Another antioxidant, ascorbic acid 2-sulfate, showed lower levels in ACF rats, indicating that the kidneys experience elevated oxidative stress due to volume overload and HF. In summary, metabolic profiles are more sensitive than clinical parameters in reacting to damage to the kidney in HF.

Plasma acylcarnitine in elderly Taiwanese: as biomarkers of possible sarcopenia and sarcopenia.

BACKGROUND: Sarcopenia is defined as the disease of muscle loss and dysfunction. The prevalence of sarcopenia is strongly age-dependent. It could bring about disability, hospitalization, and mortality. The purpose of this study was to identify plasma metabolites associated with possible sarcopenia and muscle function to improve disease monitoring and understand the mechanism of muscle strength and function decline. METHODS: The participants were a group of healthy older adult who live in retirement homes in Asia (Taiwan) and can manage their daily lives without assistance. The participants were enrolled and divided into four groups: control (Con, n = 57); low physical function (LPF, n = 104); sarcopenia (S, n = 63); and severe sarcopenia (SS, n = 65) according to Asian countries that used Asian Working Group for Sarcopenia (AWGS) criteria. The plasma metabolites were used and the results were calculated as the difference between the control and other groups. RESULTS: Clinical parameters, age, gender, body mass index (BMI), hand grip strength (HGS), gait speed (GS), blood urea nitrogen (BUN), hemoglobin, and hematocrit were significantly different between the control and LPF groups. Metabolite patterns of LPF, S, and SS were explored in our study. Plasma kynurenine (KYN) and acylcarnitines (C0, C4, C6, and C18:1-OH) were identified with higher concentrations in older Taiwanese adults with possible sarcopenia and S compared to the Con group. After multivariable adjustment, the data indicate that age, BMI, and butyrylcarnitine (C4) are more important factors to identify individuals with low physical function and sarcopenia. CONCLUSION: This metabolomic study raises the importance of acylcarnitines on muscle mass and function. It suggests that age, BMI, BUN, KYN, and C4/Cr can be important evaluation markers for LPF (AUC: 0.766), S (AUC: 0.787), and SS (AUC: 0.919).

PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.

Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.

RACK1 promotes porcine reproductive and respiratory syndrome virus infection in Marc-145 cells through ERK1/2 activation.

Porcine reproductive and respiratory syndrome (PRRS) is an acute infectious disease that spreads rapidly among pigs and seriously threatens the pig industry. Activation of ERK1/2 is a hallmark of most viral infections. RACK1 interacts with a variety of kinases and membrane receptors that closely associated with viral infections and the development and progression of cancer. However, no studies have clearly defined whether RACK1 can regulate PRRSV infection through ERK1/2 activation. In our study, using RT-qPCR, immunoblotting, indirect fluorescent staining, siRNA knockdown and protein overexpression techniques, we found that downregulation of cellular RACK1 inhibited ERK1/2 activation and subsequently suppressed PRRSV infection, while overexpression of RACK1 enhanced ERK1/2 activation and PRRSV infection. Bioinformatic and Co-immunoprecipitation experimental analysis revealed that cellular RACK1 could interact with viral N protein to exert its function. We elaborated that RACK1 promoted PRRSV replication in Marc-145 cells through ERK1/2 activation. Our study provides new insights into regulating the innate antiviral immune responses during PRRSV infection and contributes to further understanding of the molecular mechanisms underlying PRRSV replication.

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry.

BACKGROUND: During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. METHODS: In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC-MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20-87 years without obesity or diabetes were analyzed. RESULTS: We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood-brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. CONCLUSIONS: Our LC-MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.

Assessing uncertainty and heterogeneity in machine learning-based spatiotemporal ozone prediction in Beijing-Tianjin- Hebei region in China.

Accurate prediction of spatiotemporal ozone concentration is of great significance to effectively establish advanced early warning systems and regulate air pollution control. However, the comprehensive assessment of uncertainty and heterogeneity in spatiotemporal ozone prediction remains unknown. Here, we systematically analyze the hourly and daily spatiotemporal predictive performances using convolutional long short term memory (ConvLSTM) and deep convolutional generative adversarial network (DCGAN) models over the Beijing-Tianjin-Hebei region in China from 2013 to 2018. In extensive scenarios, our results show that the machine learning-based (ML-based) models achieve better spatiotemporal ozone concentration prediction performance with multiple meteorological conditions. A further comparison to the air pollution model-Nested Air Quality Prediction Modelling System (NAQPMS) and monitoring observations, the ConvLSTM model demonstrates the practical feasibility of identifying high ozone concentration distribution and capturing spatiotemporal ozone variation patterns at a high spatial resolution (here 15 km × 15 km).

Large-scale genetic surveys for main extant population of wild giant panda (Ailuropoda melanoleuca) reveals an urgent need of human management.

There are only six isolated living giant panda populations, and a comprehensive understanding of their genetic health status is crucial for the conservation of this vulnerable species. Liangshan Mountains is one of the main distribution areas of living giant pandas and is outside the newly established Giant panda national park. In this study, 971 giant panda fecal samples were collected in the heartland of Liangshan Mountains (Mabian Dafengding Nature Reserve: MB; Meigu Dafengding Nature Reserve: MG; and Heizhugou Nature Reserve: HZG). Microsatellite markers and mitochondrial D-loop sequences were used to estimate population size and genetic diversity. We identified 92 individuals (MB: 27, MG: 22, HZG: 43) from the three reserves. Our results showed that: (1) genetic diversity of three giant panda populations was moderate; (2) several loci deviated significantly from the Hardy-Weinberg equilibrium and almost all these deviated loci showed significant heterozygote deficiencies and inbreeding; (3) three giant panda populations have substantial genetic differentiation with the most differentiation between MB and the two other populations; and (4) a large amount of giant panda feces outside the three reserves were found, implying the existence of protection gap. These results indicated that under stochastic events, the giant panda populations in Liangshan Mountains are at risk of genetic decline or extinction and urgent need of human management. This study revealed that high attention should be paid to the protection of these giant panda populations outside the Giant panda national park, to ensure their survival in their distribution areas.

Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation.

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of ß-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd-/-) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.