Maize PPR-E proteins mediate RNA C-to-U editing in mitochondria by recruiting the trans deaminase PCW1.

RNA C-to-U editing in organelles is essential for plant growth and development; however, the underlying mechanism is not fully understood. Here, we report that pentatricopeptide repeat (PPR)-E subclass proteins carry out RNA C-to-U editing by recruiting the trans deaminase PPR motifs, coiled-coil, and DYW domain-containing protein 1 (PCW1) in maize (Zea mays) mitochondria. Loss-of-function of bZIP and coiled-coil domain-containing PPR 1 (bCCP1) or PCW1 arrests seed development in maize. bCCP1 encodes a bZIP and coiled-coil domain-containing PPR protein, and PCW1 encodes an atypical PPR-DYW protein. bCCP1 is required for editing at 66 sites in mitochondria and PCW1 is required for editing at 102 sites, including the 66 sites that require bCCP1. The PCW1-mediated editing sites are exclusively associated with PPR-E proteins. bCCP1 interacts with PCW1 and the PPR-E protein Empty pericarp7 (EMP7). Two multiple organellar RNA editing factor (MORF) proteins, ZmMORF1 and ZmMORF8, interact with PCW1, EMP7, and bCCP1. ZmMORF8 enhanced the EMP7-PCW1 interaction in a yeast three-hybrid assay. C-to-U editing at the ccmFN-1553 site in maize required EMP7, bCCP1, and PCW1. These results suggest that PPR-E proteins function in RNA editing by recruiting the trans deaminase PCW1 and bCCP1, and MORF1/8 assist this recruitment through protein-protein interactions.

Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.

The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.

Dynamic nonreversibility view of intrinsic brain organization and brain dynamic analysis of repetitive transcranial magnitude stimulation.

Intrinsic neural activities are characterized as endless spontaneous fluctuation over multiple time scales. However, how the intrinsic brain organization changes over time under local perturbation remains an open question. By means of statistical physics, we proposed an approach to capture whole-brain dynamics based on estimating time-varying nonreversibility and k-means clustering of dynamic varying nonreversibility patterns. We first used synthetic fMRI to investigate the effects of window parameters on the temporal variability of varying nonreversibility. Second, using real test-retest fMRI data, we examined the reproducibility, reliability, biological, and physiological correlation of the varying nonreversibility substates. Finally, using repetitive transcranial magnetic stimulation-fMRI data, we investigated the modulation effects of repetitive transcranial magnetic stimulation on varying nonreversibility substate dynamics. The results show that: (i) as window length increased, the varying nonreversibility variance decreased, while the sliding step almost did not alter it; (ii) the global high varying nonreversibility states and low varying nonreversibility states were reproducible across multiple datasets and different window lengths; and (iii) there were increased low varying nonreversibility states and decreased high varying nonreversibility states when the left frontal lobe was stimulated, but not the occipital lobe. Taken together, these results provide a thermodynamic equilibrium perspective of intrinsic brain organization and reorganization under local perturbation.

Pirin Promotes the Progression of Non-Small-Cell Lung Cancer by Increasing ODC1 to Suppress Autophagy.

Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome.

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.

Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Oxygen-Vacancy-Reinforced Vanadium Oxide/Graphene Heterojunction for Accelerated Zinc Storage with Long Life Span.

Vanadium trioxide (V6 O13 ) cathode has recently aroused intensive interest for aqueous zinc-ion batteries (AZIBs) due to their structural and electrochemical diversities. However, it undergoes sluggish reaction kinetics and significant capacity decay during prolonged cycling. Herein, an oxygen-vacancy-reinforced heterojunction in V6 O13- x /reduced graphene oxide (rGO) cathode is designed through electrostatic assembly and annealing strategy. The abundant oxygen vacancies existing in V6 O13- x weaken the electrostatic attraction with the inserted Zn2+ ; the external electric field constructed by the heterointerfaces between V6 O13- x and rGO provides additional built-in driving force for Zn2+ migration; the oxygen-vacancy-enriched V6 O13- x highly dispersed on rGO fabricates the interconnected conductive network, which achieves rapid Zn2+ migration from heterointerfaces to lattice. Consequently, the obtained 2D heterostructure exhibits a remarkable capacity of 424.5 mAh g-1 at 0.1 A g-1 , and a stable capacity retention (96% after 5800 cycles) at the fast discharge rate of 10 A g-1 . Besides, a flexible pouch-type AZIB with real-life practicability is fabricated, which can successfully power commercial products, and maintain stable zinc-ion storage performances even under bending, heavy strikes, and pressure condition. A series of quantitative investigation of pouch batteries demonstrates the possibility of pushing pouch-type AZIBs to realistic energy storage market.

Shielding Mn3+ Disproportionation with Graphitic Carbon-Interlayered Manganese Oxide Cathodes for Enhanced Aqueous Energy Storage System.

Manganese dioxide (MnO2) materials have recently garnered attention as prospective high-capacity cathodes, owing to their theoretical two-electron redox reaction in charge storage processes. However, their practical application in aqueous energy storage systems faces a formidable challenge: the disproportionation of Mn3+ ions, leading to a significant reduction in their capacity. To address this limitation, the study presents a novel graphitic carbon interlayer-engineered manganese oxide (CI-MnOx) characterized by an open structure and abundant defects. This innovative material serves several essential functions for efficient aqueous energy storage. First, a graphitic carbon layer coats the MnOx molecular interlayer, effectively inhibiting Mn3+ disproportionation and substantially enhancing electrode conductivity. Second, the phase variation within MnOx generates numerous crystal defects, vacancies, and active sites, optimizing electron-transfer capability. Third, the flexible carbon layer acts as a buffer, mitigating the volume expansion of MnOx during extended cycling. The synergistic effects of these features result in the CI-MnOx exhibiting an impressive high capacity of 272 mAh g-1 (1224 F g-1) at 0.25 A g-1. Notably, the CI-MnOx demonstrates zero capacity loss after 90 000 cycles (≈3011 h), an uncommon longevity for manganese oxide materials. Spectral characterizations reveal reversible cation intercalation and conversion reactions with multielectron transfer in a LiCl electrolyte.

Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit.

Although manifesting contrasting phenotypes, Parkinson's disease and dystonia, the two most common movement disorders, can originate from similar pathophysiology. Previously, we demonstrated that lesioning (silencing) of a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot-induced dystonia. Presently, we injected fluorescent-tagged multi-synaptic tracers into these pallidal hotspots (n = 36 Long Evans rats) and permitted 4 days for the viruses to travel along restricted connecting pathways and reach the motor cortex before sacrificing the animals. Viral injections in the Parkinson's hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.

Conditional generative adversarial network driven radiomic prediction of mutation status based on magnetic resonance imaging of breast cancer.

BACKGROUND: Breast Cancer (BC) is a highly heterogeneous and complex disease. Personalized treatment options require the integration of multi-omic data and consideration of phenotypic variability. Radiogenomics aims to merge medical images with genomic measurements but encounter challenges due to unpaired data consisting of imaging, genomic, or clinical outcome data. In this study, we propose the utilization of a well-trained conditional generative adversarial network (cGAN) to address the unpaired data issue in radiogenomic analysis of BC. The generated images will then be used to predict the mutations status of key driver genes and BC subtypes. METHODS: We integrated the paired MRI and multi-omic (mRNA gene expression, DNA methylation, and copy number variation) profiles of 61 BC patients from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). To facilitate this integration, we employed a Bayesian Tensor Factorization approach to factorize the multi-omic data into 17 latent features. Subsequently, a cGAN model was trained based on the matched side-view patient MRIs and their corresponding latent features to predict MRIs for BC patients who lack MRIs. Model performance was evaluated by calculating the distance between real and generated images using the Fréchet Inception Distance (FID) metric. BC subtype and mutation status of driver genes were obtained from the cBioPortal platform, where 3 genes were selected based on the number of mutated patients. A convolutional neural network (CNN) was constructed and trained using the generated MRIs for mutation status prediction. Receiver operating characteristic area under curve (ROC-AUC) and precision-recall area under curve (PR-AUC) were used to evaluate the performance of the CNN models for mutation status prediction. Precision, recall and F1 score were used to evaluate the performance of the CNN model in subtype classification. RESULTS: The FID of the images from the well-trained cGAN model based on the test set is 1.31. The CNN for TP53, PIK3CA, and CDH1 mutation prediction yielded ROC-AUC values 0.9508, 0.7515, and 0.8136 and PR-AUC are 0.9009, 0.7184, and 0.5007, respectively for the three genes. Multi-class subtype prediction achieved precision, recall and F1 scores of 0.8444, 0.8435 and 0.8336 respectively. The source code and related data implemented the algorithms can be found in the project GitHub at https://github.com/mattthuang/BC_RadiogenomicGAN . CONCLUSION: Our study establishes cGAN as a viable tool for generating synthetic BC MRIs for mutation status prediction and subtype classification to better characterize the heterogeneity of BC in patients. The synthetic images also have the potential to significantly augment existing MRI data and circumvent issues surrounding data sharing and patient privacy for future BC machine learning studies.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

COP1-ERF1-SCE1 regulatory module fine-tunes stress response under light-dark cycle in Arabidopsis.

ETHYLENE RESPONSE FACTOR 1 (ERF1) plays an important role in integrating hormone crosstalk and stress responses. Previous studies have shown that ERF1 is unstable in the dark and its degradation is mediated by UBIQUITIN-CONJUGATING ENZYME 18. However, whether there are other enzymes regulating ERF1's stability remains unclear. Here, we use various in vitro and in vivo biochemical, genetic and stress-tolerance tests to demonstrate that both CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) and SUMO-CONJUGATING ENZYME 1 (SCE1) regulate the stability of ERF1. We also performed transcriptomic analyses to understand their common regulatory pathways. We show that COP1 mediates ERF1 ubiquitination in the dark while SCE1 mediates ERF1 sumoylation in the light. ERF1 stability is positively regulated by SCE1 and negatively regulated by COP1. Upon abiotic stress, SCE1 plays a positive role in stress defence by regulating the expression of ERF1's downstream stress-responsive genes, whereas COP1 plays a negative role in stress response. Moreover, ERF1 also promotes photomorphogenesis and the expression of light-responsive genes. Our study reveals the molecular mechanism of how COP1 and SCE1 counteract to regulate ERF1's stability and light-stress signalling crosstalk.

A Green Environmental Protection Photocatalytic Molecular Reactor for Aerobic Oxidation of Sulfide to Sulfoxide.

The design and synthesis of metal-organic frameworks (MOFs) as photocatalytic molecular reactors for varied reactions have drawn great attention. In this work, we designed a novel photoactive perylenediimides-based (PDI) carboxylate ligand N,N'-di(3',3",5',5"-tetrakis(4-carboxyphenyl))-1,2,6,7-tetrachloroperylene-3,4,9,10-tetracarboxylic acid diimide (Cl-PDI-TA) and use it to successfully synthesize a novel Zr(IV)-based MOF 1 constructed from [Zr6 O8 (H2 O)8 ]8+ clusters bridged by Cl-PDI-TA ligands. Structural analysis revealed that Zr-MOF 1 manifests a 3D framework with (4,8)-connected csq topology and possesses triangular channels of ~17 Šand mesoporous hexagonal channels of ~26 Šalong c-axis. Moreover, the synthesized Zr-MOF 1 exhibits visible-light absorption and efficient photoinduced free radical generation property, making it a promising photocatalytic molecular reactor. When Zr-MOF 1 was used as a photocatalyst for the aerobic oxidation of sulfides under irradiation of visible light, it could afford the corresponding sulfoxides with high yield and selectivity. Experimental results demonstrated that the substrate sulfides could be fixed in the pores of 1 and directly transformed to the products sulfoxides in the solid state. Furthermore, the mechanism for the photocatalytic transformation was also investigated and the results revealed that the singlet oxygen (1 O2 ) and superoxide radical (O2 ⋅- ) generated by the energy transfer and electron transfer from the photoexcited Zr-MOF to oxidants were the main active species for the catalytic reactions. This work offers a perceptive comprehension of the mechanism in PDI-based MOFs for further study on photocatalytic reactions.

Effect of Regional Brain Activity Following Repeat Transcranial Magnetic Stimulation in SCA3: A Secondary Analysis of a Randomized Clinical Trial.

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32-55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26-58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.

Unveiling the Selectivity of Ru(II)-Catalyzed C-H Activation for Defluorinative Cyclization of 2-Arylbenzimidazole and Trifluoromethyl Diazo: A DFT Study.

The synthesis of monofluorinated heterocyclic compounds by C-H activation combined with defluorination is useful. Studies on the reaction mechanism and selectivity have shown that these processes play a positive role in promoting the development of monofluorinated reactions. Density functional theory (DFT) calculations were performed to investigate the mechanism and selectivity of Ru(II)-catalyzed 2-arylbenzimidazole with trifluoromethyl diazo. DFT calculations showed that C-H activation occurs through a concerted metalation/deprotonation (CMD) mechanism. After that, deprotonation and defluorinative cyclization are assisted by acetate and trifluoroethanol (TFE). Further mechanistic insights through noncovalent interaction (NCI) analysis were also obtained to elucidate the origin of the selectivity in the defluorination process.

Low-frequency repetitive transcranial magnetic stimulation alters the individual functional dynamical landscape.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach to modulate brain activity and behavior in humans. Still, how individual resting-state brain dynamics after rTMS evolves across different functional configurations is rarely studied. Here, using resting state fMRI data from healthy subjects, we aimed to examine the effects of rTMS to individual large-scale brain dynamics. Using Topological Data Analysis based Mapper approach, we construct the precise dynamic mapping (PDM) for each participant. To reveal the relationship between PDM and canonical functional representation of the resting brain, we annotated the graph using relative activation proportion of a set of large-scale resting-state networks (RSNs) and assigned the single brain volume to corresponding RSN-dominant or a hub state (not any RSN was dominant). Our results show that (i) low-frequency rTMS could induce changed temporal evolution of brain states; (ii) rTMS didn't alter the hub-periphery configurations underlined resting-state brain dynamics; and (iii) the rTMS effects on brain dynamics differ across the left frontal and occipital lobe. In conclusion, low-frequency rTMS significantly alters the individual temporo-spatial dynamics, and our finding further suggested a potential target-dependent alteration of brain dynamics. This work provides a new perspective to comprehend the heterogeneous effect of rTMS.

Correlation between serum trimethylamine-N-oxide and body fat distribution in middle-aged and older adults: a prospective cohort study.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is linked with obesity, while limited evidence on its relationship with body fat distribution. Herein, we investigated the associations between serum TMAO and longitudinal change of fat distribution in this prospective cohort study. METHODS: Data of 1964 participants (40-75y old) from Guangzhou Nutrition and Health Study (GNHS) during 2008-2014 was analyzed. Serum TMAO concentration was quantified by HPLC-MS/MS at baseline. The body composition was assessed by dual-energy X-ray absorptiometry at each 3-y follow-up. Fat distribution parameters were fat-to-lean mass ratio (FLR) and trunk-to-leg fat ratio (TLR). Fat distribution changes were derived from the coefficient of linear regression between their parameters and follow-up duration. RESULTS: After an average of 6.2-y follow-up, analysis of covariance (ANCOVA) and linear regression displayed women with higher serum TMAO level had greater increments in trunk FLR (mean ± SD: 1.47 ± 4.39, P-trend = 0.006) and TLR (mean ± SD: 0.06 ± 0.24, P-trend = 0.011). Meanwhile, for women in the highest TMAO tertile, linear mixed-effects model (LMEM) analysis demonstrated the annual estimated increments (95% CI) were 0.03 (95% CI: 0.003 - 0.06, P = 0.032) in trunk FLR and 1.28 (95% CI: -0.17 - 2.73, P = 0.083) in TLR, respectively. In men, there were no similar significant observations. Sensitivity analysis yielded consistent results. CONCLUSION: Serum TMAO displayed a more profound correlation with increment of FLR and TLR in middle-aged and older community-dwelling women in current study. More and further studies are still warranted in the future. TRIAL REGISTRATION: NCT03179657.

Double tract reconstruction improves the quality of life and better maintain the BMI of patients with proximal gastric cancer.

PURPOSE: The aim of this study is to investigate the effect of double-tract reconstruction on short-term clinical outcome, quality of life and nutritional status of patients after proximal gastrectomy by comparing with esophagogastrostomy and total gastrectomy with Roux-en-Y reconstruction. METHODS: The clinical data of patients who underwent double tract reconstruction (DTR), esophagogastrostomy (EG), total gastrectomy with Roux-en-Y reconstruction (TG-RY) were retrospectively collected from May 2020 to May 2022. The clinical characteristics, short-term surgical outcomes, postoperative quality of life and nutritional status were compared among the three groups. RESULTS: Compared with the DTR group, the operation time in the TG group was significantly shorter (200(180,240) minutes vs. 230(210,255) minutes, p < 0.01), and more lymph nodes were removed (28(22, 25) vs. 22(19.31), p < 0.01), there were no significant differences in intraoperative blood loss, first flatus time, postoperative hospital stay and postoperative complication rate among the three groups. Postoperative digestive tract angiography was completed in 36 patients in the DTR group, of which 21 (58.3%) showed double-tract type of food passing. The incidence of postoperative reflux symptoms was 9.2% in the DTR group, 43.8% in the EG group and 23.2% in the TG group, repectively (P < 0.01). EORTCQLQ-STO22 questionnaire survey showed that compared with EG group, DTR group had fewer reflux symptoms (P < 0.05), fewer anxiety symptoms (P < 0.05) and more swallowing symptoms (P < 0.05). Compared with TG group, DTR group had fewer reflux symptoms (P < 0.05). There were no other significant differences between the two groups. Compared with TG group and EG group, DTR can better maintain postoperative BMI, and there is no statistical difference between the three groups in terms of hemoglobin and albumin. CONCLUSIONS: Although partial double-tract reconstruction approach does not always ensure food to enter the distal jejunum along the two pathways as expected, it still shows satisfactory anti-reflux effect. Moreover, it might improve patients' quality of life and maintain better nutritional status comparing with gastroesophageal anastomosis and total gastrectomy with Roux-en-Y reconstruction.