Characterizing the distinct imaging phenotypes, clinical behavior, and genetic vulnerability of brain maturational subtypes in mood disorders.

BACKGROUND: Mood disorders are characterized by great heterogeneity in clinical manifestation. Uncovering such heterogeneity using neuroimaging-based individual biomarkers, clinical behaviors, and genetic risks, might contribute to elucidating the etiology of these diseases and support precision medicine. METHODS: We recruited 174 drug-naïve and drug-free patients with major depressive disorder and bipolar disorder, as well as 404 healthy controls. T1 MRI imaging data, clinical symptoms, and neurocognitive assessments, and genetics were obtained and analyzed. We applied regional gray matter volumes (GMV) and quantile normative modeling to create maturation curves, and then calculated individual deviations to identify subtypes within the patients using hierarchical clustering. We compared the between-subtype differences in GMV deviations, clinical behaviors, cell-specific transcriptomic associations, and polygenic risk scores. We also validated the GMV deviations based subtyping analysis in a replication cohort. RESULTS: Two subtypes emerged: subtype 1, characterized by increased GMV deviations in the frontal cortex, cognitive impairment, a higher genetic risk for Alzheimer's disease, and transcriptionally associated with Alzheimer's disease pathways, oligodendrocytes, and endothelial cells; and subtype 2, displaying globally decreased GMV deviations, more severe depressive symptoms, increased genetic vulnerability to major depressive disorder and transcriptionally related to microglia and inhibitory neurons. The distinct patterns of GMV deviations in the frontal, cingulate, and primary motor cortices between subtypes were shown to be replicable. CONCLUSIONS: Our current results provide vital links between MRI-derived phenotypes, spatial transcriptome, genetic vulnerability, and clinical manifestation, and uncover the heterogeneity of mood disorders in biological and behavioral terms.

Photodynamic antibacterial research on hypericin-loaded PEGylated mesoporous silica delivery system.

In this study, a novel drug delivery system (MSN-PEG-Hypericin) was successfully fabricated using tetraethyl orthosilicate and 3-aminopropyltriethoxysilane as raw materials, and the PEGylation of the prepared aminated mesoporous silica and grafting of hypericin onto the carrier were further conducted to obtain MSN-PEG-Hypericin. The successful preparation of MSN-PEG-Hypericin was characterized by several physical-chemical techniques. Furthermore, the MSN-PEG-Hypericin system increased the ability of hypericin to generate reactive oxygen species (ROS) in vitro. The cytotoxicity assay and hemolysis analysis showed that MSN-PEG-Hypericin had good biocompatibility. For antibacterial studies, the irradiation time and incubation time of photodynamic therapy (PDT) for S. aureus and E. coli were respectively 8 min and 8 h, and the concentrations of hypericin were 2.5 and 5 µg/mL. The result of triphenyl tetrazolium chloride assay indicated that MSN-PEG-Hypericin had stronger photodynamic antibacterial activity than free hypericin, and S. aureus was more sensitive to PDT than E. coli, which was related to their cell structural differences. The antibacterial mechanism study indicated that the generated ROS could destroy the bacterial structures and cause bacterial death due to the leakage of the contents. The MSN-PEG-Hypericin system prepared in this study had potential application prospects in the antibacterial field.

Enhancing output current in degradable flexible piezoelectric nanogenerators through internal electrode construction.

Conventional piezoelectric nanogenerators (PNGs) face challenges in terms of degradation and reusability, which have negative environmental implications. On the other hand, biocompatible and degradable piezoelectric materials often exhibit lower piezoelectric response. In this study, potassium sodium niobate (KNN) powder and the biodegradable polymer poly(ε-caprolactone) (PCL) were used to fabricate piezoelectric composite films through solution casting. By constructing staggered electrodes, the total polarized charges quantity is increased, achieving a larger current output. The three-unit PNG (3-PNG) based on the composite film with 15 wt% KNN powder, reaches a maximum output current of 0.85 µA, which exhibits higher charging efficiency compared to 1-PNG. Moreover, the prepared 3-PNG can effectively harvest mechanical energy from human activities and maintain a stable output after 10,000 cycles of bending and releasing. The film exhibits complete degradation when exposed to acidic, neutral, and alkaline solutions. This research provides a promising option for environmentally friendly piezoelectric materials selected and output performance enhanced through optimized structural designs, making them more suitable for practical applications.

Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

Thermodynamic therapy (TDT) based on oxygen-independent free radicals exhibits promising potential for the treatment of hypoxic tumors. However, its therapeutic efficacy is seriously limited by the premature release of the drug and the free radical scavenging effect of glutathione (GSH) in tumors. Herein, we report a GSH depletion and biosynthesis inhibition strategy using EGCG/Fe-camouflaged gold nanorod core/ZIF-8 shell nanoparticles embedded with azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and L-buthionine-sulfoximine (BSO) for tumor-targeting photothermal (PTT) and thermodynamic therapy (TDT). This nanoplatform (GNR@ZIF-8-AIPH/BSO@EGCG/Fe, GZABEF) endows a pH-responsive release performance. With the 67 kDa lamin receptor (67LR)-targeting ability of EGCG, GZABEF could selectively release oxygen-independent free radicals in tumor cells under 1064 nm laser irradiation. More importantly, Fe3+-mediated GSH depletion and BSO-mediated GSH biosynthesis inhibition significantly boosted the accumulation of alkyl radicals. In 4T1 cells, GZABEF induced cancer cell death via intracellular GSH depletion and GSH peroxidase 4 (GPX4) inactivation. In a subcutaneous xenograft model of 4T1, GZABEF demonstrated remarkable tumor growth inhibition (78.2%). In addition, excellent biosafety and biocompatibility of GZABEF were observed both in vitro and in vivo. This study provides inspiration for amplified TDT/PTT-mediated antitumor efficacy.

Terrihabitans rhizophilus sp. nov., isolated from the rhizosphere soil of plant in temperate semi-arid steppe.

A bacterial strain PJ23T was isolated from the rhizosphere soil of Elymus dahuricus Turcz. sampled from a temperate semi-arid steppe in the northern of Inner Mongolia Autonomous Region, China. The strain is Gram-stain-negative, aerobic, light-pink, short rod-shaped, and non-spore-forming. Cell growth could be observed at 4-29℃ (optimal at 24℃), pH 6.0-8.6 (optimal at 8.0) and in the presence of 0-5.0% (w/v) NaCl (optimal at 2.5%). The major cellular fatty acids of strain PJ23T were Summed feature 8 (C18:1 ω6c and/or C18:1 ω7c) (39.42%) and C16:0 (9.60%). The polar lipids were phosphatidylcholine, two unidentified glycolipids, one unidentified aminophospholipid, and two other unidentified polar lipids. The major respiratory quinone was ubiquinone-10. Phylogeny analysis based on 16S rRNA gene sequences retrieved from the genomes showed that, the strain was closely related to the species Terrihabitans soli IZ6T and Flaviflagellibacter deserti SYSU D60017T, with the sequence similarities of 96.79% and 96.15%, respectively. The G + C content was 65.23 mol% calculated on draft genome sequencing. Between the strains PJ23T and Terrihabitans soli IZ6T, the average nucleotide identity (ANI), amino acid identity (AAI) and digital DNA-DNA hybridization (dDDH) was 73.39%,71.12% and 15.7%, these values were lower than the proposed and generally accepted species boundaries of ANI, AAI and dDDH, respectively. Based on phenotypic, chemotaxonomic, and phylogenetic characteristics, strain PJ23T represents a novel species of Terrihabitans, for which the name Terrihabitans rhizophilus sp. nov. is proposed. The type strain is PJ23T (= KCTC 92977 T = CGMCC 1.61577 T).

Loss of OVOL2 in Triple-Negative Breast Cancer Promotes Fatty Acid Oxidation Fueling Stemness Characteristics.

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.

BL-Hi-C reveals the 3D genome structure of Brassica crops with high sensitivity.

High-throughput Chromatin Conformation Capture (Hi-C) technologies can be used to investigate the three-dimensional genomic structure of plants. However, the practical utility of these technologies is impeded by significant background noise, hindering their capability in detecting fine 3D genomic structures. In this study, we optimized the Bridge Linker Hi-C technology (BL-Hi-C) to comprehensively investigate the 3D chromatin landscape of Brassica rapa and Brassica oleracea. The Bouquet configuration of both B. rapa and B. oleracea was elucidated through the construction of a 3D genome simulation. The optimized BL-Hi-C exhibited lower background noise compared to conventional Hi-C methods. Taking this advantage, we used BL-Hi-C to identify FLC gene loops in Arabidopsis, B. rapa, and B. oleracea. We observed that gene loops of FLC2 exhibited conservation across Arabidopsis, B. rapa, and B. oleracea. While gene loops of syntenic FLCs exhibited conservation across B. rapa and B. oleracea, variations in gene loops were evident among multiple paralogs FLCs within the same species. Collectively, our findings highlight the high sensitivity of optimized BL-Hi-C as a powerful tool for investigating the fine 3D genomic organization.

Co-exposure to Environmentally Relevant Levels of Molybdenum and Cadmium Induces Oxidative Stress and Ferroptosis in the Ovary of Ducks.

Excessive doses of molybdenum (Mo) and cadmium (Cd) have toxic effects on animals. Nevertheless, the reproductive toxicity elicited by Mo and Cd co-exposure remains obscure. To evaluate the co-induce toxic impacts of Mo and Cd on ovaries, 8-day-old 40 healthy ducks were stochastically distributed to four groups and were raised a basal diet supplemented with Cd (4 mg/kg Cd) and/or Mo (100 mg/kg Mo). In the 16th week, ovary tissues were gathered. The data revealed that Mo and/or Cd decreased GSH content, CAT, T-SOD, and GSH-Px activities and increased MDA and H2O2 levels. Moreover, there was a significant decrease in nuclear Nrf2 protein level and its related downstream factors, while cytoplasmic Nrf2 protein level showed a substantial increase. Additionally, a marked elevation was observed in ferrous ion content and TFRC, GCLC, SLC7A11, ACSL4, and PTGS2 expression levels, while FTH1, FTL1, FPN1, and GPX4 expression levels were conversely reduced. These indicators exhibited more marked changes in the joint exposure group. In brief, our results announced that Mo and/or Cd resulted in oxidative stress and ferroptosis in duck ovaries. Synchronously, the Cd and Mo mixture intensified the impacts.

Molybdenum and cadmium co-induce necroptosis through Th1/Th2 imbalance-mediated endoplasmic reticulum stress in duck ovaries.

Cadmium (Cd) and excess molybdenum (Mo) pose serious threats to animal health. Our previous study has determined that Cd and/or Mo exposure can cause ovarian damage of ducks, while the specific mechanism is still obscure. To further investigate the toxic mechanism of Cd and Mo co-exposure in the ovary, forty 8-day-old female ducks were randomly allocated into four groups for 16 weeks, and the doses of Cd and Mo in basic diet per kg were as follows: control group, Mo group (100 mg Mo), Cd group (4 mg Cd), and Mo + Cd group (100 mg Mo + 4 mg Cd). Cadmium sulfate 8/3-hydrate (CdSO4·8/3H2O) and hexaammonium molybdate ((NH4)6Mo7O24·4H2O) were the origins of Cd and Mo, respectively. At the 16th week of the experiment, all ovary tissues were collected for the detection of related indexes. The data indicated that Mo and/or Cd induced trace element disorders and Th1/Th2 balance to divert toward Th1 in the ovary, which activated endoplasmic reticulum (ER) stress and then provoked necroptosis through triggering RIPK1/RIPK3/MLKL signaling pathway, and eventually caused ovarian pathological injuries and necroptosis characteristics. The alterations of above indicators were most apparent in the joint group. Above all, this research illustrates that Mo and/or Cd exposure can initiate necroptosis through Th1/Th2 imbalance-modulated ER stress in duck ovaries, and Mo and Cd combined exposure aggravates ovarian injuries. This research explores the molecular mechanism of necroptosis caused by Mo and/or Cd, which reveals that ER stress attenuation may be a therapeutic target to alleviate necroptosis.

Integrative omics analysis reveals epigenomic and transcriptomic signatures underlying brain structural deficits in major depressive disorder.

Several lines of evidence support the involvement of transcriptomic and epigenetic mechanisms in the brain structural deficits of major depressive disorder (MDD) separately. However, research in these two areas has remained isolated. In this study, we proposed an integrative strategy that combined neuroimaging, brain-wide gene expression, and peripheral DNA methylation data to investigate the genetic basis of gray matter abnormalities in MDD. The MRI T1-weighted images and Illumina 850 K DNA methylation microarrays were obtained from 269 patients and 416 healthy controls, and brain-wide transcriptomic data were collected from Allen Human Brain Atlas. The between-group differences in gray matter volume (GMV) and differentially methylated CpG positions (DMPs) were examined. The genes with their expression patterns spatially related to GMV changes and genes with DMPs were overlapped and selected. Using principal component regression, the associations between DMPs in overlapped genes and GMV across individual patients were investigated, and the region-specific correlations between methylation status and gene expression were examined. We found significant associations between the decreased GMV and DMPs methylation status in the anterior cingulate cortex, inferior frontal cortex, and fusiform face cortex regions. These DMPs genes were primarily enriched in the neurodevelopmental and synaptic transmission process. There was a significant negative correlation between DNA methylation and gene expression in genes associated with GMV changes of the frontal cortex in MDD. Our findings suggest that GMV abnormalities in MDD may have a transcriptomic and epigenetic basis. This imaging-transcriptomic-epigenetic integrative analysis provides spatial and biological links between cortical morphological deficits and peripheral epigenetic signatures in MDD.

Dynamic palmitoylation of STX11 controls injury-induced fatty acid uptake to promote muscle regeneration.

Different types of cells uptake fatty acids in response to different stimuli or physiological conditions; however, little is known about context-specific regulation of fatty acid uptake. Here, we show that muscle injury induces fatty acid uptake in muscle stem cells (MuSCs) to promote their proliferation and muscle regeneration. In humans and mice, fatty acids are mobilized after muscle injury. Through CD36, fatty acids function as both fuels and growth signals to promote MuSC proliferation. Mechanistically, injury triggers the translocation of CD36 in MuSCs, which relies on dynamic palmitoylation of STX11. Palmitoylation facilitates the formation of STX11/SNAP23/VAMP4 SANRE complex, which stimulates the fusion of CD36- and STX11-containing vesicles. Restricting fatty acid supply, blocking fatty acid uptake, or inhibiting STX11 palmitoylation attenuates muscle regeneration in mice. Our studies have identified a critical role of fatty acids in muscle regeneration and shed light on context-specific regulation of fatty acid sensing and uptake.

Fluorescence and colorimetric dual-mode multienzyme cascade nanoplatform based on CuNCs/FeMn-ZIF-8/PCN for detection of sarcosine.

It is critical to develop a highly efficient and sensitive method for detecting the biomarker sarcosine (SA) of prostate cancer due to its importance for men's health. In our work, a fluorescence (FL) and colorimetric dual-mode multienzyme cascade nanoplatform for SA detection was designed and constructed. CuNCs/FeMn-ZIF-8/PCN nanocomposites with high FL properties and peroxidase-like activity were successfully prepared by encapsulating copper nanoclusters (CuNCs) into FeMn-ZIF-8 and then loaded onto P-doped graphitic carbon nitride (PCN). Furthermore, the nanocomposites served as carriers for the immobilization of sarcosine oxidase (SOX) to construct a high-efficiency dual-mode multienzyme cascade nanoplatform CuNCs/SOX@FeMn-ZIF-8/PCN for the detection of SA. The intermediate H2O2 generated in the cascade caused the FL quenching of nanocomposites and the discoloration of 3,3',5,5'-tetramethylbenzidin. The linear ranges for SA detection in the dual-mode system were 1-100 µM (FL) and 1-200 µM (colorimetric), with detection limits of 0.34 and 0.59 µM, respectively. This nanoplatform exhibited notable repeatability, specificity, and stability, making it suitable for detecting sarcosine in real human urine samples. Therefore, this dual-mode multienzyme cascade nanoplatform would have a potential applicative prospect for detecting SA and other biomarkers in real clinical samples.

Role of PLC/IP3 /IP3 R axis in excess molybdenum exposure induced apoptosis in duck renal tubular epithelial cells.

Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP3 /IP3 R axis, primary duck renal tubular epithelial cells were exposed to 480 µM and 960 µM Mo, and joint of 960 µM Mo and 10 µM 2-APB or 0.125 µM U-73122 for 12 h (U-73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca2+ ]c induced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca2+ ]ER , elevated [Ca2+ ]mit , [Ca2+ ]c , and the expression of Ca homeostasis-related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2-APB could effectively reverse subcellular Ca2+ redistribution by inhibiting IP3 R, which confirmed that [Ca2+ ]c overload induced by Mo originated from ER. Additionally, PLC inhibitor U-73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak-1, Bax, cleaved-Caspase-3/Caspase-3, and notably increased the expression of Bcl-xL, Bcl-2, and Bcl-2/Bax ratio. Overall, the results confirmed that the Ca2+ liberation of ER via PLC/IP3 /IP3 R axis was the main cause of [Ca2+ ]c overload, and then stimulated apoptosis in duck renal tubular epithelial cells.

Visual cortex repetitive transcranial magnetic stimulation (rTMS) reversing neurodevelopmental impairments in adolescents with major psychiatric disorders (MPDs): A cross-species translational study.

AIMS: Neurodevelopmental impairments are closely linked to the basis of adolescent major psychiatric disorders (MPDs). The visual cortex can regulate neuroplasticity throughout the brain during critical periods of neurodevelopment, which may provide a promising target for neuromodulation therapy. This cross-species translational study examined the effects of visual cortex repetitive transcranial magnetic stimulation (rTMS) on neurodevelopmental impairments in MPDs. METHODS: Visual cortex rTMS was performed in both adolescent methylazoxymethanol acetate (MAM) rats and patients with MPDs. Functional magnetic resonance imaging (fMRI) and brain tissue proteomic data in rats and fMRI and clinical symptom data in patients were analyzed. RESULTS: The regional homogeneity (ReHo) analysis of fMRI data revealed an increase in the frontal cortex and a decrease in the posterior cortex in the MAM rats, representing the abnormal neurodevelopmental pattern in MPDs. In regard to the effects of rTMS, similar neuroimaging changes, particularly reduced frontal ReHo, were found both in MAM rats and adolescent patients, suggesting that rTMS may reverse the abnormal neurodevelopmental pattern. Proteomic analysis revealed that rTMS modulated frontal synapse-associated proteins, which may be the underpinnings of rTMS efficacy. Furthermore, a positive relationship was observed between frontal ReHo and clinical symptoms after rTMS in patients. CONCLUSION: Visual cortex rTMS was proven to be an effective treatment for adolescent MPDs, and the underlying neural and molecular mechanisms were uncovered. Our study provides translational evidence for therapeutics targeting the neurodevelopmental factor in MPDs.

An ultrasensitive unlabeled electrochemical immunosensor for the detection of cardiac troponin I based on Pt/Au-B,S,N-rGO as the signal amplification platform.

In this study, an ultrasensitive unlabeled electrochemical immunosensor for the detection of cardiac troponin I (cTnI) was developed based on Pt/Au modified B,S,N co-doped reduced graphene oxide (Pt/Au-B,S,N-rGO) as a signal amplification platform. First-principles calculations were employed to analyze the electron density of states of Pt/Au-B,S,N-rGO, revealing an increase in the electron density of the graphene oxide (GO) states. Furthermore, scanning electron microscopy (SEM), X-ray photoelectron diffraction spectroscopy (XPS), and electrochemical detection were used to successfully construct and analyze Pt/Au-B,S,N-rGO. The results showed that B,S,N-rGO exhibited good electrochemical activity, and the Au/Pt NPs demonstrated excellent catalytic properties, which provided a strong foundation for achieving high-sensitivity detection. Moreover, the constructed unlabeled electrochemical immunosensor had an ideal linear range (0.1 pg/mL∼50 ng/mL) and detection limit (0.082 pg/mL). In human serum detection, the results of this immunosensor were essentially similar to the ELISA results for the same samples, which suggested that the immunosensor had a promising clinical application prospect for the detection of cTnI.

Aberrant Hippocampal Development in Early-onset Mental Disorders and Promising Interventions: Evidence from a Translational Study.

Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence. The methylazoxymethanol acetate (MAM) animal model, in which disruption in neurodevelopmental processes is induced, mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective. We conducted longitudinal structural magnetic resonance imaging (MRI) scans during childhood, adolescence, and adulthood in MAM rats to identify specific brain regions and critical windows for intervention. Then, the effect of repetitive transcranial magnetic stimulation (rTMS) intervention on the target brain region during the critical window was investigated. In addition, the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders (diagnosed with major depressive disorder or bipolar disorder) to evaluate its clinical translational potential. The results demonstrated that, compared to the control group, the MAM rats exhibited significantly lower striatal volume from childhood to adulthood (all P <0.001). In contrast, the volume of the hippocampus did not show significant differences during childhood (P >0.05) but was significantly lower than the control group from adolescence to adulthood (both P <0.001). Subsequently, rTMS was applied to the occipital cortex, which is anatomically connected to the hippocampus, in the MAM models during adolescence. The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group (P <0.01), while the volume of the striatum remained unchanged (P >0.05). In the clinical trial, adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline (P <0.01), and these volumetric changes were associated with improvement in depressive symptoms (r = - 0.524, P = 0.018). These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for early-onset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.

TET2 is recruited by CREB to promote Cebpb, Cebpa, and Pparg transcription by facilitating hydroxymethylation during adipocyte differentiation.

Ten-eleven translocation proteins (TETs) are dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), an important epigenetic mark that regulates gene expression during development and differentiation. Here, we found that the TET2 expression was positively associated with adipogenesis. Further, in vitro and in vivo experiments showed that TET2 deficiency blocked adipogenesis by inhibiting the expression of the key transcription factors CCAAT/enhancer-binding protein beta (C/EBPß), C/EBPα and peroxisome proliferator-activated receptor gamma (PPARγ). In addition, TET2 promoted 5hmC on the CpG islands (CGIs) of Cebpb, Cebpa and Pparg at the initial time point of their transcription, which requires the cAMP-responsive element-binding protein (CREB). At last, specific knockout of Tet2 in preadipocytes enabled mice to resist obesity and attenuated the obesity-associated insulin resistance. Together, TET2 is recruited by CREB to promote the expression of Cebpb, Cebpa and Pparg via 5hmC during adipogenesis and may be a potential therapeutic target for obesity and insulin resistance.

Transcriptome Analysis Reveals Key Genes and Pathways Associated with the Regulation of Flowering Time in Cabbage (Brassica oleracea L. var. capitata).

Flowering time is an important agronomic trait in cabbage (Brassica oleracea L. var. capitata), but the molecular regulatory mechanism underlying flowering time regulation in cabbage remains unclear. In this study, transcriptome analysis was performed using two sets of cabbage materials: (1) the early-flowering inbred line C491 (P1) and late-flowering inbred line B602 (P2), (2) the early-flowering individuals F2-B and late-flowering individuals F2-NB from the F2 population. The analysis revealed 9508 differentially expressed genes (DEGs) common to both C491_VS_ B602 and F2-B_VS_F2-NB. The Kyoto Encyclopedia of Genes and Genomes (KEGGs) analysis showed that plant hormone signal transduction and the MAPK signaling pathway were mainly enriched in up-regulated genes, and ribosome and DNA replication were mainly enriched in down-regulated genes. We identified 321 homologues of Arabidopsis flowering time genes (Ft) in cabbage. Among them, 25 DEGs (11 up-regulated and 14 down-regulated genes) were detected in the two comparison groups, and 12 gene expression patterns closely corresponded with the different flowering times in the two sets of materials. Two genes encoding MADS-box proteins, Bo1g157450 (BoSEP2-1) and Bo5g152700 (BoSEP2-2), showed significantly reduced expression in the late-flowering parent B602 compared with the early-flowering parent C491 via qRT-PCR analysis, which was consistent with the RNA-seq data. Next, the expression levels of Bo1g157450 (BoSEP2-1) and Bo5g152700 (BoSEP2-2) were analyzed in two other groups of early-flowering and late-flowering inbred lines, which showed that their expression patterns were consistent with those in the parents. Sequence analysis revealed that three and one SNPs between B602 and C491 were identified in Bo1g157450 (BoSEP2-1) and Bo5g152700 (BoSEP2-2), respectively. Therefore, BoSEP2-1 and BoSEP2-2 were designated as candidates for flowering time regulation through a potential new regulatory pathway. These results provide new insights into the molecular mechanisms underlying flowering time regulation in cabbage.

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate.

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.

Co-exposure to molybdenum and cadmium evokes necroptosis and decreases apoptosis in duck myocardium.

Superfluous molybdenum (Mo) and cadmium (Cd) in the environment are detrimental to organisms through their accumulation. The NF-κB/TNF-α axis plays a vital part in regulating necroptosis and apoptosis. However, the impacts of Mo and/or Cd on myocardium injury in ducks and the function of NF-κB/TNF-α axis are not clear in the process. In this research, ducks exposed to different dosages of Mo and/or Cd were applied as the study object. The findings substantiated that the accumulation of Mo and/or Cd caused elements imbalance and necroptosis in myocardial tissue. As p-NF-κB/TNF-α expression up-regulated, RIPK1/RIPK3/p-MLKL expression significantly increased in all treatment groups, while the expression of c-caspase-8/3 markedly decreased. Moreover, apoptosis rate obviously decreased in Cd treated groups and clearly elevated in Mo group. Mitochondria-mediated apoptosis was activated by excessive Mo and inhibited by Mo + Cd, but Cd exposure alone had little effect on it. Collectively, our research confirmed that Mo and/or Cd evoked necroptosis via NF-κB/TNF-α axis, and decreased death receptor-mediated apoptosis in duck myocardium, the impacts of Mo and/or Cd on mitochondrial-mediated apoptosis were different. These results are significant for studying toxicology of Mo and/or Cd and preserving the ecosystem.