Background: Knowledge about the pathogenesis of depression and treatments for this disease are lacking. Epigenetics-related circRNAs are likely involved in the mechanism of depression and have great potential as treatment targets, but their mechanism of action is still unclear. Methods: Circular RNA UBE2K (circ-UBE2K) was screened from peripheral blood of patients with major depressive disorder (MDD) and brain of depression model mice through high-throughput sequencing. Microinjection of circ-UBE2K overexpression lentivirus and adeno-associated virus for interfering with microglial circ-UBE2K into the mouse hippocampus was used to observe the role of circ-UBE2K in MDD. Sucrose preference, forced swim, tail suspension and open filed tests were performed to evaluate the depressive-like behaviors of mice. Immunofluorescence and Western blotting analysis of the effects of circ-UBE2K on microglial activation and immune inflammation. Pull-down-mass spectrometry assay, RNA immunoprecipitation (RIP) test and fluorescence in situ hybridization (FISH) were used to identify downstream targets of circ-UBE2K/ HNRNPU (heterogeneous nuclear ribonucleoprotein U) axis. Results: In this study, through high-throughput sequencing and large-scale screening, we found that circ-UBE2K levels were significantly elevated both in the peripheral blood of patients with MDD and in the brains of depression model mice. Functionally, circ-UBE2K-overexpressing mice exhibited worsened depression-like symptoms, elevated brain inflammatory factor levels, and abnormal microglial activation. Knocking down circ-UBE2K mitigated these changes. Mechanistically, we found that circ-UBE2K binds to heterogeneous nuclear ribonucleoprotein U (HNRNPU) to form a complex that upregulates the expression of the parental gene ubiquitin conjugating enzyme E2 K (UBE2K), leading to abnormal microglial activation and neuroinflammation and promoting the occurrence and development of depression. Conclusions: The findings of the present study revealed that the expression of circUBE2K, which combines with HNRNPU to form the circUBE2K/HNRNPU complex, is increased in microglia after external stress, thus regulating the expression of the parental gene UBE2K and mediating the abnormal activation of microglia to induce neuroinflammation, promoting the development of MDD. These results indicate that circ-UBE2K plays a newly discovered role in the pathogenesis of depression.

Nucleolar protein 12 (NOL12), one of the nucleolar proteins which are primarily expressed in the nucleolus and play key roles in RNA metabolism, cell proliferation, cell cycle, and cell survival, is widely expressed in various species and multiple organs. Although it has been reported that the mRNA of Drosophila NOL12 homolog viriato is expressed in the eyes of Drosophila, the protein expression of NOL12 in mammalian eyes remains to be elucidated. In this study, we showed through immunohistochemistry that NOL12 was present in the rat retina, with predominant distribution in the cytoplasm of the retinal neuronal cells. In the human retinoblastoma cell line WERI-Rb1, we found that altering NOL12 expression led to a change in WERI-Rb1 cell viability. Knocking down NOL12 expression decreased cell viability. In contrast, overexpressing NOL12 increased cell viability. Furthermore, increasing NOL12 expression inhibited ultraviolet (UV)-induced apoptosis. These findings demonstrated that NOL12 may play an important protective role in retinal cells. In the WERI-Rb1 cells exposed to UV irradiation, we detected that NOL12 was degraded, but this degradation could be attenuated by a pan-Caspase inhibitor. Notably, the inhibitory effect of NOL12 against UV-induced apoptosis could be restrained by increasing the expression of ATR serine/threonine kinase (ATR), a kinase that, when activated by severe DNA damage, can result in apoptosis. We also found that upregulating NOL12 inhibited the activation of ATR caused by UV irradiation. Additionally, inhibiting ATR activity reduced apoptosis resulting from both silencing NOL12 expression and UV exposure. Thus, NOL12 may protect against UV irradiation-induced retinal damage by inhibiting ATR activity.

In this work, we examine the use of environment-sensitive fluorescent dyes in fluorescence lifetime imaging microscopy (FLIM) biosensors. We screened merocyanine dyes to find an optimal combination of environment-induced lifetime changes, photostability, and brightness at wavelengths suitable for live-cell imaging. FLIM was used to monitor a biosensor reporting conformational changes of endogenous Cdc42 in living cells. The ability to quantify activity using phasor analysis of a single fluorophore (e.g., rather than ratio imaging) eliminated potential artifacts. We leveraged these properties to determine specific concentrations of activated Cdc42 across the cell.

The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear.

As a common malignancy, lung cancer has a relatively poor prognosis and a low survival rate. In recent years, ferroptosis, as an emerging filed, has great promise in the potential treatment of cancer. Brucea javanica oil (BJO) is often used to treat various cancers. Oleic acid (OA) is the main ingredient of BJO. In this study, we investigated the role and molecular mechanism of OA in lung cancer treatment by promoting ferroptosis.

This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).

Ferroptosis is a crucial process contributing to neuronal damage following intracerebral hemorrhage (ICH). Didang Tang (DDT), a traditional therapeutic, has been used clinically to manage ICH for many years, yet the molecular mechanisms by which by DDT protects neurons from ferroptosis after ICH remain elusive.

Statistical copolymers are commercially important because their properties can be tuned by comonomer selection and composition. Rubbery-state styrene (S)/n-butyl acrylate (nBA) copolymers have previously been reported to exhibit facile, autonomous self-healing over a narrow composition band (47/53 to 53/47 mol%). The need for a narrow composition band is explained by alternating comonomer sequences that accommodate interchain secondary bonding. It is hypothesized that copolymers that achieve interchain secondary bonding without alternating sequences can exhibit facile self-healing over a broad composition range. 2-ethylhexyl acrylate (EHA) is identified as yielding sequence-independent secondary bonding interactions. For these interactions it is tested experimentally by glass transition breadth in rubbery-state S/EHA copolymers, with S/n-hexyl acrylate (nHA) and S/nBA copolymers as controls. The n-alkyl acrylate random copolymers exhibit enhanced glass transition breadths over narrow composition bands that correspond to autonomous self-healing. In contrast, S/EHA copolymers exhibit much greater glass transition breadths than S/nHA and S/nBA copolymers at all compositions tested as well as self-healing of damage over a broad composition range with full tensile-property recovery, often in 3-10 h. Characterization of glass transition breadth may serve as a simple screening tool for identifying copolymers that exhibit broad-composition-range, facile, autonomous self-healing and contribute to polymer resilience and sustainability.

Lymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD.

Kombucha, a fermented tea prepared with a symbiotic culture of bacteria and yeast (SCOBY), offers a unique and unpredictable home-brewed fermentation process. Therefore, the need for a controlled kombucha fermentation process has become evident, which requiring a thorough understanding of the microbial composition and its relationship with the metabolites produced. In this study, we investigated the dynamics of microbial communities and metabolites over a 12-day fermentation period of a conventional kombucha-making process. Our findings revealed similarities between the microbial communities in the early (0-2 days) and late (10-12 days) fermentation periods, supporting the principle of back-slopping fermentation. Untargeted metabolite analysis unveiled the presence of harmful biogenic amines in the produced kombucha, with concentrations increasing progressively throughout fermentation, albeit showing relatively lower abundance on days 8 and 12. Additionally, a contrasting trend between ethanol and caffeine content was observed. Canonical correspondence analysis highlighted strong positive correlations between specific bacterial/yeast strains and identified metabolites. In conclusion, our study sheds light on the microbial and metabolite dynamics of kombucha fermentation, emphasizing the importance of microbial control and quality assurance measures in the production process.

Evidence shows that genetic factors play important roles in the severity of coronavirus disease 2019 (COVID-19). Sulfatase modifying factor 1 (SUMF1) gene is involved in alveolar damage and systemic inflammatory response. Therefore, we speculate that it may play a key role in COVID-19.

Mentha canadensis L. is an important spice crop and medicinal herb with high economic value. The plant is covered with peltate glandular trichomes, which are responsible for the biosynthesis and secretion of volatile oils. Plant non-specific lipid transfer proteins (nsLTPs) belong to a complex multigenic family involved in various plant physiological processes. Here, we cloned and identified a non-specific lipid transfer protein gene (McLTPII.9) from M. canadensis, which may positively regulate peltate glandular trichome density and monoterpene metabolism. McLTPII.9 was expressed in most M. canadensis tissues. The GUS signal driven by the McLTPII.9 promoter in transgenic Nicotiana tabacum was observed in stems, leaves, and roots; it was also expressed in trichomes. McLTPII.9 was associated with the plasma membrane. Overexpression of McLTPII.9 in peppermint (Mentha piperita. L) significantly increased the peltate glandular trichome density and total volatile compound content compared with wild-type peppermint; it also altered the volatile oil composition. In McLTPII.9-overexpressing (OE) peppermint, the expression levels of several monoterpenoid synthase genes and glandular trichome development-related transcription factors-such as limonene synthase (LS), limonene-3-hydroxylase (L3OH), geranyl diphosphate synthase (GPPS), HD-ZIP3, and MIXTA-exhibited varying degrees of alteration. McLTPII.9 overexpression resulted in both a change in expression of genes for terpenoid biosynthetic pathways which corresponded with an altered terpenoid profile in OE plants. In addition, peltate glandular trichome density was altered in the OE plants as well as the expression of genes for transcription factors that were shown to be involved in trichome development in plants.

Visceral obesity is associated with high cardiovascular events risk in type 2 diabetes mellitus (T2DM). Whether normal-weight visceral obesity will pose a higher atherosclerotic cardiovascular disease (ASCVD) risk than body mass index (BMI)-defined overweight or obese counterparts with or without visceral obesity remains unclear. We aimed to explore the relationship between general obesity and visceral obesity and 10-year ASCVD risk in patients with T2DM.

Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes.

This study was conducted to develop and validate an individualized prediction model for spontaneous preterm birth (sPTB) in twin pregnancies.

How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in the neocortical tissue of younger (22-50 years) and older (51-72 years) adults. Aging decreases the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The protein-to-lipid ratio decreases in astrocytes and increases in neurons. Aged astrocytes show morphological atrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Atrophy correlates with the loss of gap junction coupling between astrocytes and increased input resistance. Aging is accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling is observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of cortical astrocytes, but not neurons.

Objective: To investigate the value of computed tomography-guided percutaneous lung biopsy (CT-PLB) combined with rapid on-site evaluation (ROSE) in the diagnosis of peripheral pulmonary lesions (PPLs). Methods: A total of 108 patients who diagnosed with PPLs by chest CT examination were prospectively collected and randomly divided into ROSE group (n = 56) and No-ROSE group (n = 52). Both groups received CT-PLB and pathological examination. The smear submitted for ROSE was stained using Diff Quik dye. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number of punctures, puncture time and incidence of complications were compared between the two groups. Results: The accuracy, sensitivity, specificity, PPV, and NPV of the ROSE group were 89.29%, 87.50%, 91.67%, 93.33%, and 84.62%, respectively. The number of punctures in the ROSE group was significantly lower than that in the No-ROSE group (P < .05). The incidence of pneumothorax and hemoptysis in the ROSE group were lower than those in the No-ROSE group, but there was no statistical difference between the two groups (P > .05). ROSE has good concordance with routine pathological examination in the diagnosis of unidentified PPLs (Kappa = 0.786, P < .01). Conclusions: CT-PLB combined with ROSE is a safe and effective method for the diagnosis of PPLs.

IFN-γ has been traditionally recognized as an inflammatory cytokine that involves in inflammation and autoimmune diseases. Previously we have shown that sustained IFN-γ induced malignant transformation of bovine mammary epithelial cells (BMECs) via arginine depletion. However, the molecular mechanism underlying this is still unknown.

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immune checkpoint molecule with sequence homology to programmed cell death ligand 1 (PD-L1), which is mainly expressed on macrophages and tumor cells. However, whether Siglec-15-induced immunosuppression and poor prognosis are independent of PD-L1 remains unclear. In this study, we collected samples of 135 non-small cell lung cancers and found that Siglec-15 and PD-L1 expression were independent in non-small cell lung cancer by multiple immunofluorescence staining. Siglec-15 on macrophages (Mφ-Siglec-15) was significantly associated with DFS (p < 0.05) in PD-L1- patients with non-metastasis lung adenocarcinoma, not in PD-L1+ or lung squamous cell carcinoma patients. Moreover, stromal Siglec-15+ macrophages of Mφ-Siglec-15+PD-L1- patients were significantly more than those of Mφ-Siglec-15-PD-L1- patients (p = 0.002). We further found that Siglec-15+ macrophages polarized toward M2 and produced more IL-10, negatively associated with inflamed immunophenotype in PD-L1- patients and may inhibit CD8+T cells infiltration. In conclusion, PD-L1-independent Siglec-15+ macrophages contribute to the formation of an immunosuppressive microenvironment in non-metastasis lung adenocarcinoma patients, which may cause a higher risk of recurrence. Siglec-15 could be a potential target for normalizing cancer immunotherapy, benefiting patients who fail to respond to anti-PD-L1 therapy.

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug-treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug-associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.