To clarify the effect of retinoid X receptor-α/γ (RXR-α/γ) genes functional genetic variants (RXR-α rs4842194 G>A, RXR-γ rs100537 A>G and rs2134095 T>C) on the risk of gestational diabetes mellitus (GDM), a case-control study with 573 GDM patients and 740 pregnant women with normal glucose tolerance was performed in Guangxi area of China. An odds ratio (OR) with its corresponding 95% confidence interval (CI) was used to assess the strengths of the association between genetic variation and GDM. After adjustment of age and pre-BMI, the logistic regression analysis showed that the rs2134095 was significantly associated with GDM risk (CC vs. TT/TC: adjusted OR = 0.71, 95% CI = 0.56-0.90) in all subjects, and this result remained highly significant after Bonferroni's correction for multiple testing (P=0.004). The stratified analysis showed that rs2134095 was significantly associated with the risk of GDM among age > 30 years (adjusted OR = 0.61, 95% CI = 0.39-0.97), BMI > 22 kg/m2 (adjusted OR = 0.46, 95% CI = 0.30-0.70), systolic blood pressure (SBP) > 120 mmHg (adjusted OR = 1.96, 95% CI = 1.14-3.36), glycosylated hemoglobin A1c (HbA1c) < 6.5% (adjusted OR = 1.41, 95% CI = 1.11-1.78), TG ≤ 1.7 mmol/l (adjusted OR = 2.57, 95% CI = 1.45-4.53), TC ≤ 5.18 mmol/l (adjusted OR = 1.58, 95% CI = 1.13-2.22), high-density lipoprotein cholesterol (HDL-c) ≤ 1.5 mmol/l (adjusted OR = 1.70, 95% CI = 1.16-2.49) and low-density lipoprotein cholesterol (LDL-c) > 3.12 mmol/l (adjusted OR = 1.47, 95% CI = 1.08-2.00) subjects, under the recessive genetic model. We also found that rs2134095 interacted with age (Pinteraction=0.039), pre-BMI (Pinteraction=0.040) and TG (Pinteraction=0.025) influencing individual's genetic susceptibility to GDM. The rs2134095 T>C is significantly associated with the risk of GDM by effect of a single locus and/or complex joint gene-gene and gene-environment interactions. Larger sample-size and different population studies are required to confirm the findings.

Patients with metabolic syndrome have a higher risk of type II diabetes and cardiovascular disease. The metabolic syndrome has become an urgent public health problem. Insulin resistance is the common pathophysiological basis of metabolic syndrome. The higher incidence of insulin resistance in obese groups is due to increased levels of inflammatory factors during obesity. Therefore, developing a therapeutic strategy for insulin resistance has great significance for the treatment of the metabolic syndrome. Dihydromyricetin, as a bioactive polyphenol, has been used for anti-inflammatory, antitumor, and improving insulin sensitivity. However, the target of DHM and molecular mechanism of DHM for preventing inflammation-induced insulin resistance is still unclear. In this study, we first confirmed the role of dihydromyricetin in inflammation-induced insulin resistance in vivo and in vitro. Then, we demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance by activating Ca2+-CaMKK-AMPK using signal pathway blockers, Ca2+ probes, and immunofluorescence. Finally, we clarified that dihydromyricetin activated Ca2+-CaMKK-AMPK signaling pathway by interacting with the phospholipase C (PLC), its target protein, using drug affinity responsive target stability (DARTS) assay. Our results not only demonstrated that dihydromyricetin resisted inflammation-induced insulin resistance via the PLC-CaMKK-AMPK signal pathway but also discovered that the target protein of dihydromyricetin is the PLC. Our results provided experimental data for the development of dihydromyricetin as a functional food and new therapeutic strategies for treating or preventing PLC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.

Treatment of idiopathic inflammatory myopathies (IIMs) is challenging due to a lack of safe and efficacious medication. Low-dose interleukin-2 (IL-2) treatment emerges as a new option in active IIMs. This study aims to explore the clinical and immunological effects of low-dose IL-2 in patients with active IIMs.

Chronic myeloid leukemia (CML) is an acquired hematopoietic stem malignant disease originating from the myeloid system. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis. However, their roles in CML remain largely unclear.

The stability of organic solar cells is a key issue to promote practical applications. Herein, we demonstrate that the device performance of organic solar cells is enhanced by an Ir/IrOx electron-transporting layer, benefiting from its suitable work function and heterogeneous distribution of surface energy in nanoscale. Notably, the champion Ir/IrOx-based devices exhibit superior stabilities under shelf storing (T80 = 56696 h), thermal aging (T70 = 13920 h), and maximum power point tracking (T80 = 1058 h), compared to the ZnO-based devices. It can be attributed to the stable morphology of photoactive layer resulting from the optimized molecular distribution of the donor and acceptor and the absence of photocatalysis in the Ir/IrOx-based devices, which helps to maintain the improved charge extraction and inhibited charge recombination in the aged devices. This work provides a reliable and efficient electron-transporting material toward stable organic solar cells.

Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. In this study, we investigated the effect, role, and radioprotective significance of cytosolic mitochondrial DNA (mtDNA) and its associated cGAS signaling on hematopoietic injury induced by IR in vitro culture cells and in vivo total body irradiated mice in this study. The results demonstrated that γ-ray exposure increases the release of mtDNA into the cytosol to activate cGAS signaling pathway, and the voltage-dependent anion channel (VDAC) may contribute to IR-induced mtDNA release. VDAC1 inhibitor DIDS and cGAS synthetase inhibitor can alleviate bone marrow injury and ameliorate hematopoietic suppression induced by IR via protecting hematopoietic stem cells and adjusting subtype distribution of bone marrow cells, such as attenuating the increase of the F4/80+ macrophage proportion in bone marrow cells. The present study provides a new mechanistic explanation for the radiation non-target effect and an alternative technical strategy for the prevention and treatment of hematopoietic acute radiation syndrome.

Mycoviruses are widely present in all major groups of fungi but those in entomopathogenic Metarhizium spp. remain understudied. In this investigation, a novel double-stranded (ds) RNA virus is isolated from Metarhizium majus and named Metarhizium majus partitivirus 1 (MmPV1). The complete genome sequence of MmPV1 comprises two monocistronic dsRNA segments (dsRNA 1 and dsRNA 2), which encode an RNA-dependent RNA polymerase (RdRp) and a capsid protein (CP), respectively. MmPV1 is classified as a new member of the genus Gammapartitivirus in the family Partitiviridae based on phylogenetic analysis. As compared to an MmPV1-free strain, two isogenic MmPV1-infected single-spore isolates were compromised in terms of conidiation, and tolerance to heat shock and UV-B irradiation, while these phenotypes were accompanied by transcriptional suppression of multiple genes involved in conidiation, heat shock response and DNA damage repair. MmPV1 attenuated fungal virulence since infection resulted in reduced conidiation, hydrophobicity, adhesion, and cuticular penetration. Additionally, secondary metabolites were significantly altered by MmPV1 infection, including reduced production of triterpenoids, and metarhizins A and B, and increased production of nitrogen and phosphorus compounds. However, expression of individual MmPV1 proteins in M. majus had no impact on the host phenotype, suggesting insubstantive links between defective phenotypes and a single viral protein. These findings indicate that MmPV1 infection decreases M. majus fitness to its environment and its insect-pathogenic lifestyle and environment through the orchestration of the host conidiation, stress tolerance, pathogenicity, and secondary metabolism.

Psoriasis is a common and recurrent inflammatory skin disease characterized by inflammatory cells infiltration of the dermis and excessive proliferation, reduced apoptosis, and abnormal keratosis of the epidermis. In this study, we found that G9A, an important methyltransferase that mainly mediates the mono-methylation (me1) and di-methylation (me2) of histone 3 lysine 9 (H3K9), is highly expressed in lesions of patients with psoriasis and imiquimod (IMQ)-induced psoriasis-like mouse model. Previous studies have shown that G9A is involved in the pathogenesis of various tumors by regulating apoptosis, proliferation, differentiation, and invasion. However, the role of G9A in skin inflammatory diseases such as psoriasis remains unclear. Our data so far suggest that topical administration of G9A inhibitor BIX01294 as well as keratinocyte-specific deletion of G9A greatly alleviated IMQ-induced psoriatic alterations in mice for the first time. Mechanistically, the loss function of G9A causes the downregulation of Ectodysplasin A receptor (EDAR), consequently inhibiting the activation of NF-κB pathway, resulting in impaired proliferation and increased apoptosis of keratinocytes, therefore ameliorating the psoriatic dermatitis induced by IMQ. In total, we show that inhibition of G9A improves psoriatic-like dermatitis mainly by regulating cell proliferation and apoptosis rather than inflammatory processes, and that this molecule may be considered as a potential therapeutic target for keratinocyte hyperproliferative diseases such as psoriasis.

The oocyte-to-embryo transition (OET) converts terminally differentiated gametes into a totipotent embryo and is critically controlled by maternal mRNAs and proteins, while the genome is silent until zygotic genome activation. How the transcriptome, translatome, and proteome are coordinated during this critical developmental window remains poorly understood.

The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. The apo-form structure reveals two potential Na+ binding sites within the selectivity filter, suggesting a possible mechanism for Na+ selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na+ binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into NaV1.6 structure, ion conductance, and inhibition.

Acyl-CoA medium-chain synthetase-3 (ACSM3) has been reported to be involved in the malignant progression of multiple types of human cancer. Nevertheless, the role of ACSM3 in acute myeloid leukemia (AML) and its exact mechanism of action are as yet undefined. In the present study, the expression levels of ACSM3 and IGF2 mRNA-binding protein 2 (IGF2BP2) were evaluated using the Gene Expression Profiling Interactive Analysis database and AML cells. The Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine staining were employed for the estimation of the cell proliferative activity. Induction of apoptosis and the assessment of the cell cycle were measured using flow cytometry and western blotting, respectively. The interaction of ACSM3 with IGF2BP2 was confirmed using an RNA immunoprecipitation assay. mRNA stabilization of ACSM3 following actinomycin D treatment was evaluated using reverse transcription-quantitative PCR analysis. The data indicated that the expression levels of ACSM3 were significantly downregulated, whereas those of IGF2BP2 were upregulated in tissues and AML cells. Downregulation of ACSM3 expression was closely associated with poor overall survival of patients with AML. ACSM3 overexpression repressed cell proliferative activity and induced apoptosis and cell cycle arrest. IGF2BP2 downregulated ACSM3 expression by reducing the stability of ACSM3 mRNA. In addition, IGF2BP2 overexpression counteracted the effects of ACSM3 overexpression noted on proliferation, induction of apoptosis and cell cycle arrest of HL-60 cells. In conclusion, ACSM3 repressed the cell proliferative activity and facilitated induction of apoptosis and cell cycle arrest in AML cells by modulating the expression of IGF2BP2.

Gastric cancer (GC) is the most common type of malignant tumor within the gastrointestinal tract, and GC metastasis is associated with poor prognosis. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein implicated in various types of tumor development and metastasis. However, the role of PTBP1 in GC metastasis remains elusive. In this study, we verified that PTBP1 was upregulated in GC tissues and cell lines, and higher PTBP1 level was associated with poorer prognosis. It was shown that PTBP1 knockdown in vitro inhibited GC cell migration, whereas PTBP1 overexpression promoted the migration of GC cells. In vivo, the knockdown of PTBP1 notably reduced both the size and occurrence of metastatic nodules in a nude mice liver metastasis model. We identified phosphoglycerate kinase 1 (PGK1) as a downstream target of PTBP1 and found that PTBP1 increased the stability of PGK1 by directly binding to its mRNA. Furthermore, the PGK1/SNAIL axis could be required for PTBP1's function in the promotion of GC cell migration. These discoveries suggest that PTBP1 could be a promising therapeutic target for GC.

Acremonium terricola is used in the feed of dairy animals to promote growth and control diseases. However, the effects of dietary supplementation with A. terricola on the gut microbial structure of weaning piglets remain poorly understood. Therefore, in this study, we investigated the effects of dietary supplementation with A. terricola culture (ATC) on the growth performance, antioxidant status, immunity, and gut environment of weaning piglets. Sixty piglets were fed a basal diet supplemented with 1 g ATC/kg of basal diet (experimental group). Another 60 piglets did not receive ATC (control group). The intervention lasted for 20 days.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer with high aggressive phenotype and poor prognosis. Accumulating evidence suggests that circRNAs have been identified as pivotal mediators in cancers. However, the role of circRNAs in ccRCC progression remains elusive.

Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

Necroptosis is an inflammatory cell death mode, and its association with multiple myeloma (MM) remains unclear.

The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration. Previous studies with overexpressed proteins have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on multiple sites, including an evolutionarily conserved 14-3-3-binding site whose phosphorylation is believed to inhibit YAP by excluding it from the nucleus. Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in current literature as a surrogate of YAP activation even though the physiological importance of this phosphorylation event in regulating endogenous YAP activity has not been defined. Here we address this question by introducing a Yap(S112A) knock-in mutation in the endogenous Yap locus. The Yap(S112A) mice are surprisingly normal despite nuclear localization of the mutant YAP protein in vivo and profound defects in cytoplasmic translocation in vitro. Interestingly, the mutant Yap(S112A) mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism that maintains physiological levels of YAP activity and caution against the assumptive use of YAP localization alone as a surrogate of YAP activity.

Recently, anthocyanins have been reported to have various biological activities. Furthermore, anthocyanin-rich purple corn extract (PCE) ameliorated insulin resistance and reduced diabetes-associated mesanginal fibrosis and inflammation, suggesting that it may have benefits for the prevention of diabetes and diabetes complications. In this study, we determined the anthocyanins and non-anthocyanin component of PCE by HPLC-ESI-MS and investigated its anti-diabetic activity and mechanisms using C57BL/KsJ db/db mice.

Beauveria bassiana is a kind of world-wide entomopathogenic fungus and can also colonize plant rhizosphere. Previous researches showed differential expression of genes when entomopathogenic fungi are cultured in insect or plant materials. However, so far there is no report on metabolic alterations of B. bassiana in the environments of insect or plant. The purpose of this paper is to address this problem. Herein, we first provide the metabolomic analysis of B. bassiana cultured in insect pupae extracts (derived from Euproctis pseudoconspersa and Bombyx mori, EPP and BMP), plant root exudates (derived from asparagus and carrot, ARE and CRE), distilled water and minimal media (MM), respectively. Principal components analysis (PCA) shows that mycelia cultured in pupae extracts and root exudates are evidently separated and individually separated from MM, which indicates that fungus accommodates to insect and plant environments by different metabolic regulation mechanisms. Subsequently, orthogonal projection on latent structure-discriminant analysis (OPLS-DA) identifies differential metabolites in fungus under three environments relative to MM. Hierarchical clustering analysis (HCA) is performed to cluster compounds based on biochemical relationships, showing that sphingolipids are increased in BMP but are decreased in EPP. This observation further implies that sphingolipid metabolism may be involved in the adaptation of fungus to different hosts. In the meantime, sphingolipids are significantly decreased in root exudates but they are not decreased in distilled water, suggesting that some components of the root exudates can suppress sphingolipid to down-regulate sphingolipid metabolism. Pathway analysis finds that fatty acid metabolism is maintained at high level but non-ribosomal peptides (NRP) synthesis is unaffected in mycelia cultured in pupae extracts. In contrast, fatty acid metabolism is not changed but NRP synthesis is high in mycelia cultured in root exudates and distilled water. This indicates that fungal fatty acid metabolism is enhanced when contacting insect, but when in the absence of insect hosts NRP synthesis is increased. Ornithine, arginine and GABA are decreased in mycelia cultured in pupae extracts and root exudates but remain unchanged in distilled water, which suggests that they may be associated with fungal cross-talk with insects and plants. Trehalose and mannitol are decreased while adenine is increased in three conditions, signifying carbon shortage in cells. Together, these results unveil that B. bassiana has differential metabolic responses in pupae extracts and root exudates, and metabolic similarity in root exudates and distilled water is possibly due to the lack of insect components.