ECSIT facilitates memory CD8+ T cell development by mediating fumarate synthesis during viral infection and tumorigenesis.

Memory CD8+ T cells play a crucial role in infection and cancer and mount rapid responses to repeat antigen exposure. Although memory cell transcriptional programmes have been previously identified, the regulatory mechanisms that control the formation of CD8+ T cells have not been resolved. Here we report ECSIT as an essential mediator of memory CD8+ T cell differentiation. Ablation of ECSIT in T cells resulted in loss of fumarate synthesis and abrogated TCF-1 expression via demethylation of the TCF-1 promoter by the histone demethylase KDM5, thereby impairing memory CD8+ T cell development in a cell-intrinsic manner. In addition, ECSIT expression correlated positively with stem-like memory progenitor exhausted CD8+ T cells and the survival of patients with cancer. Our study demonstrates that ECSIT-mediated fumarate synthesis stimulates TCF-1 activity and memory CD8+ T cell development during viral infection and tumorigenesis and highlights the utility of therapeutic fumarate analogues and PD-L1 inhibition for tumour immunotherapy.

ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein.

The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes-associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi-functional protein, is enriched along the crypt-villus axis. Intestinal cell-specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem "-like" cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid-based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis.

Mangcuo Lake in Hengduan Mountains: An Important Alpine Breeding and Stopover Site along Central Asian Flyway.

The stopovers provide food and habitat for migratory birds and therefore play an important role in facilitating the birds' completion of their migration. The Hengduan Mountains, which have a complex topography, are located in a large corridor of the Central Asian migratory flyway, so the lakes along the Hengduan Mountains are important for waterbird migration. The existing research on lakes in the Hengduan Mountain area is mostly concentrated in the central and southern parts of the mountains, which proves that many lakes are wintering grounds for migrating birds. We wonder whether the ecological functions of lakes will change more with further elevation. With this question, we conducted four surveys for the seasonal bird survey in Mangcuo Lake, which is located in the northwest of the Hengduan Mountains, in Markam County of Qamdo City, between October 2019 and July 2020. We recorded a total of 6109 birds from 20 species of waterbirds, including 20 species of migratory waterbirds, accounting for 100% of all bird species. The diversity and richness of waterbirds in Mangtso Lake is shown as spring > autumn ≥, summer > winter, with no waterbirds in winter. The black-necked grebe (Podiceps nigricollis), great crested grebe (Podiceps cristatus), bar-headed goose (Anser indicus), and ruddy shelduck (Tadorna ferruginea) were the dominant species in the waterbird community. The highest number of waterbird species and total individuals were found in the transition zone between the marsh wetlands and lakes, and the number of waterbird species differed significantly among habitats (X2 = 14.405, p = 0.000), with habitat complexity being an important factor influencing waterfowl abundance and distribution. The IUCN Red-listed species recorded include the black-necked crane (Grus nigricollis), painted stork (Mycteria leucocephala), and common pochard (Aythya ferina). By comparing with other lakes in Hengduan Mountain, we found that the ecological functions of the plateau lakes in the Hengduan Mountains, to support the life histories of migrating waterbirds, are gradually transforming as the altitude rises, and can be divided into approximately three levels, with the first level of Qionghai, Chenghai, Erhai, and Jianhu at altitudes of 1500-2200 m being the most important ecological function in terms of providing wintering grounds for migrating birds. The second layer, at an altitude of 2400-3300 m, includes Lashihai, Lugu Lake, and Napahai, which are not only wintering wetlands for migratory birds but also important stopover sites. The third layer of Mangcuo Lake, which is above 4000 m above sea level, provides a breeding ground for some migratory waterbirds in summer and a migratory resting place for migratory waterbirds in spring and autumn. We advocate for the importance of Mangcuo Lake in the alpine region along the central Asian flyway, as well as emerging nature conservation action that was previously neglected.

Gasdermin D restricts anti-tumor immunity during PD-L1 checkpoint blockade.

Tumor microenvironments (TMEs) require co-operation of innate and adaptive immune cells, which influence tumor progression and immunotherapy. Caspase-activated gasdermins facilitate tumor death and promote anti-tumor immunity. How pyroptosis in immune cells affects the TME remains unclear. TME expression of gasdermin D (GSDMD) is highly expressed in antigen-presenting cells (APCs) and correlates with immune checkpoint signatures. Through conditional deletion of GSDMD, we demonstrate that GSDMD in TME APCs restricts anti-tumor immunity during PD-L1 inhibition. Loss of GSDMD in APCs enhances interferon-stimulated genes (ISGs), thereby promoting CD8+ T cell activation in a cGAS-dependent manner. Moreover, pharmacological inhibition of GSDMD-mediated pyroptosis and PD-L1 improve anti-tumor immunity, highlighting the potential of combining GSDMD/PD-L1 inhibition for immunotherapy as a therapeutic strategy.

LSD1 silencing contributes to enhanced efficacy of anti-CD47/PD-L1 immunotherapy in cervical cancer.

Anti-CD47/PD-L1 immunotherapies aiming to enhance antitumor immunity are being intensively investigated and show promising results in cancer therapy; however, not all patients treated with these new drugs respond. Thus, developing new immunotherapy agents or combination treatments to enhance the efficacy of immunotherapy is an urgent challenge. Here, we found that LSD1 knockdown directly downregulated the expression of CD47 and PD-L1 through upregulating H3K4me2 levels in the CD47 and CD274 promoter regions. In addition, the LSD1/wild-type p53/miR-34a signaling axis was also involved in the regulation of CD47/PD-L1 expression by targeting the 3' untranslated regions (3'UTRs) of CD47/PD-L1. Further, the results showed that an LSD1 inhibitor (ORY-1001) combined with anti-CD47/PD-L1 monoclonal antibodies inhibited tumor growth in an established subcutaneous xenograft model more effectively than a single blockade strategy. Collectively, these findings indicate that LSD1 inhibition enhances the therapeutic efficacy of PD-L1/CD47 blockade by reducing CD47 and PD-L1 expression in cervical cancer.

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT-rich interactive domain 1A in endometrial cancer.

Mutations in the gene encoding AT-rich interactive domain 1A (ARID1A) are frequently observed in endometrial cancer (EC) but the molecular mechanisms linking the genetic changes remain to be fully understood. The present study aimed to elucidate the influence of ARID1A mutations on signaling pathways. Missense, synonymous and nonsense heterozygous ARID1A mutations in the EC HEC-1-A cell line were verified by Sanger sequencing. Mutated ARID1A small interfering RNA was transfected into HEC-1-A cells. Biochemical microarray analysis revealed 13 upregulated pathways, 17 downregulated pathways, 14 significantly affected disease states and functions, 662 upstream and 512 downstream genes in mutated ARID1A-depleted HEC-1-A cells, among which the mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin-like growth factor-1 (IGF1) signaling pathways were the 2 most downregulated pathways. Furthermore, the forkhead box protein O1 pathway was upregulated, while the IGF1 receptor, insulin receptor substrate 1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit b pathways were downregulated. Carcinoma tumorigenesis, tumor cell mitosis and tumor cell death were significantly upregulated disease states and functions, while cell proliferation and tumor growth were significantly downregulated. The results of the present study suggested that ARID1A may be a potential prognostic and therapeutic molecular drug target for the prevention of EC progression.

Removal of cadmium by bioflocculant produced by Stenotrophomonas maltophilia using phenol-containing wastewater.

Bioflocculants have been applied in numerous applications including heavy metals removal. A major bottleneck for commercial application of bioflocculant is its high production cost. Phenol-containing wastewater are abundantly available. However, the toxic phenol inhibited the microbial activities in the subsequent fermentation processes. Consequently, strains that can secrete phenol-degrading enzymes and simultaneously produce bioflocculants through directly degrading the phenol are of academic and practical interests. A phenol-degrading strain, Stenotrophomonas maltophilia ZZC-06, which can produce the bioflocculant MBF-06 using phenol-containing wastewater, was isolated in this study. The effects of culture conditions including initial pH, dissolved oxygen, phenol concentration, inoculum size, and temperature on MBF-06 production were analyzed. The experimental results showed that over 90% flocculating activity was achieved when the phenol was used as a carbon source and 4.99 g/L of MBF-06 was achieved under the optimized condition: 2.0% dissolved oxygen, 800 mg/L phenol concentration, 10% inoculum size, an initial pH of 6.0, and a temperature of 30 °C. The bioflocculant MBF-06 contained 71.2% polysaccharides and 27.9% proteins. The feasibility of cadmium removal using MBF-06 was evaluated. The highest flocculating efficiency for cadmium was 81.43%. This study shows for the first time that Stenotrophomonas maltophilia ZZC-06 can directly convert phenol into a bioflocculant, which can be used to effectively remove cadmium.

Evaluation of the peak variance in gradient liquid chromatography.

The peak variance obtained under single stepwise (SS), single linear (SL) and ladder-like (LL) gradient conditions was evaluated by taking into account the variation of plate height with mobile phase composition. LC tests were performed on a C18 column using a mixture of methanol and water as the mobile phase and six aromatic compounds (anisole, o-cresol, biphenyl, phenol, aniline and acetophenone) as the model samples. It was found that the relationship between the retention factor and mobile phase composition could be described by the linear solvent strength model. The plate height that was measured under isocratic conditions varied with mobile phase composition. This variation could be described by a quadratic polynomial in this work. Under gradient conditions, the experimental and predicted values of peak variance were found to be well consistent. The discrepancy between the experimental and predicted values in the SS gradient was larger than that in the SL or LL gradient. This may be ascribed to the distortion of the gradient profile as a result of dispersion that occurred in the mobile phase. By using the dispersive gradient profile that was obtained at the column inlet for the calculation, the discrepancy between the experimental and predicted values in the SS gradient may be minimized.

[General retention time formulae for gradient liquid chromatography with any combination of isocratic, linear and stepwise gradients].

The ideal model of liquid chromatography in gradient elution was solved by using the characteristic approach on the assumption of a linear solvent strength model. By considering the influence of the dwelling time of the chromatographic system on retention time, the retention time formulae suited for any combination of isocratic, linear and stepwise gradients were obtained. It was found that the values of the retention time obtained from these formulae were in well accordance with those computed by using the finite-difference method, which confirms the validity of the formulae. Due to the simplicity and broad scope of applications, these formulae can be easily applied in practice.

[Amino-(iminio)meth-yl]phospho-nate.

The title compound, CH(5)N(2)O(3)P, exists as a zwitterion. The N atom of the imino group is protonated and the phospho-nic acid group is deprotonated. The mol-ecular geometry about the central C atom of this zwitterionic species was found to be strictly planar with the sum of the three angles about C being precisely 360°. In the crystal, the mol-ecules are inter-linked by O-H⋯O and N-H⋯O hydrogen-bonding inter-actions, forming a three-dimensional supra-molecular network structure.