Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.

Conservation genomics analysis reveals recent population decline and possible causes in bumblebee Bombus opulentus.

Bumblebees are a genus of pollinators (Bombus) that play important roles in natural ecosystem and agricultural production. Several bumblebee species have been recorded as under population decline, and the proportion of species experiencing population decline within subgenus Thoracobombus is higher than average. Bombus opulentus is 1 species in Thoracobombus, but little is known about its recent population dynamics. Here, we employed conservation genomics methods to investigate the population dynamics of B. opulentus during the recent past and identify the likely environmental factors that may cause population decline. Firstly, we placed the scaffold-level of B. opulentus reference genome sequence onto chromosome-level using Hi-C technique. Then, based on this reference genome and whole-genome resequencing data for 51 B. opulentus samples, we reconstructed the population structure and effective population size (Ne ) trajectories of B. opulentus and identified genes that were under positive selection. Our results revealed that the collected B. opulentus samples could be divided into 2 populations, and 1 of them experienced a recent population decline; the declining population also exhibited lower genetic diversity and higher inbreeding levels. Genes related to high-temperature tolerance, immune response, and detoxication showed signals of positive selection in the declining population, suggesting that climate warming and pathogen/pesticide exposures may contribute to the decline of this B. opulentus population. Taken together, our study provided insights into the demography of B. opulentus populations and highlighted that populations of the same bumblebee species could have contrasting Ne trajectories and population decline could be caused by a combination of various stressors.

QTL Mapping for Adult-Plant Resistance to Leaf Rust in Italian Wheat Cultivar Libellula.

Wheat leaf rust (Lr), which is caused by Puccinia triticina Eriks. (Pt), is one of the most important wheat diseases affecting wheat production globally. Using resistant wheat cultivars is the most economical and environmentally friendly way to control leaf rust. The Italian wheat cultivar Libellula has demonstrated good resistance to Lr in field studies. To identify the genetic basis of Lr resistance in 'Libellula', 248 F6 recombinant inbred lines from the cross 'Libellula'/'Huixianhong' was phenotyped for Lr severity in seven environments: the 2014/2015, 2016/2017, 2017/2018, and 2018/2019 cropping seasons at Baoding, Hebei Province, and the 2016/2017, 2017/2018, and 2018/2019 crop seasons at Zhoukou, Henan Province. Bulked segregant analysis and simple sequence repeat markers were then used to identify the quantitative trait loci (QTLs) for Lr adult-plant resistance in the population. Six QTLs were consequently detected and designated as QLr.hebau-1AL and QLr.hebau-1AS that were presumed to be new and QLr.hebau-1BL, QLr.hebau-3AL, QLr.hebau-4BL, and QLr.hebau-7DS that were identified at similar physical positions as previously reported QTLs. Based on chromosome positions and molecular marker tests, QLr.hebau-1BL and QLr.hebau-7DS share similar flanking markers with Lr46 and Lr34, respectively. Lr46 and Lr34 are race nonspecific adult plant resistance (APR) genes for leaf rust and stripe rust and powdery mildew. QLr.hebau-4BL showed multiple disease resistance to leaf rust, stripe rust, Fusarium head blight, and powdery mildew. The QTL identified in this study, as well as their closely linked markers, may potentially be used in marker-assisted selection in wheat breeding.

The Progressive Utilization of Ponkan Peel Residue for Regulating Human Gut Microbiota through Sequential Extraction and Modification of Its Dietary Fibers.

As a by-product of citrus processing, ponkan (Citrus reticulata Blanco, cv. Ponkan) peel residue is a source of high quality dietary fiber (DF). To make a full utilization of this resource and give a better understanding on the probiotic function of its DF, soluble dietary fiber (SDF) and insoluble dietary fiber (IDF) were extracted from ponkan peel residue (after flavonoids were extracted) using an alkaline method, followed by modifications using a composite physical-enzymatic treatment. The in vitro fermentation properties of the modified SDF and IDF (namely, MSDF and MIDF) and their effects on short-chain fatty acids (SCFA) production and changes in the composition of human gut microbiota were investigated. Results showed that MSDF and MIDF both significantly lowered the pH value and enhanced total SCFA content in the broths after fermented for 24 h by fecal inocula (p < 0.05) with better effects found in MSDF. Both MSDF and MIDF significantly reduced the diversity, with more in the latter than the former, and influenced the composition of human gut microbiota, especially increasing the relative abundance of Bacteroidetes and decreasing the ratio of Firmicutes to Bacteroidetes (F/B) value. The more influential microbiota by MSDF were g-Collinsella, p-Actinobacteria and g-Dialister, while those by MIDF were f-Veillonellaceae, c-Negativicutes and f-Prevotellacese. These results suggested that the modified ponkan peel residue DF can be utilized by specific bacteria in the human gut as a good source of fermentable fiber, providing a basis for the exploitation of the citrus by-product.

Phase separation in cGAS-STING signaling.

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes. cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity. At the same time, cGAS-STING signaling must be carefully regulated to maintain immune homeostasis. Interestingly, exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling, including cGAS condensates, STING condensates, and IRF3 condensates. In addition, several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling. These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery. Here, we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

Primary intracranial lymphomas-incidence and survival: a population-based study.

Biopsy is recommended for patients with primary intracranial lymphoma to confirm the diagnosis, but the effect of tumor resection is still controversial. We conducted this retrospective study to better understand the epidemiology of primary intracranial lymphoma in the USA and explore the relationship between surgical resection and prognosis. Data regarding primary intracranial lymphoma, including incidence, were extracted from the SEER database. We analyzed the difference in incidence between different groups of people. We explored the effect of surgery on the survival of patients by the Kaplan-Meier method and evaluated the possible prognostic indicators by multivariate Cox proportional hazards models. The incidence significantly increased with age. The non-Hispanic Asian or Pacific Islander population exhibited the highest incidence, and the incidence was significantly higher in males than females. A total of 6428 cases were included in the cohort study, and most of the patients were diagnosed in the sixth to seventh decade of life. Sixty percent of tumors were supratentorial tumors. Surgery, especially total resection, significantly improved overall survival and cancer-specific survival. The survival of female patients, patients diagnosed before reaching 60 years of age, patients diagnosed after 2010, and patients with supratentorial lymphomas was better than that of their counterparts. The survival of patients with diffuse large B-cell lymphoma was worse than that of their counterparts. We conducted a comprehensive retrospective analysis of patients with primary intracranial lymphoma. We analyzed the difference in incidence between different groups of people. Surgery significantly improved overall and cancer-specific survival. The results of our research can help clinicians and patients better understand the epidemiology and management of primary intracranial lymphoma.

Study on the color-changing mechanism and law of visual formaldehyde sensing system based on hyperbranched polyamines.

This study focuses on addressing the limitations associated with most chemical derivatization methods commonly used for formaldehyde detection. These methods often suffer from prolonged derivative times (≥30 min) and complex procedures, which hinder their ability to meet the requirements of real-time and accurate sensing. In this research, a novel formaldehyde indicator system based on hyperbranched polyamine molecule was developed, and its mechanism and principles of color change were investigated. The findings revealed that hyperbranched polyamine molecule effectively reacts with formaldehyde, leading to a reduction in electron cloud density in the amine group N and subsequently causing a decrease in pH value. This reaction enables the visualization of formaldehyde detection through changes in the indicator spectrum. Moreover, the spectral variation pattern exhibits a strong linear correlation with the formaldehyde concentration when the PAMAM concentration is optimized. The detection limit of this method was determined to be 1.8 ppm. Notably, the reaction between PAMAM and formaldehyde is almost instantaneous, the color change is insensitive to temperature, and the method demonstrates high selectivity. Overall, this research contributes to the advancement of real-time formaldehyde monitoring technology and provides insights for future developments in this field.

Studying the effect of hyperoside on recovery from cyclophosphamide induced oligoasthenozoospermia.

Oligoasthenozoospermia is becoming a serious problem, but effective prevention or treatment is lacking. Hyperoside, one of the main active ingredients in traditional Chinese medicine, may be effective in the treatment of oligoasthenozoospermia. In this study, we used cyclophosphamide (CTX: 50 mg/kg) to establish a mouse model of Oligoasthenozoospermia to investigate the therapeutic effect of hyperoside (30 mg/kg) on CTX-induced oligoasthenozoospermia. All mice were divided into four groups: blank control group (Control), treatment control group (Hyp), disease group (CTX) and treatment group (CTX + H). Mice body weight, testicular weight, sperm parameters and testicular histology were used to assess the reproductive capacity of mice and to explore the underlying mechanism of hyperoside in the treatment of oligoasthenozoospermia by assessing hormone levels, protein levels of molecules related to hormone synthesis and transcript levels of important genes related to spermatogenesis. Treatment with hyperoside significantly improved sperm density, sperm viability and testicular function compared to untreated oligoasthenozoospermia mice. In mechanism, treatment with hyperoside resulted in significant improvement in pathological changes in spermatogenic tubules, with an increase in testosterone production, and upregulations of Protein Kinase CAMP-Activated Catalytic Subunit Beta (PRKACB), Steroidogenic Acute Regulatory Protein (STAR), and Cytochrome P450 Family 17 Subfamily A Member 1 (CYP17A1) for testosterone production. Hyperoside also promoted the cell cycle of germ cells and up-regulated meiosis and spermatogenesis-related genes, including DNA Meiotic Recombinase 1 (Dmc1), Ataxia telangiectasia mutated (Atm) and RAD21 Cohesin Complex Component (Rad21). In conclusion, hyperoside exerted protective effects on oligoasthenozoospermia mice by regulating testosterone production, meiosis and sperm maturation of germ cells.

Synchronous stabilization of Pb, Zn, Cd, and As in lead smelting slag by industrial solid waste.

In order to prevent heavy metal (HM) pollution from lead smelting slag (LSS) to the surrounding environment, this work investigated the feasibility, influencing factors, and mechanisms of using industrial solid waste such as fly ash (FA), oil sludge pyrolysis residue (PR), and steel slag (SS) as remediation amendments. The results demonstrated that the stabilization process was influenced by the material dosage, water content, and LSS particle size. Compared to single materials, the combination amendment PR2FA1 (with a mass ratio of PR to FA as 2:1) exhibited the best stabilization effect, simultaneously reducing the leaching concentrations of As, Zn, Cd, and Pb in LSS to 0.032, 0.034, 0.002, and 0.014 mg/L, respectively. The pH value of the leachate remained between 8 and 9, which met the requirements of surface water quality class IV (GB3838-2002). Through morphological analysis, microscopic characterization, and simulated solution adsorption experiments, it was determined that the stabilization process of HMs was controlled by various mechanisms, including electrostatic attraction, physical adsorption, ion exchange, and chemical precipitation. PR2FA1 had more active components, and its fine-porous structure provided more active sites, resulting in good stabilization performance for As, Zn, Cd, and Pb. Furthermore, cost analysis showed that PR2FA1, as an environmentally friendly material, could generate profits of 157.2 ¥/ton. In conclusion, the prepared PR2FA1 not only addressed the HMs pollution from lead smelting slag to the surrounding environment but also achieved the safe and resourceful disposal of hazardous waste-oil sludge. Its excellent performance in stabilizing HMs and cost-effectiveness suggested promising commercial applications.

Lactate modulates iron metabolism by binding soluble adenylyl cyclase.

Overproduction of lactate (LA) can occur during exercise and in many diseases such as cancers. Individuals with hyperlactatemia often display anemia, decreased serum iron, and elevated hepcidin, a key regulator of iron metabolism. However, it is unknown whether and how LA regulates hepcidin expression. Here, we show LA binds to soluble adenylyl cyclase (sAC) in normal hepatocytes and affects systemic iron homeostasis in mice by increasing hepcidin expression. Comprehensive in vitro, in vivo, and in silico experiments show that the LA-sAC interaction raises cyclic adenosine monophosphate (cAMP) levels, which activates the PKA-Smad1/5/8 signaling pathway to increase hepcidin transcription. We verified this regulatory axis in wild-type mice and in mice with disordered iron homeostasis. LA also regulates hepcidin in humans at rest and subjected to extensive exercise that produce elevated LA. Our study links hyperlactatemia to iron deficiency, offering a mechanistic explanation for anemias seen in athletes and patients with lactic acidosis.

Unraveling Anisotropic and Pulsating Etching of ZnO Nanorods in Hydrochloric Acid via Correlative Electron Microscopy.

Despite much technical progress achieved so far, the exact surface and shape evolution during wet chemical etching is less unraveled, especially in ionically bonded ceramics. Herein, by using in situ liquid cell transmission electron microscopy, a repeated two-stage anisotropic and pulsating periodic etching dynamic is discovered during the pencil shape evolution of a single crystal ZnO nanorod in aqueous hydrochloric acid. Specifically, the nanopencil tip shrinks at a slower rate along [0001̅] than that along the ⟨101̅0⟩ directions, resulting in a sharper ZnO pencil tip. Afterward, rapid tip dissolution happens due to accelerated etching rates along various crystal directions. Concurrently, the vicinal base region of the original nanopencil tip emerges as a new tip followed by the repeated sequence of tip shrinking and removal. The high-index surfaces, such as {101̅m} (m = 0, 1, 2, or 3) and {21̅ 1̅n} (n = 0, 1, 2, or 3), are found to preferentially expose in different ratios. Our 3D electron tomography, convergent beam electron diffraction, middle-angle bright-field STEM, and XPS results indicate the dissociative Cl- species were bound to the Zn-terminated tip surfaces. Furthermore, DFT calculation suggests the preferential Cl- passivation over the {101̅1} and (0001) surfaces of lower energy than others, leading to preferential surface exposures and the oscillatory variation of different facet etching rates. The boosted reactivity due to high-index nanoscale surface exposures is confirmed by comparatively enhanced chemical sensing and CO2 hydrogenation activity. These findings provide an in-depth understanding of anisotropic wet chemical etching of ionic nanocrystals and offer a design strategy for advanced functional materials.

GxcM-Fbp17/RacC-WASP signaling regulates polarized cortex assembly in migrating cells via Arp2/3.

The actin-rich cortex plays a fundamental role in many cellular processes. Its architecture and molecular composition vary across cell types and physiological states. The full complement of actin assembly factors driving cortex formation and how their activities are spatiotemporally regulated remain to be fully elucidated. Using Dictyostelium as a model for polarized and rapidly migrating cells, we show that GxcM, a RhoGEF localized specifically in the rear of migrating cells, functions together with F-BAR protein Fbp17, a small GTPase RacC, and the actin nucleation-promoting factor WASP to coordinately promote Arp2/3 complex-mediated cortical actin assembly. Overactivation of this signaling cascade leads to excessive actin polymerization in the rear cortex, whereas its disruption causes defects in cortical integrity and function. Therefore, apart from its well-defined role in the formation of the protrusions at the cell front, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortical subcompartment in rapidly migrating cells.

Molecular basis of RADAR anti-phage supramolecular assemblies.

Adenosine-to-inosine RNA editing has been proposed to be involved in a bacterial anti-phage defense system called RADAR. RADAR contains an adenosine triphosphatase (RdrA) and an adenosine deaminase (RdrB). Here, we report cryo-EM structures of RdrA, RdrB, and currently identified RdrA-RdrB complexes in the presence or absence of RNA and ATP. RdrB assembles into a dodecameric cage with catalytic pockets facing outward, while RdrA adopts both autoinhibited tetradecameric and activation-competent heptameric rings. Structural and functional data suggest a model in which RNA is loaded through the bottom section of the RdrA ring and translocated along its inner channel, a process likely coupled with ATP-binding status. Intriguingly, up to twelve RdrA rings can dock one RdrB cage with precise alignments between deaminase catalytic pockets and RNA-translocation channels, indicative of enzymatic coupling of RNA translocation and deamination. Our data uncover an interesting mechanism of enzymatic coupling and anti-phage defense through supramolecular assemblies.

Liquid-liquid phase separation mediates the formation of herpesvirus assembly compartments.

Virus assembly, which takes place during the late stage of viral replication, is essential for virus propagation. However, the underlying mechanisms remain poorly understood, especially for viruses with complicated structures. Here, we use correlative light and electron microscopy to examine the formation of cytoplasmic virion assembly compartments (cVACs) during infection by a γ-herpesvirus. These cVACs are membraneless organelles with liquid-like properties. Formation of cVACs during virus infection is mediated by ORF52, an abundant tegument protein. ORF52 undergoes liquid-liquid phase separation (LLPS), which is promoted by both DNA and RNA. Disrupting ORF52 phase separation blocks cVACs formation and virion production. These results demonstrate that phase separation of ORF52 is critical for cVACs formation. Our work defines herpesvirus cVACs as membraneless compartments that are generated through a process of LLPS mediated by a tegument protein and adds to the cellular processes that are facilitated by phase separation.

Hypoglycemic effect of the Phellinus baumii extract with α-glucosidase-inhibited activity and its modulation to gut microbiota in diabetic patients.

Phellinus baumii extract (PBE) possesses considerable α-glucosidase-inhibited activity. This study investigated the hypoglycemic effect in vitro and in vivo using a glucose consumption assay in HepG2 cells, intragastric administration for ten weeks in STZ-induced mice, and intestinal flora fermentation in patients with type 2 diabetes to reveal the possible underlying mechanisms. PBE was prepared, including α-glucosidase-inhibited ethanol extract (EE) and aqueous extract (AE). In vitro, PBE promoted glucose consumption and enhanced glycogen content and hexokinase activity but lowered phosphoenolpyruvate carboxylase kinase activity in HepG2 cells. In vivo, PBE treatment significantly reduced the body weight (p < 0.05) and fasting blood glucose levels of diabetic mice (p < 0.01), with the lowest blood glucose level observed in the EE+AE group. Furthermore, the serum insulin levels and insulin resistance index (HOMA) of PBE-treated groups decreased significantly (p < 0.01). Moreover, gene expression levels of the IRS-1/PI3K/AKT pathway were significantly upregulated by PBE treatment (p < 0.01). In vitro fermentation demonstrated that EE significantly inhibited the production of H2S and NH3 in the intestinal flora fermentation model in diabetic patients (p < 0.05). In addition, the ratio of Firmicutes to Bacteroidetes was reduced, the growth of Lactobacillus and Prevotella 9 was promoted, and Pseudomonas aeruginosa was inhibited. This study provides new insights and clues for using PBE as a functional food and clinical drug for glycemic control.

Germplasm resources and genetic improvement of Akebia: A new fruit crop in China.

Akebia species, belonging to Lardizabalaceae, are widespread from subtropical to temperate environments of China, Japan, and Korea. All known Akebia species have medicinal and dietary value and have been widely cultivated as a new fruit crop in many areas of China. However, compared with other crop species, the breeding improvement and commercial cultivation of Akebia remain in their infancy. This review systematically introduces the present germplasm resources, geographical distribution, biological characteristics, interspecific and intraspecific cross compatibility, molecular biology, and breeding progress in Akebia species. Akebia plants are widely distributed in Shanxi, Henan, Sichuan, Chongqing, Hunan, Hubei, Jiangxi, Zhejiang, and Fujian provinces of China, and wild Akebia plants exhibit abundant phenotypic and genetic diversity due to their wide range of geographical distribution and high adaptability in different habitats. Interspecific artificial hybridization experiments have been conducted in our Akebia germplasm resources nursery. The results showed that there was no reproductive isolation between Akebia species, and fertile progeny could be produced. The synthesis of knowledge on these species provides insights for the rational development and utilization of these germplasm resources, and can facilitate the development of new breeding lines or varieties for commercial cultivation or production. Finally, perspectives on Akebia breeding research are discussed and conclusions are provided. This review provided breeders with new insights into Akebia domestication and breeding, and we also proposed five basic steps in the domestication of new fruit crops.

Recognition of cyclic dinucleotides and folates by human SLC19A1.

Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A122,23. Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.

Submucosal esophageal abscess evolving into intramural submucosal dissection: A case report.

BACKGROUND: Here we report a rare case of submucosal esophageal abscess evolving into intramural submucosal dissection. CASE SUMMARY: An 80-year-old woman was admitted to our emergency department with a chief complaint of dysphagia and fever. Laboratory tests showed mild leukocytosis and elevated C-reactive protein level. Computed tomography showed thickening of the esophageal wall. Upper endoscopy showed a laceration of the esophageal mucosa and a submucosal mass. Spontaneous drainage occurred, and we could see purulent exudate from the crevasse. We closed the laceration with endoscopic clips. The patient did not remember swallowing a foreign body; however, she ate crabs before the symptoms occurred. We prescribed the patient with antibiotic, and the symptoms were gradually relieved. Two months later, upper endoscopy showed that the laceration was healed, and the submucosal abscess disappeared. However, intramural esophageal dissection was formed. We performed endoscopic incision of the septum using dual-knife effectively. CONCLUSION: In conclusion, we are the first to report the case of esophageal submucosal abscess evolving into intramural esophageal dissection. The significance of this case lies in clear presentation of the evolution process between two disorders. In addition, we recommend that endoscopic incision be considered as one of the routine therapeutic modalities of intramural esophageal dissection.