Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides.

Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.

Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1.

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.

Anatomically distinct fibroblast subsets determine skin autoimmune patterns.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1-3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body4-6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.

FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.

Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover.

The mitochondrial pathway of apoptosis is controlled by the ratio of anti- and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-ß-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

The impact of matched and mismatched donor-recipient genotypes for MDR1 polymorphisms (G2677TA, C1236T and C3435T) on the outcomes of patients after allogeneic haematopoietic stem cell transplantation.

In this study, we investigated whether matched and mismatched multidrug resistance gene (MDR1) genotypes (G2677TA, C1236T and C3435T) were associated with prognosis in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). One hundred patients after transplantation and their donors were enrolled. Matched MDR1 G2677TA donor-recipient was associated with an increased risk of non-relapse mortality (NRM) (29.5% vs. 6.2%, p = 0.002), poor overall survival (OS) (51.7% vs. 63.8%, p = 0.024) and disease-free survival (DFS) (38.6% vs. 67%, p = 0.005). There were no differences in OS, DFS or NRM between MDR1 C1236T- and C3435T-matched and -mismatched groups. Subgroup analysis suggested that within the matched MDR1 G2677TA group, male gender, haematopoietic cell transplantation-specific comorbidity index ≥1, serum creatinine >137.2 µmol/L and post-transplantation thrombocytopenia were associated with poor survival. Our results demonstrated that patients receiving matched MDR1 G2677TA allo-HSCT experienced a poorer prognosis compared with the mismatched group. The potential mechanism may involve increased expression of P-glycoprotein, leading to decreased accumulation of antimicrobial agents and ultimately contributing to the progression of inflammation. This identification of MDR1 G2677TA genotype compatibility holds promise as a valuable molecular tool for selecting donors for allo-HSCT.

NiCo-LDH Hollow Nanocage Oxygen Evolution Reaction Promotes Luminol Electrochemiluminescence.

Conventional luminol co-reactant electrochemiluminescence (ECL) systems suffer from low stability and accuracy due to factors such as the ease of decomposition of hydrogen peroxide and inefficient generation of reactive oxygen species (ROS) from dissolved oxygen. Inspired by the luminol ECL mechanism mediated by oxygen evolution reaction (OER), the nickel-cobalt layered double hydroxide (NiCo-LDH) hollow nanocages with hollow structure and defect state are used as co-reaction promoters to enhance the ECL emission from the luminol-H2 O system. Thanks to the hollow structure and defect state, NiCo-LDH hollow nanocages show excellent OER catalytic activity, which can stabilize and efficiently produce ROS and enhance the ECL emission. Additionally, mechanistic exploration suggests that the ROS involved in the co-reaction of the luminol-H2 O system are derived from the OER reaction process, and there is a positive correlation between ECL intensity and the OER catalytic activity of the co-reaction promoter. The selection of catalysts with excellent OER catalytic activity is a key factor in improving ECL emission. Finally, a dual-mode immunosensor is constructed for the detection and analysis of alpha-fetoprotein (AFP) based on the promoting effect of NiCo-LDH hollow nanocages on the luminol-H2 O ECL system.

Genome-wide allele and haplotype-sharing patterns suggested one unique Hmong-Mein-related lineage and biological adaptation history in Southwest China.

BACKGROUND: Fine-scale genetic structure of ethnolinguistically diverse Chinese populations can fill the gap in the missing diversity and evolutionary landscape of East Asians, particularly for anthropologically informed Chinese minorities. Hmong-Mien (HM) people were one of the most significant indigenous populations in South China and Southeast Asia, which were suggested to be the descendants of the ancient Yangtze rice farmers based on linguistic and archeological evidence. However, their deep population history and biological adaptative features remained to be fully characterized. OBJECTIVES: To explore the evolutionary and adaptive characteristics of the Miao people, we genotyped genome-wide SNP data in Guizhou HM-speaking populations and merged it with modern and ancient reference populations via a comprehensive population genetic analysis and evolutionary admixture modeling. RESULTS: The overall genetic admixture landscape of Guizhou Miao showed genetic differentiation between them and other linguistically diverse Guizhou populations. Admixture models further confirmed that Miao people derived their primary ancestry from geographically close Guangxi Gaohuahua people. The estimated identity by descent and effective population size confirmed a plausible population bottleneck, contributing to their unique genetic diversity and population structure patterns. We finally identified several natural selection candidate genes associated with several biological pathways. CONCLUSIONS: Guizhou Miao possessed a specific genetic structure and harbored a close genetic relationship with geographically close southern Chinese indigenous populations and Guangxi historical people. Miao people derived their major ancestry from geographically close Guangxi Gaohuahua people and experienced a plausible population bottleneck which contributed to the unique pattern of their genetic diversity and structure. Future ancient DNA from Shijiahe and Qujialing will provide new insights into the origin of the Miao people.

Gilteritinib combined with venetoclax and azacitidine for relapsed acute myeloid leukemia cocurrent with pure red cell aplasia after allogeneic hematopoietic stem cell transplantation: a case report.

Pure red cell aplasia (PRCA) is a rare bone marrow (BM) disorder characterized by ineffective erythropoiesis, reduced reticulocyte count, normocytic anemia, and the absence of erythroid precursors. Here, we present a rare instance of PRCA occurring after ABO-matched allo-HSCT in a refractory/relapsed acute myeloid leukemia (R/R AML) patient. In this case, the patient received a combination treatment of Gilteritinib, Venetoclax, and Azacitidine. Remarkably, this treatment not only reduced myeloblasts but also facilitated the restoration of erythroid hematopoiesis.

Folic Acid-Decorated Nanocrystals as Highly Loaded Trojan Horses to Target Cancer Cells.

The nanocrystal (NC) technology has become one of the most commonly used strategies for the formulation of poorly soluble actives. Given their large specific surface, NCs are mainly used to enhance the oral absorption of poorly soluble actives. Differently from conventional nanoparticles, which require the use of carrier materials and have limited drug loadings, NCs' drug loading approaches 100% since they are formed of the pure drug and surrounded by a thin layer of a stabilizer. In this work, we report the covalent decoration of curcumin NCs with folic acid (FA) using EDC/NHS chemistry and explore the novel systems as highly loaded "Trojan horses" to target cancer cells. The decorated NCs demonstrated a remarkable improvement in curcumin uptake, exhibiting enhanced growth inhibition in cancer cells (HeLa and MCF7) while sparing healthy cells (J774A.1). Cellular uptake studies revealed significantly heightened entry of FA-decorated NCs into cancer cells compared to unmodified NCs while also showing reduced uptake by macrophages, indicating a potential for prolonged circulation in vivo. These findings underline the potential of NC highly loaded nanovectors for drug delivery and, in particular, for cancer therapies, effectively targeting folate receptor-overexpressing cells while evading interception by macrophages, thus preserving their viability and offering a promising avenue for precise and effective treatments.

Maximizing Electrostatic Interaction in Ultramicroporous Metal-Organic Frameworks for the One-Step Purification of Acetylene from Ternary Mixture.

Developing efficient adsorbents for acetylene purification from multicomponent mixtures is of critical significance in the chemical industry, but the trade-off between regenerability and selectivity significantly restricts practical industrial applications. Here, we report ultramicroporous metal-organic frameworks with acetylene-affinity channels to enhance electrostatic interaction between C2H2 and frameworks for the efficient one-step purification of C2H2 from C2H2/CO2/C2H4 mixtures, in which the electrostatic interaction led to high regenerability. The obtained SNNU-277 exhibits significantly higher adsorption capacity for C2H2 than that for both C2H4 and CO2 at 298 K and 0.1 bar, while an ultrahigh selectivity of C2H2/C2H4 (100.6 at 298 K) and C2H2/CO2 (32.8 at 298 K) were achieved at 1 bar. Breakthrough experiments validated that SNNU-277 can efficiently separate C2H2 from C2H2/C2H4/CO2 mixtures. CO2 and C2H4 broke through the adsorption column at 4 and 14.8 min g-1, whereas C2H2 was detected until 177.6 min g-1 at 298 K. Theoretical calculations suggest that the framework is electrostatically compatible with C2H2 and electrostatically repels C2H4 and CO2 in the mixed components. This work highlights the importance of rational pore engineering for maximizing the electrostatic effect with the preferentially absorbed guest molecule for efficient multicomponent separation.

Is Pyrolysis Treatment a Viable Solution to Detoxify Metal(loid)s in Sewage Sludge toward Land Application? Case Studies of Chromium and Zinc.

Metal(loid)s in sewage sludge (SS) are effectively immobilized after pyrolysis. However, the bioavailability and fate of the immobilized metal(loid)s in SS-derived biochar (SSB) following land application remain largely unknown. Here, the speciation and bioavailability evolution of SSB-borne Cr and Zn in soil were systematically investigated by combining pot and field trials and X-ray absorption spectroscopy. Results showed that approximately 58% of Cr existing as Cr(III)-humic complex in SS were transformed into Fe (hydr)oxide-bound Cr(III), while nano-ZnS in SS was transformed into stable ZnS and ferrihydrite-bound species (accounting for over 90% of Zn in SSB) during pyrolysis. All immobilized metal(loid)s, including Cr and Zn, in SSB tended to be slowly remobilized during aging in soil. This study highlighted that SSB acted as a dual role of source and sink of metal(loid)s in soil and posed potential risks by serving a greater role of a metal(loid) source than a sink when applied to uncontaminated soils. Nevertheless, SSB could impede the translocation of metal(loid)s from soil to crop compared to SS, where coexisting elements, including Fe, P, and Zn, played critical roles. These findings provide new insights for understanding the fate of SSB-borne metal(loid)s in soil and assessing the viability of pyrolyzing SS for land application.

Multifunctionality promotes the prosperity of riverine planktonic diatoms in plateau.

Interpreting the biogeographic distribution and underlying mechanisms of functional traits not only contributes to revealing the spatiotemporal dynamics of species biodiversity but also helps to maintain ecological stability during environmental variations. However, little is known about the functional profiles of diatom communities over large river systems. Herein, we provided the first blueprints about the spatiotemporal distributions and driving forces of functional traits for both planktonic and sedimentary diatoms over the 6030 km continuum of the Yangtze River, with the help of the high-throughput sequencing and functional identification. By investigating the 28 functional traits affiliated into five categories, we found that planktonic diatom functions showed clearer landform-heterogeneity patterns (ANOSIM R = 0.336) than sedimentary functions (ANOSIM R = 0.172) along the river, represented by life-forms and ecological-guilds prominent in water-plateau as well as cell-sizes and life-forms particularly in sediment-plateau. Planktonic diatom functions also displayed higher richness and network complexity in plateau (richness: 58.70 ± 9.30, network edges: 65) than in non-plateau regions (23.82 ± 13.16, 16), promoting the stability and robustness of diatom functions against the high-radiation and low-temperature plateau environment. Environmental selection (mainly exerted by PAR, UV, and Tw) played crucial roles in determining the functional variations of planktonic diatoms (explaining 80.5%) rather than sedimentary diatoms (14.5%) between plateau and non-plateau regions. Meanwhile, planktonic diatom traits within life-forms were identified to be well responsive to the ecological environment quality (r = 0.56-0.60, P < 0.001) in the Yangtze. This study provided comprehensive insights into the multifunctionality of diatoms and their responses to environmental disturbance and environment quality, which helps to develop effective strategies for maintaining ecological stability in changing river environments.

Ginseng-derived nanoparticles alleviate inflammatory bowel disease via the TLR4/MAPK and p62/Nrf2/Keap1 pathways.

Inflammatory bowel disease (IBD) is closely linked to the homeostasis of the intestinal environment, and exosomes can be used to treat IBD due to their high biocompatibility and ability to be effectively absorbed by the intestinal tract. However, Ginseng-derived nanoparticles (GDNPs) have not been studied in this context and their mechanism of action remains unclear. Here, we investigated GDNPs ability to mediate intercellular communication in a complex inflammatory microenvironment in order to treat IBD. We found that GDNPs scavenge reactive oxygen species from immune cells and intestinal epithelial cells, inhibit the expression of pro-inflammatory factors, promote the proliferation and differentiation of intestinal stem cells, as well as enhancing the diversity of the intestinal flora. GDNPs significantly stabilise the intestinal barrier thereby promoting tissue repair. Overall, we proved that GDNPs can ameliorate inflammation and oxidative stress in vivo and in vitro, acting on the TLR4/MAPK and p62/Keap1/Nrf2 pathways, and exerting an anti-inflammatory and antioxidant effect. GDNPs mitigated IBD in mice by reducing inflammatory factors and improving the intestinal environment. This study offers new evidence of the potential therapeutic effects of GDNPs in the context of IBD, providing the conceptual ground for an alternative therapeutic strategy.

Evidence for chromium crosses blood brain barrier from the hypothalamus in chromium mice model.

It has been shown that exposure to hexavalent Chromium, Cr (Ⅵ), via nasal cavity can have neurotoxicological effects and induces behavioral impairment due to the fact that blood brain barrier (BBB) does not cover olfactory bulb. But whether Cr (Ⅵ) can cross the BBB and have a toxicological effects in central nervous system (CNS) remains unclear. Therefore, we investigated the effects of Cr (Ⅵ) on mice treated with different concentrations and exposure time (14 days and 28 days) of Cr (Ⅵ) via intraperitoneal injection. Results revealed that Cr accumulated in hypothalamus (HY) in a timely dependent manner. Much more severer neuropathologies was observed in the group of mice exposed to Cr (Ⅵ) for 28 days than that for 14 days. Gliosis, neuronal morphological abnormalities, synaptic degeneration, BBB disruption and neuronal number loss were observed in HY. In terms of mechanism, the Nrf2 related antioxidant stress signaling dysfunction and activated NF-κB related inflammatory pathway were observed in HY of Cr (Ⅵ) intoxication mice. And these neuropathologies and signaling defects appeared in a timely dependent manner. Taking together, we proved that Cr (Ⅵ) can enter HY due to weaker BBB in HY and HY is the most vulnerable CNS region to Cr (Ⅵ) exposure. The concentration of Cr in HY increased along with time. The accumulated Cr in HY can cause BBB disruption, neuronal morphological abnormalities, synaptic degeneration and gliosis through Nrf2 and NF-κB signaling pathway. This finding improves our understanding of the neurological dysfunctions observed in individuals who have occupational exposure to Cr (Ⅵ), and provided potential therapeutic targets to treat neurotoxicological pathologies induced by Cr (Ⅵ).

First Report of Fusarium proliferatum Causing Bulb Rot on Lilium davidii var. willmottiae in China.

Lilium davidii var. willmottiae, known as Lanzhou lily, is widely cultivated in China for its edible bulbs. In July 2023, symptoms of bulb rot were observed on Lanzhou lilies harvested from Lanzhou, Gansu Province, during storage at the Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences (Beijing, China), at an incidence of nearly 70%. The surface of the lily scales had dark water-stained spots, after the development of which the color gradually darkened, the bulbs became soft, accompanied by a pungent smell. Finally, the whole bulb became ruined and rotten, and there were thick mycelium layers on the bulbs. The infected bulbs were washed with clean water, sterilized with 75% ethanol for 30 s and 2% sodium hypochlorite for 5 min, and then rinsed three times with sterile distilled water. The 5 mm×5 mm tissue pieces from the junction of the diseased part and the healthy part were clipped, placed on potato dextrose agar (PDA) medium and subsequently incubated at 25 °C. Pure cultures were obtained by transferring hyphal tips to new PDA plates. A total of 10 fungal isolates were obtained, all of which exhibited typical Fusarium characteristics. The colonies were white to pink with white to cream-colored aerial mycelia. After 10 to 15 days of incubation, the macroconidia (n = 50) were hyaline, relatively slender with a curve, three to five septate, and 8.73 to 33.24 × 2.16 to 4.19 µm in length. The microconidia (n = 50) were hyaline and pyriform, without septa, and measured 4.04 to 8.48 × 1.24 to 2.65 µm. These morphological characteristics were similar to those described for Fusarium proliferatum (Leslie and Summerell 2006). For molecular identification, a cetyltrimethylammonium bromide (CTAB) protocol was used to extract total genomic DNA (O'Donnell et al., 1998), after which the internal transcribed spacer (ITS), translation elongation factor subunit 1-alpha (TEF1-α) and RNA polymerase Ⅱ subunit 2 (RPB2) genes were amplified using the universal primers ITS1/ITS4, EF1/EF2 and RPB2-5f2/fRPB2-7cr, respectively, and subsequently sequenced (White et al., 1990; O'Donnell et al., 1998; Liu et al., 1999; Reeb et al., 2004; O'Donnell et al., 2007; Jiang et al., 2018). The sequences of a representative isolate (CAAS01) were analyzed and submitted to GenBank under accession numbers OR554007 (ITS), OR594233 (TEF1-α) and OR603932 (RPB2). A BLAST analysis revealed that the sequences of the ITS, TEF1-α, and RPB2 genes shared 100%, 100%, and 100% identity, respectively, with those of Fusarium proliferatum (MT466521.1, MK952792.1, and LT841266.1) in GenBank. In addition, the ITS, TEF1-α and RPB2 sequences shared 100%, 100%, and 100% identity with those of Fusarium annulatum (LC13675, the Fusarium fujikuroi species complex; previously known as the Gibberella fujikuroi species complex) in the Fusarium-ID database. Fusarium proliferatum, whose common synonyms are Gibberella fujikuroi mating population D and Gibberella fujikuroi var. intermedia, is the anamorphic form of the Gibberella fujikuroi complex that belongs to the Nectriaceae family. A phylogenetic tree was constructed based on the combined TEF1-α and RPB2 sequences of CAAS01 and other Fusarium isolates, revealing that CAAS01 was grouped with Fusarium proliferatum. Based on sequence alignment and phylogenetic analysis, the isolate was identified as Fusarium proliferatum. To determine the pathogenicity of the isolated fungi, healthy bulbs were punctured with disposable sterilized needles and soaked in equal amounts of sterile water and conidial suspension (1×107 conidia/mL) for 30 min respectively. The pathogenicity experiment was repeated three times. After 7 days of inoculation at 25 °C and 80% relative humidity, the surface of the inoculated bulbs produced water-stained spots and mycelium layers consistent with the symptoms exhibited by Lilium davidii var. willmottiae bulbs during storage, while the uninoculated lily bulbs remained symptomless. Fusarium proliferatum was reisolated from the infected bulbs and identified based on morphological and molecular characteristics, fulfilling Koch's postulates. To our knowledge, this is the first report of bulb rot on Lilium davidii var. willmottiae caused by Fusarium proliferatum in China. This study will contribute to the development of management strategies for this postharvest disease in Lilium davidii var. willmottiae.

Improvement of lipopeptide production in Bacillus subtilis HNDF2-3 by overexpression of the sfp and comA genes.

Bacillus subtilis HNDF2-3 can produce a variety of lipopeptide antibiotics with lower production. To improve its lipopeptide production, three genetically engineered strains were constructed. The results of real-time PCR showed that the highest transcriptional levels of the sfp gene in F2-3sfp, F2-3comA and F2-3sfp-comA were 29.01, 6.65 and 17.50 times of the original strain, respectively, while the highest transcriptional levels of the comA gene in F2-3comA and F2-3sfp-comA were 10.44 and 4.13 times of the original strain, respectively. The results of ELISA showed that the malonyl-CoA transacylase activity of F2-3comA was the highest, reaching 18.53 IU/L at 24 h, the data was 32.74% higher than that of the original strain. The highest total lipopeptide production of F2-3sfp, F2-3comA and F2-3sfp-comA induced by IPTG at optimal concentration were 33.51, 46.05 and 38.96% higher than that of the original strain, respectively. The results of HPLC showed that iturin A production of F2-3sfp-comA was the highest, which was 63.16% higher than that of the original strain. This study laid the foundation for further construction of genetically engineered strains with high lipopeptide production.

[Research Progress on the Influence of Tumor Extracellular Matrix Mechanic Properties on Nanodrug Delivery]. / è‚¿ç˜¤åŸºè´¨åŠ›å­¦ç‰¹æ€§å½±å“çº³ç±³è¯ç‰©é€’é€çš„ç ”ç©¶è¿›å±•.

Nanodrugs are widely utilized in the biomedical fields, exhibiting immense potential in cancer therapy in particular. However, tumors exist in an extremely complicated microenvironment where substances like collagen are continuously deposited and remodeled, leading to significant alterations in the mechanical properties of the extracellular matrix (ECM) during tumor development. Previous research has primarily focused on the specific physicochemical properties of nanodrugs, such as particle size, electric charge, shape, surface chemistry, etc., and their effects on cellular uptake, cytotoxicity, and in vivo pharmacokinetics. Limited studies have been done to explore the impact of ECM mechanical properties on nanodrug delivery. In this review, we systematically summarized the relevant research findings on this topic from the perspective of the characteristics and testing methods of tumor ECM mechanics. Additionally, we made a thorough discussion of the potential mechanical and biological mechanisms involved in nanodrug delivery. We proposed several noteworthy research directions. Regarding the overall strategy, there is a need to emphasize targeted delivery that combines ECM mechanics and nanomechanics to achieve precise drug delivery. Regarding the spatial aspect, attention should be given to the nonlinear spatial mechanical heterogeneity within the interior of solid tumors and the construction of mechanic microenvironment-adaptive nanocarriers to improve the delivery efficiency. Regarding the temporal aspect, emphasis should be placed on the dynamic development and changes in the mechanical microenvironment during solid tumor growth and treatment processes. Based on the stromal mechanical characteristics of the tumor tissues of individual patients, personalized treatment strategies can be formulated, which will enhance treatment specificity and efficacy. In addition, issues such as mechanically targeted nanodrug delivery, degradation, and metabolism under dynamic ECM mechanical conditions warrant further investigation.

Extensive genetic admixture between Tai-Kadai-speaking people and their neighbours in the northeastern region of the Yungui Plateau inferred from genome-wide variations.

BACKGROUND: Yungui Plateau in Southwest China is characterized by multi-language and multi-ethnic communities and is one of the regions with the wealthiest ethnolinguistic, cultural and genetic diversity in East Asia. There are numerous Tai-Kadai (TK)-speaking populations, but their detailed evolutionary history and biological adaptations are still unclear. RESULTS: Here, we genotyped genome-wide SNP data of 77 unrelated TK-speaking Zhuang and Dong individuals from the Yungui Plateau and explored their detailed admixture history and adaptive features using clustering patterns, allele frequency differentiation and sharing haplotype patterns. TK-speaking Zhuang and Dong people in Guizhou are closely related to geographically close TK and Hmong-Mien (HM)-speaking populations. Besides, we identified that Guizhou TK-speaking people have a close genetic relationship with Austronesian (AN)-speaking Atayal and Paiwan people, which is supported by the common origin of the ancient Baiyue tribe. We additionally found subtle genetic differences among the newly studied TK people and previously reported Dais via the fine-scale genetic substructure analysis based on the shared haplotype chunks. Finally, we identified specific selection candidate signatures associated with several essential human immune systems and neurological disorders, which could provide evolutionary evidence for the allele frequency distribution pattern of genetic risk loci. CONCLUSIONS: Our comprehensive genetic characterization of TK people suggested the strong genetic affinity within TK groups and extensive gene flow with geographically close HM and Han people. We also provided genetic evidence that supported the common origin hypothesis of TK and AN people. The best-fitted admixture models further suggested that ancestral sources from northern millet farmers and southern inland and coastal people contributed to the formation of the gene pool of the Zhuang and Dong people.

A comprehensive overview on the transmission, pathogenesis, diagnosis, treatment, and prevention of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a single positive-strand RNA virus that is responsible for the current pandemic that the world has been facing since 2019. The primary route of transmission of SARS-CoV-2 is through respiratory tract transmission. However, other transmission routes such as fecal-oral, vertical transmission, and aerosol-eye also exist. In addition, it has been found that the pathogenesis of this virus involves the binding of the virus's S protein to its host cell surface receptor angiotensin-converting enzyme 2, which results in the subsequent membrane fusion that is required for SARS-CoV-2 to replicate and complete its entire life. The clinical symptoms of patients infected with SARS-CoV-2 can range from asymptomatic to severe. The most common symptoms seen include fever, dry cough, and fatigue. Once these symptoms are observed, a nucleic acid test is done using reverse transcription-polymerase chain reaction. This currently serves as the main confirmatory tool for COVID-19. Despite the fact that no cure has been found for SARS-CoV-2, prevention methods such as vaccines, specific facial mask, and social distancing have proven to be quite effective. It is imperative to have a complete understanding of the transmission and pathogenesis of this virus. To effectively develop new drugs as well as diagnostic tools, more knowledge about this virus would be needed.