Machine-learning and scRNA-Seq-based diagnostic and prognostic models illustrating survival and therapy response of lung adenocarcinoma.

Lung cancer is a major cause accounting for cancer-related mortalities, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Given the high clinical and cellular heterogeneities of LUAD, accurate diagnosis and prognosis are crucial to avoid overdiagnosis and overtreatment. Taking full advantage of scRNA-Seq data to resolve the tumor heterogeneities, we explored the overall landscape of LUAD microenvironment. Utilizing the stage-specific tumor cell markers, we have developed highly accurate diagnostic and prognostic models with elevated sensitivity and specificity. The diagnostic model, developed through random forest algorithms with a thirteen-gene signature, achieved an accuracy of 96.4% and an AUC of 0.993. These metrics were further demonstrated by benchmarking with available models and scoring systems in independent cohorts. Concurrently, the prognostic model, formulated via Cox regression with a six-gene signature, effectively predicted overall survival, with elevated risk scores associated with increased fractions of cancer-associated fibroblasts, and higher likelihood of immune escape and T-cell exclusion. Subsequently, two nomograms were developed to predict survival and drug responses, facilitating their integration into clinical practice. Overall, this study underscores the potential of our models for efficient, rapid, and cost-effective diagnosis and prognosis of LUAD, adaptable to multiple expression profiling platforms and quantification methods.

Recruitment of plasma cells from IL-21-dependent and IL-21-independent immune reactions to the bone marrow.

Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.

Interface Engineering-Modulated Nanoscale Bimetallic CoFe-MIL-88A In-Situ-Grown on 2D V2CTx MXene for Electrocatalytic Nitrogen Reduction.

The electrochemical nitrogen reduction reaction (eNRR) provides a sustainable green development route for the nitrogen-neutral cycle. In this work, bimetallic CoFe-MIL-88A with two active sites (Fe, Co) were immobilized on a 2D V2CTx MXene surface by in situ growth method to achieve the purpose of the control interface. A large number of heterostructures are formed between small CoFe-MIL-88A and V2CTx, which regulate the electron transfer between the catalyst interfaces. The adsorption and activation of nitrogen on the active sites were enhanced, and the NRR reaction kinetics was accelerated. CoFe-MIL-88A is tightly arranged on V2CTx, which makes CoFe-MIL-88A/V2CTx have better hydrophobicity and can significantly inhibit the hydrogen evolution reaction. The synergistic effect of multicatalytic active sites and multi-interface structure of CoFe-MIL-88A/V2CTx MXene is propitious to nitrogen efficiently and stably to convert into ammonia under environmental conditions with superior selectivity and good catalytic activity. The NH3 yield rate is 29.47 µg h-1 mgcat-1 at -0.3 V vs RHE, and the Faradaic efficiency (FE) is 28.86% at -0.1 V vs RHE. The catalytic mechanism was verified to conform to the distal pathway. This work will provide a new way to develop an MXene-based electrocatalyst for eNRR.

IL-4-secreting CD40L+ MAIT cells support antibody production in the peripheral blood of Heonch-Schönlein purpura patients.

OBJECTIVE: Here, we explored the phenotype and function of MAIT cells in the peripheral blood of patients with HSP. METHODS: Blood samples from HSP patients and HDs were assessed by flow cytometry and single-cell RNA sequencing to analyze the proportion, phenotype, and function of MAIT cells. Th-cytokines in the serum of HSP patients were analyzed by CBA. IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. RESULTS: The percentage of MAIT cells in HSP patients was significantly reduced compared with that in HDs. Genes related to T cell activation and effector were up-regulated in HSP MAIT cells, indicating a more activated phenotype. In addition, HSP MAIT cells displayed a Th2-like profile with the capacity to produce more IL-4 and IL-5, and IL-4 was correlated with IgA levels in the serum of HSP patients. Furthermore, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an increased ability to produce IL-4 and to enhance IgA production by B cells. CONCLUSION: Our data demonstrate that MAIT cells in HSP patients exhibit an activated phenotype. The enhanced IL-4 production and CD40L expression of MAIT cells in HSP patients could take part in the pathogenesis of HSP.

Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron.

SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development of broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, with potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 with aRBD-5 and aRBD-7, respectively. Here, we resolved the crystal structures of these Nbs in complex with the receptor-binding domain (RBD) of the spike protein, and found that aRBD-2 contacts with highly-conserved RBD residues and retains binding to the RBD of the Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, and BA.2 variants. In contrast, aRBD-5 and aRBD-7 bind to less-conserved RBD epitopes non-overlapping with the epitope of aRBD-2, and do not show apparent binding to the RBD of some variants. However, when fused with aRBD-2, they effectively enhance the overall binding affinity. Consistently, aRBD-2-5-Fc and aRBD-2-7-Fc potently neutralized all of the tested authentic or pseudotyped viruses, including WT, Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.1.1 and BA.2. Furthermore, aRBD-2-5-Fc provided prophylactic protection against the WT and mouse-adapted SARS-CoV-2 in mice, and conferred protection against the Omicron BA.1 variant in hamsters prophylactically and therapeutically, indicating that aRBD-2-5-Fc could potentially benefit the prevention and treatment of COVID-19 caused by the emerging variants of concern. Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19.

CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus.

Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3- plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+ and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++CD326++ ASC subpopulation in autoimmunity.

Natural Vegetation Encroachment Improves Nutritional Conditions of Bauxite Residue Disposal Area.

The deficiencies of certain nutrients limit plant growth in bauxite residue disposal areas. In this study, residue samples at different depths (0-2 cm, 2-10 cm, 10-20 cm, 20-40 cm, and 40-60 cm) and stacking ages were collected to analyze the changes of nutritional conditions following natural vegetation encroachment processes. With the encroachment of natural vegetation, the nutrient components improved greatly. The contents of organic carbon, total nitrogen, and available phosphorus increased from 5.6 g/kg to 10.8 g/kg, 0.07 g/kg to 0.73 g/kg, and 6.3 mg/kg to 24.9 mg/kg, respectively. With the increase of natural weathering time, microbial carbon, nitrogen, and phosphorus increased significantly. Natural weathering process and vegetation encroachment improved the circulation and accumulation of nutrient substances in bauxite residues.

Novel Plant Growth-Promoting Bacteria Isolated from Bauxite Residue: The Application for Revegetation.

Microbial inoculation with appropriate inorganic-organic amendments is a promising strategy for ecological rehabilitation at bauxite residue disposal areas. Nevertheless, research on screening suitable plant growth-promoting bacteria with tolerance to highly sodic-alkalinity is very limited in the literature. In this study, novel plant growth-promoting bacteria isolated from bauxite residue were used to investigate their potential for revegetation. Under high saline-alkalinity stress, inoculation of Z18 and Z28 increased the activity of antioxidative enzymes, whilst improving chlorophyll and carotenoid contents in ryegrass. Inoculation of the selected strains greatly reduced damage to organelles in ryegrass as observed by transmission electron microscopy. Based on 90-day soil incubation, inoculated strains improved physicochemical properties of bauxite residue and improved plant growth. These findings suggest that Z18 and Z28 may be selected as potential strains for vegetation establishment, aiding microbial remediation at bauxite disposal areas.

Analgesic Effects of Epidural Labor Analgesia at Different Periods and Its Effects on Maternal and Infant Outcomes and MiRNA-146b Level.

This paper aimed to analyze the analgesic effects of continuous epidural labor analgesia (ELA) at different periods and its effects on postpartum depression, maternal and infant outcomes, and maternal blood pressure. Giving birth in our hospital from September 2017 to August 2019, 119 primiparas with spontaneous delivery were enrolled and divided into an observation group (65 cases) and a control group (54 cases). Patients in the observation group received epidural block analgesia in advance, whereas those in the control group received epidural block analgesia routinely. At 25 days after delivery, breast milk samples were collected, in which miRNA-146b level was detected by PCR. The patients were compared between the two groups with respect to progress of labor, analgesic effects during 3 stages of labor, labor outcomes, adverse reactions, and levels of NO, ANP, and ET-1 in the parturients' umbilical artery blood. Compared with those in the control group, patients in the observation group had a remarkably higher miRNA-146b level in the breast milk (P < 0.05), remarkably lower average Visual Analogue Scale (VAS) scores during the active phase and the second stage of labor (P < 0.05), and remarkably higher levels of NO, ANP, and ET-1 (P < 0.05). There were no statistically significant differences in adverse reactions and modes of delivery between the two groups (P < 0.05). ELA starting from the latent phase can improve the miRNA-146b level in maternal breast milk, alleviate labor pain of parturients, and shorten stages of labor. Therefore, our study is worthy of clinical promotion. We still need to do more experiments and use more data to conclude more scientific results in future research work.

RGL2 as an age-dependent factor regulates colon cancer progression.

Colon cancer is the fourth leading cause of cancer-related death, and exhibited clinical differences among patients of different ages, including malignancy, metastasis, and mortality rate. Few studies, however, focus on the communications between aging and colon cancer. Here we identified age-dependent differentially expressed genes (DEGs) in colon cancer using TCGA transcriptome data. Through analyzing multi-omics high throughput data, including ATAC-Seq, DNaseI-Seq and ChIP-Seq, we obtained six age-dependent transcription factors in colon cancer, and their age-dependent targets, significantly affecting patients' overall survivals. Transcription factor ETS1 potentially functioned in both aging process and colon cancer progression through regulating its targets, RGL2 and SLC2A3. In addition, comparing with its relative lower expression levels in elderly patients, higher levels of RGL2 were detected in young patients, and significantly associated with larger tumor size, higher metastasis, and invasions of colon cancer, consistent with the clinical traits that young patients' colon cancer exhibited late stages with more aggressiveness. Thus, these elements may serve as keys linking aging and colon cancer, and providing new insights and basis for mechanism researches, as well as diagnosis and therapies of colon cancer, especially in young patients.

Immunological memory in rheumatic inflammation - a roadblock to tolerance induction.

Why do we still have no cure for chronic inflammatory diseases? One reason could be that current therapies are based on the assumption that chronic inflammation is driven by persistent 'acute' immune reactions. Here we discuss a paradigm shift by suggesting that beyond these reactions, chronic inflammation is driven by imprinted, pathogenic 'memory' cells of the immune system. This rationale is based on the observation that in patients with chronic inflammatory rheumatic diseases refractory to conventional immunosuppressive therapies, therapy-free remission can be achieved by resetting the immune system; that is, by ablating immune cells and regenerating the immune system from stem cells. The success of this approach identifies antigen-experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The 'dark side' of immunological memory primarily involves memory plasma cells secreting pathogenic antibodies and memory T lymphocytes secreting pathogenic cytokines and chemokines, but can also involve cells of innate immunity. New therapeutic strategies should address the persistence of these memory cells. Selective targeting of pathogenic immune memory cells could be based on their specificity, which is challenging, or on their lifestyle, which differs from that of protective immune memory cells, in particular for pathogenic T lymphocytes. The adaptations of such pathogenic memory cells to chronic inflammation offers entirely new therapeutic options for their selective ablation and the regeneration of immunological tolerance.

LYAR Promotes Colorectal Cancer Progression by Upregulating FSCN1 Expression and Fatty Acid Metabolism.

Colorectal cancer (CRC) is a highly malignant tumor associated with poor prognosis, yet the molecular mechanisms are not fully understood. In this study, we showed that LYAR, a nucleolar protein, is expressed at a higher level in CRC tissue than in adjacent normal tissue and that LYAR expression is closely associated with distant CRC metastasis. LYAR not only significantly promotes the migration and invasion of CRC cells in vitro, but knockdown (KD) of LYAR in CRC cells also inhibits xenograft tumor metastasis in vivo. Microarray analysis of LYAR KD cells combined with a chromatin immunoprecipitation (ChIP) assay, gene reporter assay, and rescue experiment indicated that FSCN1 (encoding fascin actin-bundling protein 1 (Fascin-1)) serves as a novel key regulator of LYAR-promoted migration and invasion of CRC cells. Knockdown of FSCN1 significantly inhibits subcutaneous tumorigenesis of CRC cells and leads to the downregulation of FASN and SCD, genes encoding key enzymes in fatty acid synthesis. In summary, this study reveals a novel mechanism by which LYAR promotes tumor cell migration and invasion by upregulating FSCN1 expression and affecting fatty acid metabolism in CRC.

Senescence-associated genes and non-coding RNAs function in pancreatic cancer progression.

Pancreatic cancer is a major cause of mortality with a poor diagnosis and prognosis that most often occurs in elderly patients. Few studies, however, focus on the interplay of age and pancreatic cancer at the transcriptional level. Here we evaluated the possible roles of age-dependent, differentially expressed genes (DEGs) in pancreatic cancer. These DEGs were used to construct a correlation network and clustered in six gene modules, among which two modules were highly correlated with patients' survival time. Integrating different datasets, including ATAC-Seq and ChIP-Seq, we performed multi-parallel analyses and identified eight age-dependent protein coding genes and two non-coding RNAs as potential candidates. These candidates, together with KLF5, a potent functional transcription factor in pancreatic cancer, are likely to be key elements linking cellular senescence and pancreatic cancer, providing insights on the balance between them, as well as on diagnosis and subsequent prognosis of pancreatic cancer.

Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies.

Antibody-mediated diseases affect more than 10% of the human population. For most, no cure is available, particularly when the pathogenic antibodies are secreted by long-lived plasma cells resistant to conventional immunosuppressive therapies. Current therapeutic approaches target not only the plasma cells that secrete pathogenic antibodies, but also those providing protective antibodies. Here, in a murine model bearing long-lived plasma cells secreting anti-OVA and -chicken gamma globulin (CGG) antibodies, we describe the first-time use of an antigen-antibody (OVA/anti-CD138 antibody) conjugate for in vivo labeling and selective ablation of plasma cells that secrete antibodies specific for the antigen OVA. The selective depletion also led to a stable reduction of the corresponding serum anti-OVA antibody levels. In contrast, CGG-specific plasma cells and circulating anti-CGG antibody levels remained unchanged. The method described here should enable the development of unique causative treatment strategies for established antibody-mediated diseases sparing humoral immunity.

The Maintenance of Memory Plasma Cells.

It is now well accepted that plasma cells can become long-lived (memory) plasma cells and secrete antibodies for months, years or a lifetime. However, the mechanisms involved in this process of humoral memory, which is crucial for both protective immunity and autoimmunity, still are not fully understood. This article will address a number of open questions. For example: Is longevity of plasma cells due to their intrinsic competence, extrinsic factors, or a combination of both? Which internal signals are involved in this process? What factors provide external support? What survival factors play a part in inflammation and autoreactive disease? Internal and external factors that contribute to the maintenance of memory long-lived plasma cells will be discussed. The aim is to provide useful additional information about the maintenance of protective and autoreactive memory plasma cells that will help researchers design effective vaccines for the induction of life-long protection against infectious diseases and to efficiently target pathogenic memory plasma cells.

Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow.

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella A SiiE-derived peptide with homology to laminin ß1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin ß1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.

Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors.

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.

CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice.

Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1-/- mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.

Pollution characteristics of surface runoff under different restoration types in manganese tailing wasteland.

A great deal of manganese and associated heavy metals (such as Ni, Cu, Zn, Cd, Pb, etc.) was produced in manganese mining, smelting, and other processes and weathering and leaching of waste slag, which entered rainwater runoff by different means under the action of rainfall runoff. It caused heavy metal pollution in water environment to surrounding areas, and then environmental and human health risks were becoming increasingly serious. In the Xiangtan manganese mine, we studied the characteristics of nutritional pollutants and heavy metals by using the method of bounded runoff plots on the manganese tailing wasteland after carrying out some site treatments using three different approaches, such as (1) exposed tailings, the control treatment (ET), (2) external-soil amelioration and colonization of Cynodon dactylon (Linn.) Pers. turf (EC), and (3) external-soil amelioration and seedling seeding propagation of Cynodon dactylon (Linn.) Pers. (ES). The research showed that the maximum runoff occurred in 20,140,712 rainfall events, and the basic law of runoff was EC area > ET area > ES area in the same rainfall event. The concentration of total suspended solids (TSS) and chemical oxygen demand (COD) of three ecological restoration areas adopted the following rule: ET area > EC area > ES area. Nitrogen (N) existed mainly in the form of water soluble while phosphorus (P) was particulate. The highest concentrations of total nitrogen (TN) and total phosphorus (TP) were 11.57 ± 2.99 mg/L in the EC area and 1.42 ± 0.56 mg/L in the ET area, respectively. Cr, Ni, Pb, Zn, Mn, and Cu in surface runoff from three restoration types all exceeded the class V level of the environmental quality standard for surface water except Cu in EC and ES areas. Pollution levels of heavy metals in surface runoff from three restoration areas are shown as follows: ET area > EC area > ES area. There was a significant positive correlation between TSS and runoff, COD, and TP. And this correlation was significant between total dissolved nitrogen (TDN), TN, total dissolved phosphorus (TDP), and TP. The six heavy metals (Cu, Ni, Pb, Zn, Mn, and Cr) in surface runoff of different ecological restoration areas were strongly related to each other, and were significantly related to the TSS.