Negative regulation of angiogenesis and the MAPK pathway may be a shared biological pathway between IS and epilepsy.

Ischemia stroke and epilepsy are two neurological diseases that have significant patient and societal burden, with similar symptoms of neurological deficits. However, the underlying mechanism of their co-morbidity are still unclear. In this study, we performed a combined analysis of six gene expression profiles (GSE58294, GSE22255, GSE143272, GSE88723, GSE163654, and GSE174574) to reveal the common mechanisms of IS and epilepsy. In the mouse datasets, 74 genes were co-upregulated and 7 genes were co-downregulated in the stroke and epilepsy groups. Further analysis revealed that the co-expressed differentially expressed genes (DEGs) were involved in negative regulation of angiogenesis and the MAPK signaling pathway, and this was verified by Gene Set Enrichment Analysis of human datasets and single cell RNA sequence of middle cerebral artery occlusion mice. In addition, combining DEGs of human and mouse, PTGS2, TMCC3, KCNJ2, and GADD45B were identified as cross species conserved hub genes. Meanwhile, molecular docking results revealed that trichostatin A and valproic acid may be potential therapeutic drugs. In conclusion, to our best knowledge, this study conducted the first comorbidity analysis of epilepsy and ischemic stroke to identify the potential common pathogenic mechanisms and drugs. The findings may provide an important reference for the further studies on post-stroke epilepsy.

Integrative analysis of single-cell and bulk RNA sequencing unveils the senescence landscape in ischemic stroke.

Ischemic stroke (IS) is a fatal neurological disease that occurs when the blood flow to the brain is disrupted, leading to brain tissue damage and functional impairment. Cellular senescence, a vital characteristic of aging, is associated with a poor prognosis for IS. This study explores the potential role of cellular senescence in the pathological process following IS by analyzing transcriptome data from multiple datasets (GSE163654, GSE16561, GSE119121, and GSE174574). By using bioinformatics methods, we identified hub-senescence-related genes such as ANGPTL4, CCL3, CCL7, CXCL16, and TNF and verified them using quantitative reverse transcription polymerase chain reaction. Further analysis of single-cell RNA sequencing data suggests that MG4 microglial is highly correlated with cellular senescence in MCAO, and might play a crucial role in the pathological process after IS. Additionally, we identified retinoic acid as a potential drug for improving the prognosis of IS. This comprehensive investigation of cellular senescence in various brain tissues and peripheral blood cell types provides valuable insights into the underlying mechanisms of the pathology of IS and identifies potential therapeutic targets for improving patient outcomes.

Insufficient epitope-specific T cell clones are responsible for impaired cellular immunity to inactivated SARS-CoV-2 vaccine in older adults.

Aging is a critical risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy. The immune responses to inactivated vaccine for older adults, and the underlying mechanisms of potential differences to young adults, are still unclear. Here we show that neutralizing antibody production by older adults took a longer time to reach similar levels in young adults after inactivated SARS-CoV-2 vaccination. We screened SARS-CoV-2 variant strains for epitopes that stimulate specific CD8 T cell response, and older adults exhibited weaker CD8 T-cell-mediated responses to these epitopes. Comparison of lymphocyte transcriptomes from pre-vaccinated and post-vaccinated donors suggested that the older adults had impaired antigen processing and presentation capability. Single-cell sequencing revealed that older adults had less T cell clone expansion specific to SARS-CoV-2, likely due to inadequate immune receptor repertoire size and diversity. Our study provides mechanistic insights for weaker response to inactivated vaccine by older adults and suggests the need for further vaccination optimization for the old population.

Changes in gut microbial community upon chronic kidney disease.

With the increasing incidence and mortality of chronic kidney disease (CKD), targeted therapies for CKD have been explored constantly. The important role of gut microbiota on CKD has been emphasized increasingly, it is necessary to analyze the metabolic mechanism of CKD patients from the perspective of gut microbiota. In this study, bioinformatics was used to analyze the changes of gut microbiota between CKD and healthy control (HC) groups using 315 samples from NCBI database. Diversity analysis showed significant changes in evenness compared to the HC group. PCoA analysis revealed significant differences between the two groups at phylum level. In addition, the F/B ratio was higher in CKD group than in HC group, suggesting the disorder of gut microbiota, imbalance of energy absorption and the occurrence of metabolic syndrome in CKD group. The study found that compared with HC group, the abundance of bacteria associated with impaired kidney was increased in CKD group, such as Ralstonia and Porphyromonas, which were negatively associated with eGFR. PICRUSt2 was used to predict related functions and found that different pathways between the two groups were mainly related to metabolism, involving the metabolism of exogenous and endogenous substances, as well as Glycerophospholipid metabolism, which provided evidence for exploring the relationship between gut microbiota and lipid metabolism. Therefore, in subsequent studies, special attention should be paid to these bacteria and metabolic pathway, and animal experiments and metabolomics studies should be conducted explore the association between bacterial community and CKD, as well as the therapeutic effects of these microbial populations on CKD.

Tumor-intrinsic CD21 expression impacts the response of B-cell malignancy cells to CD19-CAR-T cells.

CD19-chimeric antigen receptor (CAR)-based T-cell therapy has produced promising clinical responses in patients with relapsed or refractory B-cell malignancies. However, a significant portion of patients with mature B cell-derived malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), do not respond to CD19-CAR-T cell therapy. Whether any characteristics and biomarkers intrinsic to cancer cells themselves can predict the CD19-CAR-T cell therapeutic response remains largely unknown. Surprisingly, by using experimental models, we show here that malignant B cells bearing CD21, a mature B cell marker, could not be efficiently killed by CD19-CAR-T cells. CD19, CD21, and CD81, together with CD225, form the B cell coreceptor complex that enhances B cell-mediated signaling. Our results indicated that CD21 affected the recognition of CD19-positive tumor cells by CD19-CAR-T cells and impaired the antitumor capacities of these effector cells. We have not only uncovered a mechanism underlying the impairment of CD19-CAR-T cells in mature B cell-derived CLL and NHL, but also proposed a pretreatment biomarker that may predict CD19-CAR-T cell therapeutic response, thus preventing foreseeable therapy failure and suggesting optimal personized therapies.

Simultaneous bio-reduction of nitrate and Cr(VI) by mechanical milling activated corn straw.

Abundant lignocellulose waste is an ideal energy source for environmental bioremediation, but its recalcitrance to bioavailability makes this a challenging prospect. We hypothesized that the disruption of straw's recalcitrant structure by mechanochemical ball milling would enhance its availability for the simultaneous bioreduction of nitrate and Cr(VI). The results showed that the ball-milling process increased the quantity of water-soluble organic matter released from corn straw and changed the composition of organic matter by strongly disrupting its lignocellulose structure. The increase in ball-milling time increased the specific surface area of the straw and favored the adhesion of microorganisms on the straw surface, which enhanced the bioavailability of the energy in the straw. Substantially increased removal of NO3--N (206.47 ± 0.67 mg/g) and Cr(VI) (37.62 ± 0.09 mg/g) was achieved by using straw that was ball milled for 240 min, which validated that ball milling can improve the utilization efficiency of straw by microorganisms. Cellular and molecular biological analyses showed that ball-milled straw increased microbial energy metabolism and cellular activity related to the electron transport chain. This work offers a potential way to achieve the win-win goal of utilizing agricultural wastes and remediating environmental pollution.

SARS-CoV-2 variant B.1.1.7 caused HLA-A2+ CD8+ T cell epitope mutations for impaired cellular immune response.

Here, we evaluated the immune properties of the HLA-A2 restricted CD8+ T cell epitopes containing mutations from B.1.1.7, and furthermore performed a comprehensive analysis of the SARS-CoV-2 specific CD8+ T cell responses from COVID-19 convalescent patients and SARS-CoV-2 vaccinees recognizing the ancestral Wuhan strain compared to B.1.1.7. First, most of the predicted CD8+ T cell epitopes showed proper binding with HLA-A2, whereas epitopes from B.1.1.7 had lower binding capability than those from the ancestral strain. In addition, these peptides could effectively induce the activation and cytotoxicity of CD8+ T cells. Our results further showed that at least two site mutations in B.1.1.7 resulted in a decrease in CD8+ T cell activation and a possible immune evasion, namely A1708D mutation in ORF1ab1707-1716 and I2230T mutation in ORF1ab2230-2238. Our current analysis provides information that contributes to the understanding of SARS-CoV-2-specific CD8+ T cell responses elicited by infection of mutated strains or vaccination.

Changes in microbial community diversity, composition, and functions upon nitrate and Cr(VI) contaminated groundwater.

With the increasing occurrences of nitrate and Cr(VI) pollution globally, microbially driven pollutant reduction and its interaction effects were of growing interest. Despite the increasing number of experimental reports on the simultaneous reduction of nitrate and Cr(VI), a broad picture of the keystone species and metabolic differences in this process remained elusive. This study explored the changing of microorganisms with the introduction of Cr(VI)/NO3- through analyzing 242 samples from the NCBI database. The correlation between microbial abundance and environmental factors showed that, the types of energy substances and pollutants species in the environment had an impact on the diversity of microorganisms and community structure. The genus of Zoogloea, Candidatus Accumulibacter, and Candidatus Kapabacteria sp. 59-99 had the ability of denitrification, while genus of Alcaligenes, Kerstersia, Petrimonas, and Leucobacter showed effectively Cr(VI) resistance and reducing ability. Azoarcus, Pseudomonas, and Thauera were recognized as important candidates in the simultaneous reduction of nitrate and Cr(VI). Metagenomic predictions of these microorganisms using PICRUSt2 further highlighted the enrichment of Cr(VI)and nitrate reduction-related genes (such as chrA and norC). Special attention should therefore be paid to these bacteria in subsequent studies to evaluate their performance and mechanisms involved in simultaneous denitrification and chromium removal. The microbial co-occurrence network analysis conducted on this basis emphasized a strong association between community collaboration and pollution removal. Collectively, either site surveys or laboratory experiments, subsequent studies should focus on these microbial populations and the interspecific collaborations as they strongly influence the occurrence of simultaneous nitrate and Cr(VI) reduction.

Identification of HLA-A2 restricted CD8+ T cell epitopes in SARS-CoV-2 structural proteins.

The outbreak of coronavirus disease 2019 (COVID-19) has now become a pandemic, and the etiologic agent is the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). T cell mediated immune responses play an important role in virus controlling; however, the understanding of the viral protein immunogenicity and the mechanisms of the induced responses are still limited. So, identification of specific epitopes and exploring their immunogenic properties would provide valuable information. In our study, we utilized the Immune Epitope Database and Analysis Resource and NetMHCpan to predict HLA-A2 restricted CD8+ T cell epitopes in structural proteins of SARS-CoV-2, and screened out 23 potential epitopes. Among them, 18 peptides showed strong or moderate binding with HLA-A2 with a T2A2 cell binding model. Next, the mixed peptides induced the increased expression of CD69 and highly expressed levels of IFN-γ and granzyme B in CD8+ T cells, indicating effective activation of specific CD8+ T cells. In addition, the peptide-activated CD8+ T cells showed significantly increased killing to the target cells. Furthermore, tetramer staining revealed that the activated CD8+ T cells mainly recognized seven epitopes. All together, we identified specific CD8+ T cell epitopes in SARS-CoV-2 structural proteins, which could induce the production of specific immune competent CD8+ T cells. Our work contributes to the understanding of specific immune responses and vaccine development for SARS-CoV-2.

Iron oxide minerals promote simultaneous bio-reduction of Cr(VI) and nitrate: Implications for understanding natural attenuation.

Nitrate and Cr(VI) coexist in aquifers, posing a potential threat to ecological environment and public health. Iron oxide minerals (hematite and magnetite) exist ubiquitously in groundwater, which are hot spots for biogeochemical transformation. However, there is still a knowledge gap anout the effect of iron oxide minerals on bioreduction of nitrate and Cr(VI). Here we observed that iron oxide minerals can significantly improve the ability of microorganisms to simultaneously reduce nitrate and Cr(VI), the reduction rates of nitrate and Cr(VI) increased by 7.3 and 8.5 times, respectively. The addition of minerals reinforced biofilm formation and shaped microbial communities with a new dominant strain of Azoarcus. The expression levels of functional genes were also upregulated, including napA, narG, nfsA, yieF, POD, and CAT. Furthermore, nitrate and chromate reductases' activities increased by 11 and 5 folds, respectively. These results demonstrated that iron oxide minerals participated in the bio-transformation of nitrate and Cr(VI) co-contamination, alleviating oxidative stress, shaping the microbial community, and ultimately accelerating bio-transformation. These findings offer a window into the biological transformation of co-contamination in the presence of iron oxide minerals, and insights to reveal strategies for microbial detoxification and to develop promising approaches for dealing with complex pollution conditions.

High redox potential promotes oxidation of pyrite under neutral conditions: Implications for optimizing pyrite autotrophic denitrification.

Pyrite autotrophic denitrification (PAD) represents an important natural attenuation process of nitrate pollution and plays a pivotal role in linking nitrogen, sulfur, and iron cycles in a variety of anoxic environments. However, there are knowledge gaps about the oxidation mechanism of pyrite under anaerobic neutral conditions. This study explored the performance of PAD in the presence of EDTA and revealed the mechanism of anaerobic pyrite oxidation and microbial mineral transformation. It was demonstrated that ~200 mV was the electrochemical threshold for converting pyrite into bioavailable forms in PAD conditions, and accelerated pyrite oxidation by Fe3+-EDTA complexes can improve the performance of PAD effectively. Furthermore, genus related to sulfur and nitrogen cycle (Sulfurimonas, Denitrobacter) were found at higher abundances in cultures containing EDTA. The analysis of metagenomic binning showed that the microbial community in PAD culture with EDTA addition exhibited higher levels of functional diversity and redundancy. These results will further the understanding of the oxidation mechanism of pyrite under anaerobic neutral conditions and the corresponding microbial activities, and provide insights into the practical application of PAD.

Stronger Stimulation of Waste Activated Sludge Anaerobic Fermentation by a Particular Amount of Micron-Sized Zero Valent Iron.

An emerging contaminant, micron-sized zero valent iron (mZVI) has been reported to be accumulated in waste activated sludge (WAS). In the present study, the potential effects of mZVI on WAS anaerobic fermentation performance, as well as the shift of the microbial community composition and function, were assessed. Results from batch experiments indicated that a particular concentration of mZVI (1.5 g/L, in the range of 0.0 to 5.0 g/L) improved volatile fatty acids (VFA) accumulation by 4.84 times that in the control group, the ability (dosage dependent) to remove phosphorus, and the dewaterability of fermented WAS from 126 ± 5 s (control group) to 104 ± 3 s (group with 1.5 g/L mZVI). Furthermore, high-throughput sequencing revealed that mZVI had no significant impact on the shift of microbial community structure, but directly stimulated the functional performance related to anaerobic fermentation. This study will provide new insights into the mZVI application and its effect on WAS utilization.

The mechanism of nitrate-Cr(VI) reduction mediated by microbial under different initial pHs.

To date, comparatively little research is known about the role of pH conditions in bioremediation of Cr(VI) contaminated aquifers. This study explored microbial Cr(VI) reduction and denitrification under different initial pHs. The underlying mechanism was also investigated. When testing 50 mg/L-N nitrate and 10 mg/L Cr(VI), complete contaminants removal was observed at initial pH 10.0 and 11.0, and only 10 %-30 % of removal achieved under other conditions, which might be ascribe to the significant up-regulation of functional genes narG (8.31 and 10.46 folds) and azoR (24.90 and 15.96 folds) at initial pH 10.0 and 11.0. Metagenomic sequencing showed that alkali tolerant bacteria played major roles in the NO3--Cr(VI) reduction (i.e. Pannonibacter increased by 13.08 % and 25.24 % at initial pH 10.0 and 11.0), and metabolic pathways of Degradation and Energy were found of increased abundant. Furthermore, a significative study suggested that potential interspecies cooperation existed at initial pH 11.0 to facilitating the simultaneous removal of contaminants, and Pannonibacter indicus might be an important participant in the degradation of contaminants. The results of this study will fully understand the metabolic patterns of bacteria under alkaline conditions, expand the range of available functional bacteria, and enhance the practical aspects of co-contaminants remediation.

Coupling enhancement of Chromium(VI) bioreduction in groundwater by phosphorus minerals.

Groundwater contaminated by hexavalent chromium (Cr(VI)) has posed severe threat to the environment and public health. Although heterotrophic bioremediation has been known as an efficient approach, little is explored on mineral nutrient source addition such as phosphorus minerals. In this study, the stabilization and sustainability of phosphorus minerals for providing phosphorus has been investigated, and the enhancement of Cr(VI) removal by mixed bacterial consortium coupled with phosphorus minerals was also observed and further verified, with 1.4-3.9 times K values (first-order) increase under different conditions. We demonstrated that the applied of phosphorus minerals facilitated the reduction of Cr(VI) and the removal of Cr(III), promoted the resistance of Cr(VI) and the generation of antioxidase, and engendered the evolution of microbial community structures and functional genes. These findings provide a new insight for enhancement of Cr(VI)-contaminated groundwater in-situ remediation.

Feasibility and mechanism of microbial-phosphorus minerals-alginate immobilized particles in bioreduction of hexavalent chromium and synchronous removal of trivalent chromium.

Chromium(VI) contaminated groundwater has become an increasingly prominent problem due to its extensive application in industry. Based on the easy-loss defect of microbial in practical application and previous research on the coupling enhancement of Cr(VI) bioreduction by phosphorus minerals, Microbial-Phosphorus minerals-Alginate (MPA) immobilized particles were proposed and investigated in this study. The feasibility of MPA immobilized particles were proved, with the higher reduction efficiency, lower phosphorus surplus, significant 94% of total Cr reduction and 85% of intragranular fixation. These superiorities were also obtained at different pH and initial Cr(VI) concentration conditions. Furthermore, the mechanisms of the enhancement of MPA were investigated from microbial level (microbial biomass, antioxidase, gene expression and microbial community analysis) and physics level (adsorption kinetic and isotherm), where the speculation that the reduction mainly took place outside the particles was proposed. This research provides a new approach for the practical application of Cr(VI)-contaminated groundwater in-situ bioremediation.

Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates.

A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 °C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3 S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr -N bonds.