Effects of multi-heavy metal composite pollution on microorganisms around a lead-zinc mine in typical karst areas, southwest China.

Heavy metal pollution poses a serious hazard to the soil bacterial community. The purpose of this study is to understand the characteristics of soil heavy metal pollution in lead-zinc mines in karst areas and the response of Pb, Zn, Cd, and As-induced composite pollution to soil microorganisms. This paper selected soil samples from the lead-zinc mining area of Xiangrong Mining Co., Ltd., Puding County, Guizhou Province, China. The soil in the mining area is contaminated by multiple heavy metals such as Pb, Zn, Cd and As. The average levels of Pb, Zn, Cd and As in the Pb-Zn mining soil were 14.5, 7.8, 5.5 and 4.4 times higher than the soil background in this area, respectively. Bacterial community structures and functions were analyzed using 16 S rRNA high-throughput sequencing technology and the PICRUSt method. A total of 19 bacterial phyla, 34 classes and 76 orders were detected in the tested soil. At the phylum level, the Proteobacteria are the dominant flora of the soil in the tailings reservoir area of the lead-zinc mine, respectively GWK1 (49.64%), GWK2 (81.89%), GWK3 (95.16%); and for the surrounding farmland soil, the Proteobacteria, Actinobacteriota, Acidobacteriota, Chloroflexi and Firmicutes are the most abundant in five bacterial groups. RDA analyses revealed that the heavy metal pollution of the lead-zinc mining area has a significant impact on the diversity of soil microorganisms. As the distance from the mining area increased, the heavy metal comprehensive pollution and potential risk value decreased, and the bacterial diversity increased. Additionally, various types of heavy metals have different effects on bacterial communities, and soil heavy metal content will also change the bacterial community structure. Proteobacteria positively related to Pb, Cd, and Zn, therefore, Proteobacteria were highly resistant to heavy metals. PICRUSt analysis suggested that heavy metals significantly affect the metabolic function of microorganisms. Microorganisms might generate resistance and enable themselves to survive by increasing the transport of metal ions and excreting metal ions. These results can be used as a basis for the microbial remediation of heavy metal-contaminated farmland in mining areas.

A Novel Fluorescent Probe for Hydrogen Peroxide and Its Application in Bio-Imaging.

Hydrogen peroxide (H2O2) plays an important role in the human body and monitoring its level is meaningful due to the relationship between its level and diseases. A fluorescent sensor (CMB) based on coumarin was designed and its ability for detecting hydrogen peroxide by fluorescence signals was also studied. The CMB showed an approximate 25-fold fluorescence enhancement after adding H2O2 due to the interaction between the CMB and H2O2 and had the potential for detecting physiological H2O2. It also showed good biocompatibility and permeability, allowing it to penetrate cell membranes and zebrafish tissues, thus it can perform fluorescence imaging of H2O2 in living cells and zebrafish. This probe is a promising tool for monitoring the level of H2O2 in related physiological and pathological research.

Microstructure and Mechanical Properties of Mg-Li/Al Dissimilar Joints via Dynamic Support Friction Stir Lap Welding.

In this study, two-mm-thick dual-phase LA103Z Mg-Li and 6061 Al alloys, known for their application in lightweight structural designs, were joined using dynamic support friction stir lap welding (DSFSLW). The microstructural evolution and mechanical properties of dissimilar joints were investigated at different welding speeds. The analysis revealed two distinct interfaces: the diffusion interface and the mixed interface. The diffusion interface, characterized by a pronounced diffusion zone, is formed under slower welding speeds. The diffusion zone height, the effective lap width, and the interface layer thickness decrease with increasing welding speed due to low plastic deformation capacity and weak interfacial reactions. Conversely, the mixed interface, associated with higher welding speeds, contained large Al fragments. The extremely high microhardness values (130.5 HV) can be ascribed to the formation of intermetallic compounds (IMCs) and strain-hardened Al fragments. Notably, the maximum shear strength achieved was 175 N/mm at a welding speed of 20 mm/min. The fracture behavior varied significantly with the interface type; the diffusion interface showed enhanced mechanical strength due to better intermetallic reactions and interlocking structures, while the mixed interface displayed more linear crack propagation due to weaker IMCs and the absence of hook structures. Fracture surface analysis indicates that fractures are more likely to propagate through the Al matrix and interface layers.

Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with In Vivo Activity.

Interleukin-2-inducible T-cell kinase (ITK) is a promising therapeutic target for human autoimmune diseases and T-cell malignant lymphomas. This paper reports the development of a series of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy. The representative compounds 23 and 28 exhibited potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays indicated that compounds 23 and 28 are highly selective ITK degraders. Moreover, compound 28 showed good plasma exposure levels and elicited efficient, rapid, and prolonged ITK degradation in Balb/c mice. Furthermore, it significantly suppressed IL-2 secretion stimulated by anti-CD3 antibody. Compound 28 represents the first effective and highly selective ITK degrader. Thus, 28 is a valuable tool compound for further in vitro and in vivo studies exploring the underlying biological effects and potential therapeutic utility of ITK degradation in human diseases.

Discovery of 2,5-diaminopyrimidine derivatives as the first series of selective monomeric degraders of B-lymphoid tyrosine kinase.

B-lymphoid tyrosine kinase (BLK) is an important knot of B cell receptor signaling, and regulates the function and development of B cells subset. Dysfunction of BLK is correlated with autoimmune diseases and cancer. There is an urgent need to develop selective BLK modulators to facilitate the studies of BLK in biological processes. Herein, we report the discovery of a series of 2,5-diaminopyrimidine-based compounds capable of selectively degrading BLK. The optimized compounds 9-11 possess weak biochemical inhibitory activities against BLK, yet they effectively degrade BLK and show high selectivity for BLK over other structurally and functionally related SRC family and TEC family kinases. Furthermore, compounds 9 and 11 demonstrate potent inhibitory activities in several B-lymphoid cell lines. As the first series of effective and selective monomeric BLK degraders, compounds 9-11 serve as valuable tools for further investigation of the functions of BLK.

Discovery of selective irreversible inhibitors of B-Lymphoid tyrosine kinase (BLK).

B-lymphoid tyrosine kinase (BLK), a member of the SRC family nonreceptor tyrosine kinase, is involved in the B-cell receptor (BCR) signaling pathway and B cell development and function. Dysregulation of BLK is associated with autoimmune diseases and cancer. However, there is an absence of good tool compounds for BLK, and the molecular mechanisms by which BLK mediates physiological and pathological processes are poorly understood. Herein, we present the discovery of a novel series of selective and irreversible inhibitors of BLK with nanomolar potency against BLK in biochemical and cellular assays. Compound 25 demonstrated potent antiproliferative activities against several B cell lymphoma cell lines. These compounds constitute the first series of selective inhibitors developed for BLK and could help expedite the exploration of BLK functions.

Synthesis of ortho-Phenolic Sulfilimines via an Intermolecular Sulfur Atom Transfer Cascade Reaction.

To expand the toolbox for the synthesis of ortho-phenolic sulfilimines, sigmatropic rearrangements were introduced to the field of sulfilimine chemistry. Herein we report a N-H sulfenylation/[2,3]-sigmatropic rearrangement cascade reaction. This mild reaction enables commercially available thiols to serve as the sulfenylation reagent and generates water as the sole byproduct. Moreover, the reaction has a wide substrate scope and can be conducted on a gram scale with excellent reaction efficiency.

Protein degradation through covalent inhibitor-based PROTACs.

Tremendous advancements in proteolysis targeting chimera (PROTAC) technology have been made in recent years. However, whether a covalent inhibitor-based PROTAC can be developed remains controversial. Here, we successfully developed chimeric degraders based on covalent inhibitors to degrade BTK and BLK kinases, demonstrating that covalent inhibitor-based PROTACs are viable and useful tools.

A novel 2,5-diaminopyrimidine-based affinity probe for Bruton's tyrosine kinase.

As a critical regulator of the B-cell receptor signaling pathway, Bruton's tyrosine kinase (Btk) has attracted intensive drug discovery efforts for treating B-cell lineage cancers and autoimmune disorders. In particular, covalent inhibitors targeting Cys481 in Btk have demonstrated impressive clinical benefits, and their companion affinity probes have been crucial in the drug development process. Recently, we have discovered a novel series of 2,5-diaminopyrimidine-based covalent irreversible inhibitors of Btk. Here, we present the discovery of a novel affinity Btk probe based on the aforementioned scaffold and demonstrate its usage in evaluating the target engagement of Btk inhibitors in live cells.

Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity.

Bruton's tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared with ibrutinib, these inhibitors exhibited a different selectivity profile for the analyzed kinases as well as a dual-action mode of inhibition of both Btk activation and catalytic activity, which counteracts a negative regulation loop for Btk. Two compounds from this series, 31 and 38, showed potent antiproliferative activities toward multiple B-cell lymphoma cell lines, including germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) cells. In addition, compound 31 significantly prevented tumor growth in a mouse xenograft model.