Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Ne2 encodes protein(s) and the altered RuBisCO could be the proteomics leader of hybrid necrosis in wheat (Triticum aestivum L.).

Wheat hybrid necrosis is caused by the interaction of two dominant complementary genes, Ne1 and Ne2, located on chromosome arms 5BL and 2BS, respectively. The sequences of Ne1 or Ne2 have not yet been identified. It is also not known whether Ne1 and Ne2 are structural or regulatory genes. Understanding the proteomic pathways may provide a knowledge base for protecting or maximizing the photosynthesis capacity of wheat. Using DIGE and MALDITOF- TOF MS, the flag leaf protein patterns of the two unique F14 near-isogenic line siblings (NILs), the necrotic ShunMai 12Ah (Ne1Ne1Ne2Ne2) and the normal ShunMai 12Af (Ne1Ne1ne2ne2) were compared. Due to the presence or absence of Ne2, (i) three protein spots were expressed or disappeared, (ii) seven RuBisCO-related proteins were altered significantly, and (iii) 21 photosynthesis/glucose related proteins were changed significantly. Three hypotheses were deduced, (i) Ne1 may also encode protein(s), (ii) genetic maladjustment of RuBisCO could lead to early leaf death, and (iii) interactions between nuclear genes and chloroplast genes could determine photosynthetic traits. Our hypothetical model presents the RuBisCO pathway of hybrid necrosis in wheat and explains how Ne1 and Ne2 interact at molecular level.

Cytogenic and molecular studies of male infertility in cases of Y chromosome balanced reciprocal translocation.

Y-autosomal translocation has been previously reported in association with male infertility; however, the mechanisms of Y-autosomal translocation and non­obstructive azoospermia or severe oligospermia remain unclear. G­banding and fluorescence in situ hybridization (FISH) were performed to analyze the translocation of chromosomes, and a single nucleotide polymorphism (SNP) genotyping assay was used to test mutations. The present study describes three new cases with a de novo balanced translocation t(Y;13), t(Y;9) and t(Y;6). To further explore the genotype­phenotype correlation, G­banding and FISH were performed and indicated the presence of a derivative chromosome. The SNP genotyping assay using a microarray revealed no abnormality, especially in the Y chromosome. Molecular deletion analysis demonstrated that no microdeletion was detected in the azoospermia factor region of the Y chromosome in the examined, infertile men. Based on these observations, the authors proposed the hypothesis that a position effect involving unknown spermatogenesis regulatory gene(s) serves a key role in male infertility.

[Distribution and activation of dendritic cells in immune thrombocytopenia patients].

Defective dendritic cell (DC) functions have been implicated in ITP. The purpose of this study was to investigate the distribution and activation of dendritic cells in immune thrombocytopenia (ITP) patients. ITP patients were divided into 3 groups: the newly diagnosed, refractory and effective treatment group. The distributions of plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC) in peripheral blood, bone marrow and spleen were detected with flow cytometry. The expression level of CD80 and CD86 on surface of pDC and mDC was also detected with flow cytometry. The results indicated that the percentage of mDC was higher than that of pDC in all sites of all groups. The percentage of mDC and pDC in all site of refractory group was higher than that in newly diagnosed and effective groups, but the percentage of mDC in spleen of refractory group was obviously higher than that in other sites. The percentage of pDC was no significant different in all groups. The expression level of CD86 in all groups was higher than that of CD80, the expression level of CD80 was lower in mDC and pDC of all groups, but there was no obvious difference in all sites. The CD86 expression in all site of refractory group was higher than that in newly diagnosed and effective treatment groups, while the CD86 expression of mDC in spleen of newly diagnosed group obviously higher than that in other sites. It is concluded that the distribution abnormality of mDC and pDC exists in ITP patients, the mDC are more accumulated in spleen, and differentiation of mDC to maturity is more obvious in spleen, spleen-derived mDC significantly express CD86, spleen-derived mDC may play an important role in the pathogenesis of ITP.

[BAFF level in bone marrow and expression of BAFF receptor on B cells in multiple myeloma patients].

This study was purposed to investigate the B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) levels in bone marrow, and the BAFF receptor expression level on B cells in multiple myeloma (MM) patients, in order to explore the characteristics of B cells in bone marrow of MM patients. MM patients were studied before treatment (newly diagnosed group, 19 patients) and after treatment with improvement (stable group, 17 patients), 10 non-hematologic patients were selected as control (control group). The BAFF receptors (BAFF-R) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) on B cell (CD19(+)), naive B cell (CD19(+)IgD(+)) and memory B cell (CD19(+)CD27(+)) of bone marrow in all groups were detected by flow cytometry. The BAFF, APRIL level in bone marrow supernatant were tested with ELISA. The results showed that the BAFF-R expression level on CD19(+) cells in newly diagnosed group were higher than that in stable group and control group; there was no significant difference between the BAFF-R expression level on CD19(+)IgD(+) cells in newly diagnosed group and stable group, but BAFF-R expression level on CD19(+)IgD(+) cells in newly diagnosed group was higher than that in control group; the BAFF-R expression level on CD19(+)CD27(+) cells in newly group was higher than that in stable group and control group; there was no significant difference between the BAFF-R expression level on CD19(+) cells, CD19(+)IgD(+) cells or CD19(+)CD27(+) cells in stable group and control group. There was no significant difference among the TACI expression level on CD19(+) cells, CD19(+)IgD(+) cells or CD19(+)CD27(+) cells in newly diagnosed group, stable group and control group. The bone marrow supernatant BAFF level in newly diagnosed group was higher than that in stable group and control group, but there was no significant difference between stable group and control group. There was no significant difference among the bone marrow TACI levels in newly diagnosed group, stable group and control group. It is concluded that both the bone marrow BAFF level and the BAFF-R expression level on CD19(+) cell, CD19(+)IgD(+) cells and CD19(+)CD27(+) cells in MM patients increase, which may help to stimulate B cells, thereby may relate with to MM pathogenesis.

Proteomic analysis of 'hybrid necrosis' in wheat (Triticum aestivum) leaves.

Wheat hybrid necrosis has been genetically characterised for many years, but the specific gene(s) and the protein products involved in the processes remains unknown. In this study, protein expression in the base (B), mid (M) and tip (T) segments of the FL-2 leaves of a necrotic hybrid, PZF1 and its parents, Pan555 and Zheng891, was analysed and compared using a high throughput proteomic approach. Twenty-three protein spots, with significant variations in intensity across the necrotic leaf segments, were analysed by MALDI-TOF-MS, of which, 18 were matched to protein accessions in the NCBI database. Several of these proteins are enzymes involved in the methylation cycle, including AdoHcy hydrolase, AdoMet synthase 3 and methionine synthase 1; AdoHcy hydrolase was downregulated sharply in M and T, and AdoMet synthase 3 and methionine synthase 1 were upregulated gradually from M to T. This result suggests that methylation-associated processes, including epigenetic mechanisms, may play a role in the initiation and development of hybrid necrosis. Several energy cycle-associated proteins and cytoprotective proteins were also differentially expressed across the leaf segments, suggesting their direct association with or possible involvement in the necrotic processes. The significant imbalance of a heat-shock protein, a transposon protein and a RNA- and ssDNA-binding protein also makes these proteins potential molecular components in the necrotic processes.