Aberrant functional connectivity of the globus pallidus in the modulation of the relationship between childhood trauma and major depressive disorder.

BACKGROUND: Childhood trauma plays a crucial role in the dysfunctional reward circuitry in major depressive disorder (MDD). We sought to explore the effect of abnormalities in the globus pallidus (GP)-centric reward circuitry on the relationship between childhood trauma and MDD. METHODS: We conducted seed-based dynamic functional connectivity (dFC) analysis among people with or without MDD and with or without childhood trauma. We explored the relationship between abnormal reward circuitry, childhood trauma, and MDD. RESULTS: We included 48 people with MDD and childhood trauma, 30 people with MDD without childhood trauma, 57 controls with childhood trauma, and 46 controls without childhood trauma. We found that GP subregions exhibited abnormal dFC with several regions, including the inferior parietal lobe, thalamus, superior frontal gyrus (SFG), and precuneus. Abnormal dFC in these GP subregions showed a significant correlation with childhood trauma. Moderation analysis revealed that the dFC between the anterior GP and SFG, as well as between the anterior GP and the precentral gyrus, modulated the relationship between childhood abuse and MDD severity. We observed a negative correlation between childhood trauma and MDD severity among patients with lower dFC between the anterior GP and SFG, as well as higher dFC between the anterior GP and precentral gyrus. This suggests that reduced dFC between the anterior GP and SFG, along with increased dFC between the anterior GP and precentral gyrus, may attenuate the effect of childhood trauma on MDD severity. LIMITATIONS: Cross-sectional designs cannot be used to infer causality. CONCLUSION: Our findings underscore the pivotal role of reward circuitry abnormalities in MDD with childhood trauma. These abnormalities involve various brain regions, including the postcentral gyrus, precentral gyrus, inferior parietal lobe, precuneus, superior frontal gyrus, thalamus, and middle frontal gyrus. CLINICAL TRIAL REGISTRATION: ChiCTR2300078193.

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors.

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments.

Data Mining and Graph Network Deep Learning for Band Gap Prediction in Crystalline Borate Materials.

Crystalline borates are an important class of functional materials with wide applications in photocatalysis and laser technologies. Obtaining their band gap values in a timely and precise manner is a great challenge in material design due to the issues of computational accuracy and cost of first-principles methods. Although machine learning (ML) techniques have shown great successes in predicting the versatile properties of materials, their practicality is often limited by the data set quality. Here, by using a combination of natural language processing searches and domain knowledge, we built an experimental database of inorganic borates, including their chemical compositions, band gaps, and crystal structures. We performed graph network deep learning to predict the band gaps of borates with accuracy, and the results agreed favorably with experimental measurements from the visible-light to the deep-ultraviolet (DUV) region. For a realistic screening problem, our ML model could correctly identify most of the investigated DUV borates. Furthermore, the extrapolative ability of the model was validated against our newly synthesized borate crystal Ag3B6O10NO3, supplemented by the discussion of an ML-based material design for structural analogues. The applications and interpretability of the ML model were also evaluated extensively. Finally, we implemented a web-based application, which could be utilized conveniently in material engineering for the desired band gap. The philosophy behind this study is to use cost-effective data mining techniques to build high-quality ML models, which can provide useful clues for further material design.

Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors.

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/ß signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.

Value of repeat renal biopsy in the evaluation of AL amyloidosis patients lacking renal response despite of complete hematologic remission: a case report and literature review.

BACKGROUNDS: Published literatures on repeat renal biopsy of AL amyloidosis have basically reached a consensus that amyloid material deposit does not disappear or diminish after satisfactory hematologic response, regardless of renal response. However, the need of a repeat renal biopsy in such situation is still controversial. CASE PRESENTATION: Here we reported a case of histologically confirmed λ Type renal AL amyloidosis who had been classified as Stage I and low risk at initial diagnosis. The patient received a total of six courses of CyBorD chemotherapy. She had achieved complete hematologic remission after two courses of chemotherapy but consistently had large amount of proteinuria over 10 g/day during follow up. A repeat renal biopsy was performed nine months after the first one and indicated mild to moderate increase of amyloid deposits as well as significant glomerulosclerosis and interstitial lesions, suggesting a lack of histological renal improvement despite her satisfactory hematologic response. CONCLUSIONS: This case indicated renal involvement in AL amyloidosis could progress after successful hematologic treatment, and supported the value of repeat renal biopsy in the evaluation of AL amyloidosis patients lacking renal response despite of complete hematologic remission.

WNT1-inducible signaling protein-1 mediates TGF-ß1-induced renal fibrosis in tubular epithelial cells and unilateral ureteral obstruction mouse models via autophagy.

Renal fibrosis is a common pathway for the progression of all chronic kidney diseases to end-stage kidney disease. Studies show that WNT1-inducible signaling pathway protein-1 (WISP-1) is involved in the fibrosis of various organs. The aim of the study was to explore the functional role and potential mechanism of WISP-1 in renal fibrosis. We observed that overexpression of WISP-1 in rat tubular epithelial cells (TECs) enhanced transforming growth factor-ß1 (TGF-ß1)-induced production of fibrotic markers, including collagen I (Col I), fibronectin (FN) and TGF-ß1, while inhibition of WISP-1 suppressed such production. In vivo, the messenger RNA and protein levels of Col I, FN, and α-smooth muscle actin were significantly inhibited after anti-WISP-1 antibody treatment for 7 days in unilateral ureteral obstruction mouse models. Moreover, blockade of WISP-1 by anti-WISP-1 antibody significantly reduced autophagy-related markers, including anti-microtubule-associated protein-1 light chain 3 (LC3) and beclin 1, while increasing sequestosome 1. In addition, overexpression of WISP-1 in TECs increased autophagy as evidenced by greater numbers of GFP-LC3 puncta and increased expression of LC3 and beclin 1 in response to TGF-ß1. In contrast, knockdown of WISP-1 by small interfering RNA decreased the number of GFP-LC3 puncta and the expression of LC3 and beclin 1 in TGF-ß1-treated TECs. Collectively, these data suggest that WISP-1, as a profibrotic protein, may mediate renal fibrosis by inducing autophagy in both obstructive nephropathy and TGF-ß1-treated TECs. WISP-1 may serve as an effective therapeutic target for the treatment of renal fibrosis.

Clinicopathological features of IgG4-related kidney disease
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AIMS: To explore the clinicopathological features of IgG4-related kidney disease (IgG4-RKD) in Chinese patients. MATERIALS AND METHODS: We retrospectively analyzed the clinicopathological features of 7 patients with IgG4-RKD and reviewed relevant literature. RESULTS: There were 7 patients (4 males and 3 females) aged 41 - 78 years (median age: 57.1 years), with a mean affliction of 2.6 organs per patient. All 7 patients had elevated serum IgG4 levels, and most of them had acute or chronic renal insufficiency. Two patients had positive myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA), and another 2 patients had positive serum antinuclear antibodies (ANA). All 7 patients had tubulointerstitial nephritis (TIN) with IgG4+ plasma cell infiltration, 3 patients also had glomerular lesions, 2 patients had ANCA-associated glomerulonephritis (ANCA-GN), and the remaining patient had membranous nephropathy (MN). All these patients were treated with glucocorticoids, and 3 of them were given cyclophosphamide simultaneously. Six patients achieved remission and had improved renal function, while 1 patient was on maintenance dialysis. CONCLUSION: IgG4-RKD should be diagnosed by combining the clinical data and renal pathological changes, and it should be differentiated from a variety of diseases. Although ANCA-associated vasculitis (AAV) and IgG4-related disease are distinguishable in most cases, coexistence of ANCA-GN and IgG4-RKD should be considered in some special cases.

COL4A5 mutation causes Alport syndrome with focal segmental glomerulosclerosis lesion: Case report and literature review
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COL4A5 gene mutations are known as the cause of Alport syndrome (AS), which typically manifests with hematuria, progressive renal failure, sensorineural hearing loss, and ocular abnormalities. Here we report a case of a 20-year-old male patient presenting with nephrotic syndrome who was diagnosed as having AS with focal segmental glomerulosclerosis (FSGS) lesion after the renal biopsy was performed. In this patient, the link between AS and FSGS lesion is complicated. Whole-exome sequencing was performed to identify its causal genetic variants, and the results revealed that AS with FSGS lesion is caused by mutation of the COL4A5 gene. COL4A5 gene mutations have phenotypic heterogeneity and thus, we suggest that genetic testing should be considered in such patients for accurate diagnosis and appropriate treatment.

Machine Learning Models Combined with Virtual Screening and Molecular Docking to Predict Human Topoisomerase I Inhibitors.

In this work, random forest (RF), support vector machine, k-nearest neighbor and C4.5 decision tree, were used to establish classification models for predicting whether an unknown molecule is an inhibitor of human topoisomerase I (Top1) protein. All these models have achieved satisfactory results, with total prediction accuracies from 89.70% to 97.12%. Through comparative analysis, it can be found that the RF model has the best forecasting effect. The parameters were further optimized to generate the best-performing RF model. At the same time, features selection was implemented to choose properties most relevant to the inhibition of Top1 from 189 molecular descriptors through a special RF procedure. Subsequently, a ligand-based virtual screening was performed from the Maybridge database by the optimal RF model and 596 hits were picked out. Then, 67 molecules with relative probability scores over 0.7 were selected based on the screening results. Next, the 67 molecules above were docked to Top1 using AutoDock Vina. Finally, six top-ranked molecules with binding energies less than -10.0 kcal/mol were screened out and a common backbone, which is entirely different from that of existing Top1 inhibitors reported in the literature, was found.

The value of non-invasive measurement of cardiac output and total peripheral resistance to categorize significant changes of intradialytic blood pressure: a prospective study.

BACKGROUND: Blood pressure (BP) is currently the main hemodynamic parameter used to assess the influence of fluid removal during hemodialysis session. Since BP is dependent on cardiac output (CO) and total peripheral resistance (TPRI), investigating these parameters may help to better understand the influence of fluid removal on patient's hemodynamics. We used a novel non-invasive whole-body bio-impedance cardiography device, recently validated in hemodialysis patients, to examine mechanisms of intradialytic hemodynamics in a Chinese dialysis population. METHODS: Chronic hemodialysis patients in Sichuan Provincial People's Hospital were enrolled. Demographic data and dialysis prescriptions were collected. Hemodynamic measurements were made pre-treatment, every 20 min during treatment and immediately after treatment in each random dialysis session. These included blood pressure, cardiac index (CI), total peripheral resistance (TPRI) and cardiac power index (CPI). Patients were divided into 5 hemodynamic groups as per their major hemodynamic response to fluid removal: low CPI, low TPRI, high TPRI, High CPI and those with normal hemodynamics. RESULTS: Twenty-seven patients were enrolled, with 12 (44.4%) males. The average age was 65 ± 12 y. The average body mass index (BMI) was 23.7 ± 3.9 kg/m2. 12 (44.4%) patients were diabetic. Three hundred twenty-four hemodynamic measurements were made. Weight, BMI, total fluid removal, pretreatment systolic BP, CI, TPRI and CI differed significantly among the 5 hemodynamic groups.11.1% of patients had low CPI, 25.9% had low TPRI, 18.5% had high CPI, 3.7% had high TPRI and 40.7% had normal hemodynamics. Hemodynamic differences among the 5 subgroups were significant. CONCLUSION: This technology provides multi-dimensional insight into intradialytic hemodynamic parameters, which may be more informative than blood pressure only. Using hemodynamic parameters to describe patients' status is more specific and accurate, and could help to work out specific and effective therapeutic actions according to underlying abnormalities.

Replication of genome-wide association study identified seven susceptibility genes, affirming the effect of rs2856717 on renal function and poor outcome of IgA nephropathy.

AIM: Meta-analysis of data from a genome-wide association study (GWAS) identified seven single nucleotide polymorphisms (SNPs) as strong predictors of IgA nephropathy (IgAN). To replicate the association of these seven SNPs and understand whether they influence the clinical characteristics of IgAN, a case-control study including 521 IgAN patients and 535 controls was conducted in a Western Han cohort. METHODS: Data were analyzed using logistic regression and multifactor dimensionality reduction (MDR). Clinical data collected from 459 IgAN patients were investigated to estimate the relationship between the genotype and phenotype of IgAN. A retrospective cohort study of 315 IgAN patients was conducted to investigate the relationship between genotype and progression of renal disease over a mean period of 44.49 ± 19.94 months. RESULTS: Upon Bonferroni correction, none of the seven SNPs were associated with IgAN (corrected P-value [Pc], >0.05). A combination of the rs2856717T/C, rs9275596C/T, and rs2412971A/G had effects on the susceptibility of IgAN (P = 0.001). Marginally significant association of rs2856717 T/C recessive model for the T allele was significantly associated with estimated glomerular filtration rate (eGFR) (<60 mL/min per 1.73 m2 ) in IgAN patients (P = 0.008, Pc = 0.056, odds ratio [OR] = 1.527). The T allele at rs9275596 was significantly associated with macroscopic haematuria of IgAN patients under the dominant and additive models of inheritance, (P < 0.001, Pc = 0.007, OR = 2.983) and (P < 0.001, Pc = 0.007, OR = 2.17), respectively. Kaplan-Meier survival analysis showed that patients carrying the TT + TC genotype for rs2856717 had reduced renal survival rate than those carrying the CC genotype (85.1% vs. 92.7%, P = 0.046). CONCLUSION: rs2856717 may influence the clinical characteristics and poor outcome of IgAN. Further studies are warranted to explore the mechanisms for such genotype-disease phenotype association.

Erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating PI3K/Akt signalling.

AIM: Renal ischaemia-reperfusion (I/R) injury, a primary cause of acute renal failure, can induce high morbidity and mortality. This study aimed to explore the effect of erythropoietin on renal I/R injury and its underlying mechanism. METHODS: Fifty male Sprague-Dawley rats were randomly allocated to three groups (n = 10): the sham group, the renal ischaemia-reperfusion-saline (IRI) group, and the IRI+-Erythropoietin (EPO) group. Erythropoietin (250, 500, 1000 U/kg) was intraperitoneally injected 30 min before inducing I/R. Renal I/R injury were induced by clamping the left renal artery for 30 min followed by reperfusion, along with a contralateral nephrectomy. Renal function and histological damage were determined after 24 h reperfusion. The expression of pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1 ß (IL-1ß), and tumour necrosis factor-α (TNF-α) in the serum and renal tissue were evaluated by enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Further, the effects of erythropoietin on PI3K/Akt signalling, erythropoietin receptor (EPOR) and nuclear factor (NF)-κB activation were measured by Western blotting. RESULTS: Erythropoietin pretreatment can significantly decrease the level of renal dysfunction in a dose-dependent manner, attenuated the renal histological changes, the expression of TNF-α, IL-1ß, and IL-6, the levels of reactive oxygen species (ROS) production and NF-κB p65 phosphorylation in renal tissue upon IRI. Moreover, erythropoietin pretreatment could further activate the PI3K/Akt signalling and induced EPOR activity. CONCLUSIONS: Erythropoietin pretreatment could attenuate renal I/R injury by suppressing inflammation, which was associated with activating PI3K/Akt signalling though EPOR activation. Our findings suggest that erythropoietin may be a novel practical strategy to prevent renal I/R injury.

M133S mutation possibly involve in the ER stress and mitophagy pathway in maintenance hemodialysis patients with occult hepatitis B infection.

Occult hepatitis B virus infection (OBI) is characterized by the presence of HBV DNA in the absence of detectable HBsAg. OBI is an important risk factor for cirrhosis and hepatocellular carcinoma, but its pathogenesis has not been fully elucidated. Mutations in the HBV preS/S genes can lead to impaired secretion of either HBsAg or S-protein resulting in the accumulation of defective viruses or S protein in cells. In our previous work, the M133S mutation was present in the HBV S gene of maintenance hemodialysis (MHD) patients with OBI. In this study, we investigated the potential role of amino acid substitutions in S proteins in S protein production and secretion through the construction of mutant S gene plasmids, structural prediction, transcriptome sequencing analysis, and in vitro functional studies. Protein structure prediction showed that the S protein M133S mutant exhibited hydrophilic modifications, with greater aggregation and accumulation of the entire structure within the membrane phospholipid bilayer. Differential gene enrichment analysis of transcriptome sequencing data showed that differentially expressed genes were mainly concentrated in protein processing in the endoplasmic reticulum (ER). The expression of heat shock family proteins and ER chaperone molecules was significantly increased in the wild-type and mutant groups, whereas the expression of mitochondria-associated proteins was decreased. Immunofluorescence staining and protein blotting showed that the endoplasmic reticulum-associated protein PDI, the autophagy marker LC3, and the lysosome-associated protein LAMP2 co-localized with the S proteins in the wild-type and mutant strains, and their expression was increased. The mitochondria-associated TOMM20 protein was also co-expressed with the S protein, but expression was significantly reduced in the mutant. The M133S mutation in the S gene is expressed as a defective and misfolded protein that accumulates in the endoplasmic reticulum causing secretion-impaired endoplasmic reticulum stress, which in turn triggers mitochondrial autophagy and recruits lysosomes to fuse with the autophagosome, leading to mitochondrial clearance. This study preliminarily demonstrated that the mutation of M133S in the S gene can cause OBI and is associated with disease progression, providing a theoretical basis for the diagnosis and treatment of OBI.

The role of the thalamic subregions in major depressive disorder with childhood maltreatment: Evidences from dynamic and static functional connectivity.

BACKGROUND: Major depressive disorder (MDD) with a history of childhood maltreatment represents a highly prevalent clinical phenotype. Previous studies have demonstrated functional alterations of the thalamus among MDD. However, no study has investigated the static and dynamic changes in functional connectivity (FC) within thalamic subregions among MDD with childhood maltreatment. METHODS: This study included four groups: MDD with childhood maltreatment (n = 48), MDD without childhood maltreatment (n = 30), healthy controls with childhood maltreatment (n = 57), and healthy controls without childhood maltreatment (n = 46). Sixteen thalamic subregions were selected as seed to investigate group-differences in dynamic FC (dFC) and static FC (sFC). Correlation analyses were performed to assess the associations between abnormal FC and maltreatment severity. Eventually, moderation analyses were employed to explore the moderating role of abnormal FC in the relationship between maltreatment and depressive severity. RESULTS: MDD with childhood maltreatment exhibit abnormal thalamic subregions FC compared to MDD without childhood maltreatment, characterized by abnormalities with the sFC of the rostral anterior cingulate cortex, with the dFC of the calcarine, middle cingulate cortex, precuneus cortex and superior temporal gyrus. Furthermore, sFC with the rostral anterior cingulate cortex and dFC with the middle cingulate cortex were correlated with the severity of maltreatment. Additionally, dFC with the superior temporal gyrus moderates the relationship between maltreatment and depression severity. LIMITATIONS: The cross-sectional designs fail to infer causality. CONCLUSIONS: Our findings support thalamic dysfunction as neurobiological features of childhood maltreatment as well as vulnerability to MDD.

Effects of childhood maltreatment and major depressive disorder on functional connectivity in hippocampal subregions.

Major Depressive Disorder (MDD) with childhood maltreatment is a prevalent clinical phenotype. Prior studies have observed abnormal hippocampal activity in MDD patients, considering the hippocampus as a single nucleus. However, there is limited research investigating the static and dynamic changes in hippocampal subregion functional connectivity (FC) in MDD patients with childhood maltreatment. Therefore, we employed static and dynamic FC analyses using hippocampal subregions, including the anterior hippocampus and posterior hippocampus, as seed regions to investigate the neurobiological alterations associated with MDD resulting from childhood maltreatment. This study involved four groups: MDD with (n = 48) and without childhood maltreatment (n = 30), as well as healthy controls with (n = 57) and without (n = 46) childhood maltreatment. Compared to MDD patients without childhood maltreatment, those with childhood maltreatment exhibit altered FC between the hippocampal subregion and multiple brain regions, including the anterior cingulate gyrus, superior frontal gyrus, putamen, calcarine gyrus, superior temporal gyrus, angular gyrus, and supplementary motor area. Additionally, dynamic FC between the right medial-2 hippocampal head and the right calcarine gyrus shows a positive correlation with childhood maltreatment across all its subtypes. Moreover, dFC between the right hippocampal tail and the left angular gyrus moderates the relationship between childhood maltreatment and the depression severity. Our findings of distinct FC patterns within hippocampal subregions provide new clues for understanding the neurobiological basis of MDD with childhood maltreatment.

The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease.

Pin1 is a member of the peptidyl-prolyl cis/trans isomerase subfamily and is widely expressed in various cell types and tissues. Alterations in Pin1 expression levels play pivotal roles in both physiological processes and multiple pathological conditions, especially in the onset and progression of kidney diseases. Herein, we present an overview of the role of Pin1 in the regulation of fibrosis, oxidative stress, and autophagy. It plays a significant role in various kidney diseases including Renal I/R injury, chronic kidney disease with secondary hyperparathyroidism, diabetic nephropathy, renal fibrosis, and renal cell carcinoma. The representative therapeutic agent Juglone has emerged as a potential treatment for inhibiting Pin1 activity and mitigating kidney disease. Understanding the role of Pin1 in kidney diseases is expected to provide new insights into innovative therapeutic interventions and strategies. Consequently, this review delves into the molecular mechanisms of Pin1 and its relevance in kidney disease, paving the way for novel therapeutic approaches.

Cope with copper: From molecular mechanisms of cuproptosis to copper-related kidney diseases.

Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases.

Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies.

Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.

Identifying Protein-Ligand Interactions via a Novel Distance Self-Feedback Biomolecular Interaction Network.

Efficient and accurate characterizations of protein-ligand interactions are key to understanding biology at the molecular level. They are particularly useful in pharmaceutical industry applications. They are usually computationally demanding for those widely applied dynamics-based methods in identifying important residues or calculating ligand binding free energy. In this work, we proposed a graph deep learning (DL) framework, namely, the distance self-feedback biomolecular interaction network (DSBIN), in which the relationship between the complex structure and binding affinity can be established by means of a carefully designed distance self-feedback module and interaction layer. Our model can directly provide a quantitative evaluation of inhibitor binding affinities (pKd). More importantly, the DSBIN model efficiently identifies key interactions for inhibitor binding and thus intrinsically bears the interpretability. Its generalization performance was further verified using 1405 unseen structures. The predicted binding free energies' deviations were calculated to be less than 1.37 kcal/mol for more than 55% structures. Moreover, we also compared the DSBIN model with a commonly used theoretical method in calculating the substrate binding free energy, MM/GBSA. Our results show that the current DL model has generally better performance in predicting the binding free energy. For a specific complex system, mannopentaose/TmCBM27, the DSBIN predicted binding free energy is -8.21 kcal/mol, which is very close to experimentally measured -7.76 kcal/mol and MM/GBSA calculated -7.16 kcal/mol. Meanwhile, all important aromatic residues around the binding pocket can be identified by our DL model. Considering the accuracy and efficiency of the newly developed DL model, it may be very helpful in the field of drug design and molecular recognition.

Effects of childhood neglect on regional brain activity and corresponding functional connectivity in major depressive disorder and healthy people: Risk factor or resilience?

BACKGROUND: Childhood neglect is a high risk factor for major depressive disorder (MDD). However, the effects of childhood neglect on regional brain activity and corresponding functional connectivity in MDD patients and healthy populations remains unclear. METHODS: Regional homogeneity, amplitude of low-frequency fluctuations (ALFF), fractional ALFF, degree centrality, and voxel-mirrored homotopic connectivity were extensively calculated to explore intraregional brain activity in MDD patients with childhood neglect and in healthy populations with childhood neglect. Functional connectivity analysis was then performed using regions showing abnormal brain activity in regional homogeneity/ALFF/fractional ALFF/degree centrality/voxel-mirrored homotopic connectivity analysis as seed. Partial correlation analysis and moderating effect analysis were used to explore the relationship between childhood neglect, abnormal brain activity, and MDD severity. RESULTS: We found decreased brain function in the inferior parietal lobe and cuneus in MDD patients with childhood neglect. In addition, we detected that childhood neglect was significant associated with abnormal cuneus brain activity in MDD patients and that abnormal cuneus brain activity moderated the relationship between childhood neglect and MDD severity. In contrast, higher brain function was observed in the inferior parietal lobe and cuneus in healthy populations with childhood neglect. CONCLUSIONS: Our results provide new evidence for the identification of neural biomarkers in MDD patients with childhood neglect. More importantly, we identify brain activity characteristics of resilience in healthy populations with childhood neglect, providing more clues to identify neurobiological markers of resilience to depression after suffering childhood neglect.