Search Results (31)

We describe the design and synthesis of a series of N-[arylsulfonyl]-1H-pyrrole-2-carboxamides as hybrid analogs of the DCAF15 binders E7820 and tasisulam, two representative SPLAMs (sulfonamide-containing molecular glues). These hybrid molecules were designed to combine the key interactions of both parent ligands within the DCAF15 binding site, as supported by docking studies. Binding affinity was evaluated using fluorescence polarization assays, and structure–activity relationships were established, highlighting the importance of dichlorinated pyrrole moieties. Selected compounds were also tested in HCT116 cells to assess in vitro activity. Full article

We describe the design and synthesis of a series of 7-(N-aryl pyrrolidinyl) indoles and oxo-analogs as isosteric mimics of the DCAF15 binder E7820, a well-known member of aryl sulfonamides known as SPLAMs. The functionalization of C-7 in indoles was achieved by metal-catalyzed CH-activation with unexpected results. Binding assays revealed the pyrrolidine N-aryl carboxylic acid analog to be as equally active as E7820. Full article

Researchers encounter substantial challenges in medical image classification, mainly due to limited image resolution and low signal-to-noise ratios. This situation makes it difficult for deep learning algorithms to identify abnormal regions based solely on image content accurately. This paper proposes ResGDANet (Residual Group Dual-Channel Attention Network), an enhanced architecture that builds upon ResGANet by incorporating two novel modules: a Dual-Channel Attention Fusion (DCAF) module and a Retention-Memory Transformer (RMT) module. The DCAF module utilizes a dual-path architecture that integrates global average pooling and max pooling operations, effectively enhancing local feature representation through the fusion of channel-wise and spatial attention mechanisms. The RMT module enhances rotation-invariant feature extraction by integrating the retention mechanism from Retentive Networks and the global context modeling capabilities of Vision Transformers. Extensive experiments on the COVID19-CT and ISIC2018 datasets demonstrate the superiority of ResGDANet, achieving classification accuracies of 83.74% and 81.73% respectively, outperforming state-of-the-art models including ResGANet, GvT, and SENet. Ablation studies and visualization analyses further validate the efficacy of the proposed attention module, showing notable enhancements in feature representation capability and classification accuracy. By introducing a more robust and precise classification framework, this research contributes importantly to the progress in medical image analysis. Full article

The Human Immunodeficiency Virus (HIV) encodes several proteins that contort the host cell environment to promote viral replication and spread. This is often accomplished through the hijacking of cellular ubiquitin ligases. These reprogrammed complexes initiate or enhance the ubiquitination of cellular proteins that may otherwise act to restrain viral replication. Ubiquitination of target proteins may alter protein function or initiate proteasome-dependent destruction. HIV Viral Protein R (Vpr) and the related HIV-2 Viral Protein X (Vpx), engage the CRL4-DCAF1 ubiquitin ligase complex to target numerous cellular proteins. In this review we describe the CRL4-DCAF1 ubiquitin ligase complex and its interactions with HIV Vpr and Vpx. We additionally summarize the cellular proteins targeted by this association as well as the observed or hypothesized impact on HIV. Full article

An advanced driving assistant system (ADAS) is critical for improving traffic efficiency and ensuring driving safety. By anticipating the driver’s steering intentions in advance, the system can alert the driver in time to avoid a vehicle collision. This paper proposes a novel end-to-end dual-branch network (EDNet) that utilizes both in-cabin and out-of-cabin data. In this study, we designed an in-cabin driver intent feature extractor based on 3D residual networks and atrous convolution, which is applicable to video data and is capable of capturing a larger range of driver behavior. In order to capture the long-term dependency of temporal data, we designed the depthwise-separable max-pooling (DSMax) module and combined it with a convolutional LSTM to obtain the road environment feature extractor outside the cabin. In addition, to effectively fuse different features inside and outside the cockpit, we designed and propose the dynamic combined-feature attention fusion (D-CAF) module. EDNet employs a freeze-training method, which enables the creation of a lightweight model while simultaneously enhancing the final classification accuracy. Extensive experiments on the Brain4Cars dataset and the Zenodo dataset show that the proposed EDNet was able to recognize the driver’s steering intention up to 3 s in advance. It outperformed the existing state of the art in most driving scenarios. Full article

Lysine methylation is a major post-translational protein modification that occurs in both histones and non-histone proteins. Emerging studies show that the methylated lysine residues in non-histone proteins provide a proteolytic signal for ubiquitin-dependent proteolysis. The SET7 (SETD7) methyltransferase specifically transfers a methyl group from S-Adenosyl methionine to a specific lysine residue located in a methylation degron motif of a protein substrate to mark the methylated protein for ubiquitin-dependent proteolysis. LSD1 (Kdm1a) serves as a demethylase to dynamically remove the methyl group from the modified protein. The methylated lysine residue is specifically recognized by L3MBTL3, a methyl-lysine reader that contains the malignant brain tumor domain, to target the methylated proteins for proteolysis by the CRL4^DCAF5 ubiquitin ligase complex. The methylated lysine residues are also recognized by PHF20L1 to protect the methylated proteins from proteolysis. The lysine methylation-mediated proteolysis regulates embryonic development, maintains pluripotency and self-renewal of embryonic stem cells and other stem cells such as neural stem cells and hematopoietic stem cells, and controls other biological processes. Dysregulation of the lysine methylation-dependent proteolysis is associated with various diseases, including cancers. Characterization of lysine methylation should reveal novel insights into how development and related diseases are regulated. Full article

Candida albicans is a major human pathogenic fungus that is distinguished by its capability to switch from a yeast to a hyphal morphology under different conditions. Here, we analyze the cellular effects of high concentrations of the iron chelator bathophenanthroline disulfonate (BPS). BPS inhibits cellular growth by withholding iron, but when iron chelation is overcome by the addition of hemoglobin as an iron source, the cells resume growth as hyphae. The BPS hyphal induction pathway was characterized by identifying the hyphal-specific transcription factors that it requires and by a forward genetic screen for mutants that fail to form hyphae in BPS using a transposon library generated in a haploid strain. Among the mutants identified are the DYRK1-like kinase Yak1 and Orf19.384, a homolog of the DYRK1-associated protein WDR68/DCAF7. Orf19.384 nuclear localization depends on Yak1, similar to their mammalian counterparts. We identified the hyphal suppressor transcription factor Sfl1 as a candidate target of Yak1-Orf19.384 and show that Sfl1 modification is similarly affected in the yak1 and orf19.384 mutant strains. These results suggest that DYRK1/Yak1 and WDR68/Orf19.384 represent a conserved protein pair that regulates cell differentiation from fungi to animals. Full article

Biological aging is a relevant risk factor for chronic diseases, and several indicators for measuring this factor have been proposed, with telomere length (TL) among the most studied. Oxidative stress may regulate telomere shortening, which is implicated in the increased risk. Using a novel estimator for TL, we examined whether adherence to the Mediterranean diet (MedDiet), a highly antioxidant-rich dietary pattern, is associated with longer TL. We determined TL using DNA methylation algorithms (DNAmTL) in 414 subjects at high cardiovascular risk from Spain. Adherence to the MedDiet was assessed by a validated score, and genetic variants in candidate genes and at the genome-wide level were analyzed. We observed several significant associations (p < 0.05) between DNAmTL and candidate genes (TERT, TERF2, RTEL1, and DCAF4), contributing to the validity of DNAmTL as a biomarker in this population. Higher adherence to the MedDiet was associated with lower odds of having a shorter TL in the whole sample (OR = 0.93; 95% CI: 0.85–0.99; p = 0.049 after fully multivariate adjustment). Nevertheless, this association was stronger in women than in men. Likewise, in women, we observed a direct association between adherence to the MedDiet score and DNAmTL as a continuous variable (beta = 0.015; SE: 0.005; p = 0.003), indicating that a one-point increase in adherence was related to an average increase of 0.015 ± 0.005 kb in TL. Upon examination of specific dietary items within the global score, we found that fruits, fish, “sofrito”, and whole grains exhibited the strongest associations in women. The novel score combining these items was significantly associated in the whole population. In the genome-wide association study (GWAS), we identified ten polymorphisms at the suggestive level of significance (p < 1 × 10⁻⁵) for DNAmTL (intergenics, in the IQSEC1, NCAPG2, and ABI3BP genes) and detected some gene–MedDiet modulations on DNAmTL. As this is the first study analyzing the DNAmTL estimator, genetics, and modulation by the MedDiet, more studies are needed to confirm these findings. Full article

Alpine Merino Sheep is a novel breed reared from Australian Merino Sheep as the father and Gansu Alpine Fine-Wool Sheep as the mother, living all year in cold and arid alpine areas with exceptional wool quality and meat performance. Body weight is an important economic trait of the Alpine Merino Sheep, but there is limited research on identifying the genes associated with live weight in the 14th month for improving the accuracy of the genomic prediction of this trait. Therefore, this study’s sample comprised 1310 Alpine Merino Sheep ewes, and the Fine Wool Sheep 50K Panel was used for genome-wide association study (GWAS) analysis to identify candidate genes. Moreover, the trial population (1310 ewes) in this study was randomly divided into two groups. One group was used as the population for GWAS analysis and screened for the most significant top 5%, top 10%, top 15%, and top 20% SNPs to obtain prior marker information. The other group was used to estimate the genetic parameters based on the weight assigned by heritability combined with different prior marker information. The aim of this study was to compare the accuracy of genomic breeding value estimation when combined with prior marker information from GWAS analysis with the optimal linear unbiased prediction method for genome selection (GBLUP) for the breeding value of target traits. Finally, the accuracy was evaluated using the five-fold cross-validation method. This research provides theoretical and technical support to improve the accuracy of sheep genome selection and better guide breeding. The results demonstrated that eight candidate genes were associated with GWAS analysis, and the gene function query and literature search results suggested that FAM184B, NCAPG, MACF1, ANKRD44, DCAF16, FUK, LCORL, and SYN3 were candidate genes affecting live weight in the 14th month (WT), which regulated the growth of muscle and bone in sheep. In genome selection analysis, the heritability of GBLUP to calculate the WT was 0.335–0.374, the accuracy after five-fold cross-verification was 0.154–0.190, and after assigning different weights to the top 5%, top 10%, top 15%, and top 20% of the GWAS results in accordance with previous information to construct the G matrix, the accuracy of the WT in the GBLUP model was improved by 2.59–7.79%. Full article

Background: Woodhouse–Sakati syndrome (WSS) is a rare multisystemic disease resulting from an autosomal recessive gene mutation characterized by distinctive facial appearance, alopecia, impaired HbA1c, and hypogonadism. Purpose: To present the successful management of primary amenorrhea in a WSS patient. Case Presentation: We report a 19-year-old Saudi female referred to the gynecology clinic at the age of 16 as a case of primary amenorrhea. The patient underwent a genetic analysis, which revealed mutations in the DCAF17 gene, confirming the diagnosis of WSS. Treatment includes hormonal replacement therapy for the induction of puberty. Conclusions: Careful and detailed medical and physical examination led to appropriate testing confirming the WSS diagnosis. Genetic tests for family members and the offspring of the patient are strongly recommended. Treatment timing and dosage are determined by the patient’s individual needs, which take into consideration the patient’s potential for growth, the family’s readiness, and any comorbidities. Full article

The polysaccharide FucoPol has recently been shown to yield hydrogel membranes (HMs) characterized by good mechanical properties, biocompatibility, and anti-inflammatory activity that render them promising biomaterials for use in the biomedical field. Subsequently to such findings, envisaging their development into novel delivery systems for topical applications, in this study, FucoPol HMs prepared by crosslinking the biopolymer with iron cations were loaded with caffeine or diclofenac sodium as model drugs. Two loading methods, namely diffusion and mixing, were applied to evaluate the FucoPol’s HM drug-loading capacity and entrapment efficiency. The diffusion method led to a higher caffeine loading (101.9 ± 19.1 mg/g) in the HM1_D_CAF membranes, while the mixing method resulted in a higher diclofenac sodium loading (82.3 ± 5.1 mg/g) in the HM1_D_DS membranes. The HM1_D_CAF membranes were characterized by increased mechanical and rheological parameters, such as their hardness (130.0 ± 5.3 kPa) and storage modulus (1014.9 ± 109.7 Pa), compared to the HM1_D_DS membranes that exhibited lower values (7.3 ± 1.2 kPa and 19.8 ± 3.8 Pa, respectively), probably due to leaching occurring during the drug-loading process. The release profiles revealed a fast release of both APIs from the membranes loaded by diffusion, while a prolonged and sustained release was obtained from the membranes loaded by mixing. Moreover, for all API-loaded membranes, the release mechanism followed Fickian diffusion, with the release rate being essentially governed by the diffusion process. These findings, together with their previously shown biological properties, support the suitability of the developed FucoPol HMs to be used as platforms for the topical delivery of drugs. Full article

Vpr binding protein (VprBP), also known as DDB1- and CUL4-associated factor1 (DCAF1), is a recently identified atypical kinase and plays an important role in downregulating the transcription of tumor suppressor genes as well as increasing the risk for colon and prostate cancers. Melanoma is the most aggressive form of skin cancer arising from pigment-producing melanocytes and is often associated with the dysregulation of epigenetic factors targeting histones. Here, we demonstrate that VprBP is highly expressed and phosphorylates threonine 120 (T120) on histone H2A to drive the transcriptional inactivation of growth-regulatory genes in melanoma cells. As is the case for its epigenetic function in other types of cancers, VprBP acts to induce a gene silencing program dependent on H2AT120 phosphorylation (H2AT120p). The significance of VprBP-mediated H2AT120p is further underscored by the fact that VprBP knockdown- or VprBP inhibitor-induced lockage of H2AT120p mitigates melanoma tumor growth in xenograft models. Collectively, our results establish VprBP-mediated H2AT120p as a key epigenetic signal for melanomagenesis and suggest the therapeutic potential of targeting VprBP kinase activity for effective melanoma treatment. Full article

Pancreatic ductal adenocarcinoma (PDAC), the second most prevalent gastrointestinal malignancy and the most common type of pancreatic cancer is linked with poor prognosis and, eventually, with high mortality rates. Early detection is seldom, while tumor heterogeneity and microarchitectural alterations benefit PDAC resistance to conventional therapeutics. Although emerging evidence suggest the core role of cancer stem cells (CSCs) in PDAC aggressiveness, unique stem signatures are poorly available, thus limiting the efforts of anti-CSC-targeted therapy. Herein, we report the findings of the first genome-wide analyses of mRNA/lncRNA transcriptome profiling and co-expression networks in PDAC cell line-derived CD133+/CD44+ cells, which were shown to bear a CSC-like phenotype in vitro and in vivo. Compared to CD133−/CD44− cells, the CD133+/CD44+ population demonstrated significant expression differences in both transcript pools. Using emerging bioinformatic tools, we performed lncRNA target coding gene prediction analysis, which revealed significant Gene Ontology (GO), pathway, and network enrichments in many dyregulated lncRNA nearby (cis or trans) mRNAs, with reported involvement in the regulation of CSC phenotype and functions. In this context, the construction of lncRNA/mRNA networks by ingenuity platforms identified the lncRNAs ATF2, CHEK1, DCAF8, and PAX8 to interact with “hub” SC-associated mRNAs. In addition, the expressions of the above lncRNAs retrieved by TCGA-normalized RNAseq gene expression data of PAAD were significantly correlated with clinicopathological features of PDAC, including tumor grade and stage, nodal metastasis, and overall survival. Overall, our findings shed light on the identification of CSC-specific lncRNA signatures with potential prognostic and therapeutic significance in PDAC. Full article

The role of hypoxia-regulated long non-coding RNA (lncRNA) in the development of head and neck squamous cell carcinoma (HNSCC) remains to be elucidated. In the current study, we initially screened hypoxia-regulated lncRNA in HNSCC cells by RNA-seq, before focusing on the rarely annotated lncRNA USP2 antisense RNA 1 (USP2-AS1). We determined that USP2-AS1 is a direct target of HIF1α and is remarkably elevated in HNSCC compared with matched normal tissues. Patients with a higher level of USP2-AS1 suffered a poor prognosis. Next, loss- and gain-of-function assays revealed that USP2-AS1 promoted cell proliferation and invasion in vitro and in vivo. Mechanically, RNA pulldown and LC–MS/MS demonstrated that the E3 ligase DDB1- and CUL4-associated factor 13 (DCAF13) is one of the binding partners to USP2-AS1 in HNSCC cells. In addition, we assumed that USP2-AS1 regulates the activity of DCAF13 by targeting its substrate ATR. Moreover, the knockdown of DCAF13 restored the elevated cell proliferation and growth levels achieved by USP2-AS1 overexpression. Altogether, we found that lncRNA USP2-AS1 functions as a HIF1α-regulated oncogenic lncRNA and promotes HNSCC cell proliferation and growth by interacting and modulating the activity of DCAF13. Full article

DNA damage in early-stage embryos impacts development and is a risk factor for segregation of altered genomes. DNA damage response (DDR) encompasses a sophisticated network of proteins involved in sensing, signaling, and repairing damage. DDR is regulated by reversible post-translational modifications including acetylation, methylation, phosphorylation, ubiquitylation, and SUMOylation. While important regulators of these processes have been characterized in somatic cells, their roles in early-stage embryos remain broadly unknown. The objective of this study was to explore how ubiquitylation and SUMOylation are involved in the regulation of early development in porcine embryos by assessing the mRNA profile of genes encoding ubiquitination (UBs), deubiquitination (DUBs), SUMOylation (SUMOs) or deSUMOylation (deSUMOs) enzymes in oocyte and embryos at different stages of development, and to evaluate if the induction of DNA damage at different stages of embryo development would alter the mRNA abundance of these genes. Pig embryos were produced by in vitro fertilization and DNA damage was induced by ultraviolet (UV) light exposure for 10 s on days 2, 4 or 7 of development. The relative mRNA abundance of most UBs, DUBs, SUMOs, and deSUMOs was higher in oocytes and early-stage embryos than in blastocysts. Transcript levels for UBs (RNF20, RNF40, RNF114, RNF169, CUL5, DCAF2, DECAF13, and DDB1), DUBs (USP16), and SUMOs (CBX4, UBA2 and UBC9), were upregulated in early-stage embryos (D2 and/or D4) compared to oocytes and blastocysts. In response to UV-induced DNA damage, transcript levels of several UBs, DUBs, SUMOs, and deSUMOs decreased in D2 and D4 embryos, but increased in blastocysts. These findings revealed that transcript levels of genes encoding for important UBs, DUBs, SUMOs, and deSUMOs are regulated during early embryo development and are modulated in response to induced DNA damage. This study has also identified candidate genes controlling post-translational modifications that may have relevant roles in the regulation of normal embryo development, repair of damaged DNA, and preservation of genome stability in the pig embryo. Full article