The pathogenic mechanism of autosomal dominant polycystic kidney disease (ADPKD) is unclear. Similar to tumour cells, polycystic kidney cells are primarily dependent on aerobic glycolysis for ATP production. Compared with rodents, miniature pigs are more similar to humans. This study is the first time to investigate the effects of the combination of metformin and 2-deoxyglucose (2DG) in a pig model of chronic progressive ADPKD.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.

The pathogenic mechanism of polycystic kidney disease (PKD) is unclear. Abnormal glucose metabolism is maybe involved in hyper-proliferation of renal cyst epithelial cells. Mini-pigs are more similar to humans than rodents and therefore, are an ideal large animal model. In this study, for the first time, we systematically investigated the changes in glucose metabolism and cell proliferation signaling pathways in the kidney tissues of chronic progressive PKD mini-pig models created by knock-outing PKD1gene. The results showed that in the kidneys of PKD mini-pigs, the glycolysis is increased and the expressions of key oxidative phosphorylation enzymes Complexes I and IV significantly decreased. The activities of mitochondrial respiration chain Complexes I and IV significantly decreased; the phosphorylation level of key metabolism-modulating molecule AMP-activated protein kinase (AMPK) significantly decreased; and the mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) signaling pathway are activated obviously. This study showed that in the kidneys of PKD mini-pigs, the level of glycolysis significantly increased, oxidative phosphorylation significantly decreased, and cell proliferation signaling pathways significantly activated, suggesting that metabolic changes in PKD may result in the occurrence and development of PKD through the activation of proliferation signaling pathways.

Generally, a teleostean group possesses only one type or a set of similar mitochondrial gene arrangements. However, a new type of gene arrangement has been identified in the mitochondrial genomes (mitogenomes) of Moenkhausia. Here, three newly sequenced complete mitogenomes of tetras (Characidae: Moenkhausia) are presented (M. costae, M. pittieri, and M. sanctaefilomenae). The three mitogenomes had a classical circular structure, with total lengths ranging from 15,811 to 18,435 bp. Base composition analysis indicated that the sequences were biased toward adenine (A) and thymine (T), with A + T content of 54.63% in M. costae, 58.47% in M. pittieri, and 59.98% in M. sanctaefilomenae. The gene order and organization of M. sanctaefilomenae differed from those of typical teleostean mitogenomes. The genes tRNA-Ile, tRNA-Gln, and tRNA-Pro were translocated between tRNA-Trp and tRNA-Asn. One extra tRNA-Met and an extra CR were also discovered in the mitogenome. BI and ML analyses based on sequences of 38 different mitogenomes showed that M. costae and M. pittieri were classified together, and M. sanctaefilomenae was slightly further from other fish of the same genus. These results provide insight into the gene arrangement features of Characidae mitogenomes and lay the foundation for further phylogenetic studies on Characidae.

Members of the genus Treron (Columbidae) are widely distributed in southern Asia and the Indo-Malayan Region but their relationships are poorly understood. Better knowledge of the systematic status of this genus may help studies of historical biogeography and taxonomy. The complete mitochondrial genome of T. curvirostra was characterized, a first for the genus. It is 17,414 base pairs in length, containing two rRNAs, 22 tRNAs, 13 protein coding genes (PCGs), and one D-loop with a primary structure that is similar to that found in most members of Columbidae. Most PCGs start with the common ATG codon but are terminated by different codons. The highest value of the Ka/Ks ratio within 13 PCGs was found in ATP8 with 0.1937, suggesting that PCGs of the mitochondrial genome tend to be conservative in Columbidae. Moreover, the phylogenetic relationships within Columbidae, which was based on sequences of 13 PCGs, showed that (T. curvirostra + Hemiphaga novaeseelandiae) were clustered in one clade, suggesting a potentially close relationship between Treron and Hemiphaga. However, the monophyly of the subfamilies of Columbidae recognized by the Interagency Taxonomic Information System could not be corroborated. Hence, the position of the genus Treron in the classification of Columbidae may have to be revised.

This study conducted a comprehensive analysis of the members of the PTPN family and emphasized the key role of PTPN2 as a potential therapeutic target and diagnostic biomarker in improving the survival rate of PAAD.

To date, the taxonomic status and phylogenetic affinities within Hyphessobrycon, even among other genera in Characidae, remain unclear. Here, we determined five new mitochondrial genomes (mitogenomes) of Hyphessobrycon species (H. elachys, H. flammeus, H. pulchripinnis, H. roseus, and H. sweglesi). The mitogenomes were all classical circular structures, with lengths ranging from 16,008 to 17,224 bp. The type of constitutive genes and direction of the coding strand that appeared in the mitogenomes were identical to those of other species in Characidae. The highest value of the Ka/Ks ratio within 13 protein-coding genes (PCGs) was found in ND2 with 0.83, suggesting that they were subject to purifying selection in the Hyphessobrycon genus. Comparison of the control region sequences among seven Hyphessobrycon fish revealed that repeat units differ in length and copy number across different species, which led to sharp differences in mitogenome sizes. Phylogenetic trees based on the 13 PCGs did not support taxonomic relationships, as the Hyphessobrycon fish mixed with those from other genera. These data were combined to explore higher level relationships within Characidae and could aid in the understanding of the evolution of this group.