Targeted Overexpression of CKI-Insensitive Cyclin-Dependent Kinase 4 Increases Functional b-Cell Number Through Enhanced Self-Replication in Zebrafish

β-Cells of the islet of Langerhans produce insulin to maintain glucose homeostasis. Self-replication of β-cells is the predominant mode of postnatal β-cell production in mammals, with about 20% of rodent β cells dividing in a 24-hour period. However, replicating β-cells are rare in adults. Induction of self-replication of existing β-cells is a potential treatment for diabetes. In zebrafish larvae, β-cells rarely self-replicate, even under conditions that favor β-cell genesis such overnutrition and β-cell ablation. It is not clear why larval β-cells are refractory to replication. In this study, we tested the hypothesis that insufficient activity of cyclin-dependent kinase 4 may be responsible for the low replication rate by ectopically expressing in β-cells a mutant CDK4 (CDK4(R24C)) that is insensitive to inhibition by cyclin-dependent kinase inhibitors. Our data show that expression of CDK4(R24C) in β-cells enhanced β-cell replication. CDK4(R24C) also dampened compensatory β-cell neogenesis in larvae and improved glucose tolerance in adult zebrafish. Our data indicate that CDK4 inhibition contributes to the limited β-cell replication in larval zebrafish. To our knowledge, this is the first example of genetically induced β-cell replication in zebrafish

Bimodal Sintered Silver Nanoparticle Paste with Ultrahigh Thermal Conductivity and Shear Strength for High Temperature Thermal Interface Material Applications

A bimodal silver nanoparticle (AgNP) paste has been synthesized via the simple ultrasonic mixing of two types of unimodal AgNPs (10 and 50 nm in diameter). By sintering this paste at 250 °C for 30 min, we obtained an ultrahigh thermal conductivity of 278.5 W m^–1 K^–1, approximately 65% of the theoretical value for bulk Ag. The shear strength before and after thermal cycling at 50–200 °C for 1000 cycles was approximately 41.80 and 28.75 MPa, respectively. The results show that this excellent performance is attributable to the unique sintered structures inside the bimodal AgNP paste, including its low but stable porosity and the high density coherent twins. In addition, we systematically discuss the sintering behavior of this paste, including the decomposition of the organic layers and the formation of the coherent twins. On the basis of these results, we confirm that our bimodal AgNP paste has excellent potential as a thermal interface material for high temperature power device applications

Highly Conductive Cu–Cu Joint Formation by Low-Temperature Sintering of Formic Acid-Treated Cu Nanoparticles

Highly conductive Cu–Cu interconnections of SiC die with Ti/Ni/Cu metallization and direct bonded copper substrate for high-power semiconductor devices are achieved by the low-temperature sintering of Cu nanoparticles with a formic acid treatment. The Cu–Cu joints formed via a long-range sintering process exhibited good electrical conductivity and high strength. When sintered at 260 °C, the Cu nanoparticle layer exhibited a low resistivity of 5.65 μΩ·cm and the joints displayed a high shear strength of 43.4 MPa. When sintered at 320 °C, the resistivity decreased to 3.16 μΩ·cm and the shear strength increased to 51.7 MPa. The microstructure analysis demonstrated that the formation of Cu–Cu joints was realized by metallurgical bonding at the contact interface between the Cu pad and the sintered Cu nanoparticle layer, and the densely sintered layer was composed of polycrystals with a size of hundreds of nanometers. In addition, high-density twins were found in the interior of the sintered layer, which contributed to the improvement of the performance of the Cu–Cu joints. This bonding technology is suitable for high-power devices operating under high temperatures

Table_2_Potential therapeutic effect of NK1R antagonist in diabetic non-healing wound and depression.docx

Diabetes is a global disease with huge impacts on patients due to its complications, among which non-healing wounds and depression are common and challenging. The neurokinin 1 receptor (NK1R) inhibitor, aprepitant has been broadly applied for an antidepressant effect in depressive patients. Recent literature has indicated a therapeutic effect of downregulation in NK1R to diabetes-related fracture, cardiomyopathy, gastroparesis, and ocular surface disorders. In this study, differential expression genes in diabetes and depression were analyzed based on several RNA sequencing datasets from the GEO database to confirm NK1R in the overlapping set. Interaction network and gene set enrichment analysis were subsequently conducted. As a result, NK1R-related genes took part in angiogenesis, epithelial-mesenchymal transition (EMT), collagen deposition, and inflammation in diabetes and depression. In vivo, the downregulation of NK1R was proved to promote vascular proliferation and enhance diabetic wound healing, which provides a potential therapeutic target for the management of diabetic non-healing wounds and depression.</p

Table_1_Potential therapeutic effect of NK1R antagonist in diabetic non-healing wound and depression.docx

Diabetes is a global disease with huge impacts on patients due to its complications, among which non-healing wounds and depression are common and challenging. The neurokinin 1 receptor (NK1R) inhibitor, aprepitant has been broadly applied for an antidepressant effect in depressive patients. Recent literature has indicated a therapeutic effect of downregulation in NK1R to diabetes-related fracture, cardiomyopathy, gastroparesis, and ocular surface disorders. In this study, differential expression genes in diabetes and depression were analyzed based on several RNA sequencing datasets from the GEO database to confirm NK1R in the overlapping set. Interaction network and gene set enrichment analysis were subsequently conducted. As a result, NK1R-related genes took part in angiogenesis, epithelial-mesenchymal transition (EMT), collagen deposition, and inflammation in diabetes and depression. In vivo, the downregulation of NK1R was proved to promote vascular proliferation and enhance diabetic wound healing, which provides a potential therapeutic target for the management of diabetic non-healing wounds and depression.</p

Table_3_Potential therapeutic effect of NK1R antagonist in diabetic non-healing wound and depression.docx

Diabetes is a global disease with huge impacts on patients due to its complications, among which non-healing wounds and depression are common and challenging. The neurokinin 1 receptor (NK1R) inhibitor, aprepitant has been broadly applied for an antidepressant effect in depressive patients. Recent literature has indicated a therapeutic effect of downregulation in NK1R to diabetes-related fracture, cardiomyopathy, gastroparesis, and ocular surface disorders. In this study, differential expression genes in diabetes and depression were analyzed based on several RNA sequencing datasets from the GEO database to confirm NK1R in the overlapping set. Interaction network and gene set enrichment analysis were subsequently conducted. As a result, NK1R-related genes took part in angiogenesis, epithelial-mesenchymal transition (EMT), collagen deposition, and inflammation in diabetes and depression. In vivo, the downregulation of NK1R was proved to promote vascular proliferation and enhance diabetic wound healing, which provides a potential therapeutic target for the management of diabetic non-healing wounds and depression.</p

Annotation of large yellow croaker unique sequences, according to GO.

<p>GO terms were derived based on the similarity search with web-based database, DAVID. The top ten GO terms in the cellular component, molecular function, and biological process groups are displayed.</p

Map of the T-cell receptor signaling pathway, as generated by KEGG.

<p>Genes that were identified from the transcriptome of the large yellow croaker spleen are shown in green. White denotes genes that were not identified in the transcriptome analysis.</p

KEGG orthology classification of unigenes.

<p>KEGG gene function was performed using the web-based database, DAVID. The numbers of sequences assigned to the twenty top KO categories were calculated.</p

Top 20 most abundant unigenes in the transcriptome of the large yellow croaker.

<p>Top 20 most abundant unigenes in the transcriptome of the large yellow croaker.</p