Regulation by the RNA-binding protein Unkempt at its effector interface.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of 'dual-purpose' peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface.

Role of MCP-1/CCR2 axis in renal fibrosis: Mechanisms and therapeutic targeting.

Renal fibrosis is a common pathological manifestation in various chronic kidney diseases. Inflammation plays a central role in renal fibrosis development. Owing to their significant participation in inflammation and autoimmunity, chemokines have always been the hot spot and focus of scientific research and clinical intervention. Among the chemokines, monocyte chemoattractant protein-1 (MCP-1), also known as C-C motif chemokine ligand 2, together with its main receptor C-C chemokine receptor type 2 (CCR2) are important chemokines in renal fibrosis. The MCP-1/CCR2 axis is activated when MCP-1 binds to CCR2. Activation of MCP-1/CCR2 axis can induce chemotaxis and activation of inflammatory cells, and initiate a series of signaling cascades in renal fibrosis. It mediates and promotes renal fibrosis by recruiting monocyte, promoting the activation and transdifferentiation of macrophages. This review summarizes the complex physical processes of MCP-1/CCR2 axis in renal fibrosis and addresses its general mechanism in renal fibrosis by using specific examples, together with the progress of targeting MCP-1/CCR2 in renal fibrosis with a view to providing a new direction for renal fibrosis treatment.

A paradigm for regulation at the effector interface with RNA-binding proteins.

RNA-binding proteins (RBPs) are key regulators of gene expression, but how RBPs convey regulatory instructions to the core effectors of RNA processing is unclear. Here we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a deeply conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of 'dual-purpose' peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by the recruiting RBP. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface, with implications for the evolution and function of RBP-operated regulatory networks.

The nexus between RNA-binding proteins and their effectors.

RNA-binding proteins (RBPs) regulate essentially every event in the lifetime of an RNA molecule, from its production to its destruction. Whereas much has been learned about RNA sequence specificity and general functions of individual RBPs, the ways in which numerous RBPs instruct a much smaller number of effector molecules, that is, the core engines of RNA processing, as to where, when and how to act remain largely speculative. Here, we survey the known modes of communication between RBPs and their effectors with a particular focus on converging RBP-effector interactions and their roles in reducing the complexity of RNA networks. We discern the emerging unifying principles and discuss their utility in our understanding of RBP function, regulation of biological processes and contribution to human disease.

Effects of salvianolic acid A and salvianolic acid B in renal interstitial fibrosis via PDGF-C/PDGFR-α signaling pathway.

BACKGROUND: Renal interstitial fibrosis (RIF) is the main pathological feature of end-stage renal disease (ESRD) caused by various chronic kidney diseases (CKD), and is closely related to renal dysfunction and patient prognosis. Salvianolic acid A (Sal A) and salvianolic acid B (Sal B), isolated from traditional Chinese medicine Salviae miltiorrhizae, have been confirmed to have anti-fibrotic effects on liver, cardiac and kidney. However, the precise molecular mechanism underlying the nephroprotective effects of Sal A and Sal B, and whether there is a difference between the two in RIF are still unclear. PURPOSE: This study investigated the pharmacological effects of Sal A and Sal B in RIF and explore the underlying mechanisms by in vivo and in vitro experiments. METHODS: The nephroprotective effects of Sal A, Sal B and Sal A+B were evaluated by assessing the parameters related to kidney function such as renal histology, renal function, urinary protein NAG, urinary ß2 microglobulin. In addition, RIF-related markers such as CTCF and Par3 were also detected. Thereafter, the related protein or gene levels of PDGF-C/PDGFR-α signaling pathways, apoptosis and endoplasmic reticulum stress (ERS) were determined by western blot, real-time PCR, flow cytometry or immunofluorescence staining. RESULTS: In vivo, the results showed that Sal A, Sal B and Sal A+B partially improved kidney dysfunction, increased the expression of Par-3 and reduced the expression of CTGF, PDGF-C and PDGFR-α. In vitro, the results also showed that Sal A, Sal B and Sal A+B reversed apoptosis and ERS in HSA-induced HK-2 cells via regulating PDGF-C/PDGFR-α signaling pathway. CONCLUSION: This article revealed a novel mechanism linking PDGF-C/PDGFR-α signaling pathway to RIF and suggested that Sal A, Sal B and Sal A+B were considered as potential therapeutic agents for the amelioration of RIF.

Regulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity.

Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs). The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. Accumulating evidence supports a substantial role of CAF-1 in cell fate maintenance, but the mechanisms by which CAF-1 restricts lineage choice remain poorly understood. Here, we investigate how CAF-1 influences chromatin dynamics and TF activity during lineage differentiation. We show that CAF-1 suppression triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state. We find that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 TF at newly-accessible diverging regulatory elements. Together, our findings decipher key traits of chromatin accessibility that sustain lineage integrity and point to a powerful strategy for dissecting transcriptional circuits central to cell fate commitment.

Semiconductor glass with superior flexibility and high room temperature thermoelectric performance.

Most crystalline inorganic materials, except for metals and some layer materials, exhibit bad flexibility because of strong ionic or covalent bonds, while amorphous materials usually display poor electrical properties due to structural disorders. Here, we report the simultaneous realization of extraordinary room temperature flexibility and thermoelectric performance in Ag2Te1-x S x -based materials through amorphization. The coexistence of amorphous main phase and crystallites results in exceptional flexibility and ultralow lattice thermal conductivity. Furthermore, the flexible Ag2Te0.6S0.4 glass exhibits a degenerate semiconductor behavior with a room temperature Hall mobility of ~750 cm2 V-1 s-1 at a carrier concentration of 8.6 × 1018 cm-3, which is at least an order of magnitude higher than other amorphous materials, leading to a thermoelectric power factor also an order of magnitude higher than the best amorphous thermoelectric materials known. The in-plane prototype uni-leg thermoelectric generator made from this material demonstrates its potential for flexible thermoelectric device.

High Thermoelectric Performance of Cu-Doped PbSe-PbS System Enabled by High-Throughput Experimental Screening.

Recent advances in high-throughput (HTP) computational power and machine learning have led to great achievements in exploration of new thermoelectric materials. However, experimental discovery and optimization of thermoelectric materials have long relied on the traditional Edisonian trial and error approach. Herein, we demonstrate that ultrahigh thermoelectric performance in a Cu-doped PbSe-PbS system can be realized by HTP experimental screening and precise property modulation. Combining the HTP experimental technique with transport model analysis, an optimal Se/S ratio showing high thermoelectric performance has been efficiently screened out. Subsequently, based on the screened Se/S ratio, the doping content of Cu has been subtly adjusted to reach the optimum carrier concentration. As a result, an outstanding peak zT~1.6 is achieved at 873 K for a 1.8 at% Cu-doped PbSe0.6S0.4 sample, which is the superior value among the n-type Te-free lead chalcogenides. We anticipate that current work will stimulate large-scale unitization of the HTP experimental technique in the thermoelectric field, which can greatly accelerate the research and development of new high-performance thermoelectric materials.

TACC3 transcriptionally upregulates E2F1 to promote cell growth and confer sensitivity to cisplatin in bladder cancer.

Accumulating evidence has shown that transforming acidic coiled-coil 3 (TACC3) is deregulated in a broad spectrum of cancers. In the present study, we reported that TACC3 was markedly elevated in bladder cancer, especially in muscle-invasive bladder cancers (MIBCs). The upregulation of TACC3 was positively associated with tumor invasiveness, grade, T stage, and progression in patients with bladder cancer. Furthermore, a Kaplan-Meier survival analysis showed that patients with bladder cancer whose tumors had high TACC3 expression experienced a dismal prognosis compared with patients whose tumors had low TACC3 expression. Functional studies have found that TACC3 is a prerequisite for the development of malignant characteristics of bladder cancer cells, including cell proliferation and invasion. Moreover, TACC3 promoted G1/S transition, which was mediated via activation of the transcription of E2F1, eventually enhancing cell proliferation. Notably, the overexpression of TACC3 or E2F1 indicates a high sensitivity to cisplatin. Taken together, these findings define a tumor-supportive role for TACC3, which may also serve as a prognostic and therapeutic indicator in bladder cancers.

Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat.

Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome-wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS-based target enrichment strategy could be applied to SNP chip design in other species.

TBK1 Promote Bladder Cancer Cell Proliferation and Migration via Akt Signaling.

Bladder cancer is a challenging and fatal malignancy and the improvement in prognosis is limited over years. Deep understanding the mechanism of bladder cancer tumorigenesis and progression will help to discover novel and effective treatment strategies. In this study, we identify non-canonical IkB kinase TBK1 is up-regulated in bladder cancer tissue and cell lines. Knockdown of TBK1 markedly inhibits cell proliferation and migration. Inhibition of TBK1 kinase activity by BX795 significantly attenuates bladder cancer cell proliferation and migration. Mechanistic study shows that overexpression of TBK1 promoted the phosphorylation of Akt, whereas knockdown of TBK1 reverses this action. Taken together, our data suggest that TBK1 modulates the malignant behaviors of bladder cancer cell via Akt signaling, revealing new insights in discovering new therapy target for bladder cancer.

The complete mitochondrial genome of great cormorant, Phalacrocorax carbo (Phalacrocorax, Phalacrocoracidae).

The great cormorant (Phalacrocorax carbo) is widely distributed in the world. Here, we report the complete mitogenome sequence of P. carbo, which was 18,995 bp long and composed of 15 protein-coding genes, 25 tRNA genes, 2 rRNA genes and 2 control regions. Most genes were located on H-strand except for 10 tRNAs and 2 ND6 genes. In protein-coding genes, ATG, ATC and GTG were used as initiation codons, and TAA, AGA, AGG and TAG were used as stop codons. The 25 tRNA genes ranged in size from 67 to 75 bp. And 12S and 16S rRNA were respectively 983 and 1517 bp. Except for a tRNA-Ala in P. carbo which was different from the tRNA-Lys annotated in P. chalconotus, both species of Phalacrocorax had the same order of other genes. In addition, a phylogenetic analysis may help us understand the evolutionary status of this widespread species better.

Signatures of Crested Ibis MHC Revealed by Recombination Screening and Short-Reads Assembly Strategy.

Whole-genome shotgun (WGS) sequencing has become a routine method in genome research over the past decade. However, the assembly of highly polymorphic regions in WGS projects remains a challenge, especially for large genomes. Employing BAC library constructing, PCR screening and Sanger sequencing, traditional strategy is laborious and expensive, which hampers research on polymorphic genomic regions. As one of the most highly polymorphic regions, the major histocompatibility complex (MHC) plays a central role in the adaptive immunity of all jawed vertebrates. In this study, we introduced an efficient procedure based on recombination screening and short-reads assembly. With this procedure, we constructed a high quality 488-kb region of crested ibis MHC that consists of 3 superscaffolds and contains 50 genes. Our sequence showed comparable quality (97.29% identity) to traditional Sanger assembly, while the workload was reduced almost 7 times. Comparative study revealed distinctive features of crested ibis by exhibiting the COL11A2-BLA-BLB-BRD2 cluster and presenting both ADPRH and odorant receptor (OR) gene in the MHC region. Furthermore, the conservation of the BF-TAP1-TAP2 structure in crested ibis and other vertebrate lineages is interesting in light of the hypothesis that coevolution of functionally related genes in the primordial MHC is responsible for the appearance of the antigen presentation pathways at the birth of the adaptive immune system.

The Sinocyclocheilus cavefish genome provides insights into cave adaptation.

BACKGROUND: An emerging cavefish model, the cyprinid genus Sinocyclocheilus, is endemic to the massive southwestern karst area adjacent to the Qinghai-Tibetan Plateau of China. In order to understand whether orogeny influenced the evolution of these species, and how genomes change under isolation, especially in subterranean habitats, we performed whole-genome sequencing and comparative analyses of three species in this genus, S. grahami, S. rhinocerous and S. anshuiensis. These species are surface-dwelling, semi-cave-dwelling and cave-restricted, respectively. RESULTS: The assembled genome sizes of S. grahami, S. rhinocerous and S. anshuiensis are 1.75 Gb, 1.73 Gb and 1.68 Gb, respectively. Divergence time and population history analyses of these species reveal that their speciation and population dynamics are correlated with the different stages of uplifting of the Qinghai-Tibetan Plateau. We carried out comparative analyses of these genomes and found that many genetic changes, such as gene loss (e.g. opsin genes), pseudogenes (e.g. crystallin genes), mutations (e.g. melanogenesis-related genes), deletions (e.g. scale-related genes) and down-regulation (e.g. circadian rhythm pathway genes), are possibly associated with the regressive features (such as eye degeneration, albinism, rudimentary scales and lack of circadian rhythms), and that some gene expansion (e.g. taste-related transcription factor gene) may point to the constructive features (such as enhanced taste buds) which evolved in these cave fishes. CONCLUSION: As the first report on cavefish genomes among distinct species in Sinocyclocheilus, our work provides not only insights into genetic mechanisms of cave adaptation, but also represents a fundamental resource for a better understanding of cavefish biology.

The complete mitochondrial genome sequence of a cavefish Sinocyclocheilus anshuiensis (Cypriniformes: Cyprinidae).

Sinocyclocheilus anshuiensis is a special cavefish that lives in the Southwestern China with many specific regressive features, such as rudimentary eyes and scales, and loss of pigmentation. In this study, we performed sequencing and assembly of its complete mitochondrial genome. We confirmed that total length of the mitochondrion is 16 618 bp with an AT ratio of 55.4%. The complete mitochondrial genome contains 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs and a 963 bp control region. Our current data provide important resources for the research of cavefish mitochondrial evolution and energy metabolism.

The complete mitochondrial genome of Astatotilapia burtoni.

Astatotilapia burtoni is a species of fish in the Cichlidae family. Astatotilapia burtoni has been used as a model organism to research the behaviors and physical systems of cichlids. Here, we reported the complete mitogenome sequence of A. burtoni, which was 16,583 bp and composed of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 control region, with a base composition of lower G + C content (45.5%). Similar to Astatotilapia calliptera, all genes were located on H-strand except for eight tRNAs and ND6 genes. Most protein-coding genes started with an ATG codon except for COX1, ATP6 and ND3, which initiated with GTG or ATC instead, and terminated with the typical stop condon (TAA/TAG)or a single T. In this article, 12 protein-coding genes of other 10 closely species were used to construct the species phylogenetic tree to convince the mitogenome sequences. These results provided basic information for researching A. burtoni on genetics, phylogeny and adaptive evolution.

The complete mitochondrial genome sequence of Eudocimus ruber (Pelecaniformes:Threskiornithidae).

The Eudocimus ruber (Scarlet ibis) belongs to the bird order Pelecaniformes. Here, we sequenced the mitochondrial genome of E. ruber. The complete mitochondrial genome of E. ruber is 16 697 bp in length and contains 22 tRNA genes, 2 rRNA genes, 13 protein-coding genes and a non-coding control region. Consistent with other sequenced birds, most genes are encoded on the heavy strand, except for ND6 and 8 tRNA genes. The overall base composition of the E. ruber is 30.8% A, 30.8% C, 13.8%G and 24.6% T. The molecular-based phylogenetic tree suggested that E. ruber has close affinities with birds from family Threskiornithidae as expected.

Development and characterization of microsatellite markers from the transcriptome of Firmiana danxiaensis (Malvaceae s.l.).

PREMISE OF THE STUDY: Firmiana consists of 12-16 species, many of which are narrow endemics. Expressed sequence tag (EST)-simple sequence repeat (SSR) markers were developed and characterized for size polymorphism in four Firmiana species. • METHODS AND RESULTS: A total of 102 EST-SSR primer pairs were designed based on the transcriptome sequences of F. danxiaensis; these were then characterized in four Firmiana species-F. danxiaensis, F. kwangsiensis, F. hainanensis, and F. simplex. In these four species, 17 primer pairs were successfully amplified, and 14 were polymorphic in at least one species. The number of alleles ranged from one to 13, and the observed and expected heterozygosities ranged from 0 to 1 and 0 to 0.925, respectively. The lowest level of polymorphism was observed in F. danxiaensis. • CONCLUSIONS: These polymorphic EST-SSR markers are valuable for conservation genetics studies in the endangered Firmiana species.