Curcumin Inhibits α-Synuclein Aggregation by Acting on Liquid-Liquid Phase Transition.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is linked to α-synuclein (α-Syn) aggregation. Despite no specific drug being available for its treatment, curcumin, from the spice turmeric, shows promise. However, its application in PD is limited by a lack of understanding of its anti-amyloidogenic mechanisms. In this study, we first reconstructed the liquid-liquid phase separation (LLPS) of α-Syn in vitro under different conditions, which may be an initial step in entraining the pathogenic aggregation. Subsequently, we evaluated the effects of curcumin on the formation of droplets, oligomers, and aggregated fibers during the LLPS of α-synuclein, as well as its impact on the toxicity of aggregated α-synuclein to cultured cells. Importantly, we found that curcumin can inhibit amyloid formation by inhibiting the occurrence of LLPS and the subsequent formation of oligomers of α-Syn in the early stages of aggregation. Finally, the molecular dynamic simulations of interactions between α-Syn decamer fibrils and curcumin showed that van der Waal's interactions make the largest contribution to the anti-aggregation effect of curcumin. These results may help to clarify the mechanism by which curcumin inhibits the formation of α-Syn aggregates during the development of PD.

Micro-environment triple-responsive hyaluronic acid hydrogel dressings to promote antibacterial activity, collagen deposition, and angiogenesis for diabetic wound healing.

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.

The variation of antigenic and histo-blood group binding sites synergistically drive the evolution among chronologically emerging GII.4 noroviruses.

Norovirus, commonly found on shellfish and vegetables, is a foodborne virus with GII.4 as the dominant genotype responsible for widespread outbreaks since 1995. Continuous variation of major capsid protein VP1 can lead to changes in the immunogenicity and host receptor binding ability of norovirus, which is an important evolutionary mechanism. Therefore, analyzing the immunogenicity of VP1 and its binding ability to various HBGAs in GII.4 variants could improve our understanding of the persistent prevalence of GII.4. Here, the results suggest that GII.4 has gradually enhanced its HBGAs binding ability over time for various types of receptors. Variants exhibit significantly stronger immune response to homologous mouse antiserum than heterologous ones, highlighting the importance of variation of antigenic and histo-blood group binding sites in driving the evolution of GII.4. These synergistic forces constantly lead to antigenic drift and changes in receptor binding, resulting in continuous emergence of new variant strains and sustained prevalence.

Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Differences in the effectiveness of the high-efficient concentrated pretreatment method on the norovirus detection in oysters and mussels.

Oysters and mussels are important vectors for norovirus (NoV). An efficient pretreatment method for NoV detection in oysters based on ISO 15216-2:2019 was established in our previous work, but its effectiveness for other types of shellfish remains unknown. Therefore, this study systematically compared the differences between the standard and modified ISO methods in detecting NoV for oysters and mussels. Using the standard ISO method, the recovery rates of NoV in oysters (2.10 ± 0.80 %) and mussels (2.39 ± 0.56 %) were comparable (p > 0.05, unpaired t-test). In contrast, the virus recovery rates in oysters (19.83 ± 3.64 %) and mussels (46.96 ± 3.55 %) were both significantly improved by the modified method. Also, a significant difference was found between the virus recovery rates in two shellfish (p < 0.05, unpaired t-test), resulting in a 2.09-fold difference in their virus concentrations. Additionally, the limits of detection at 95 % probability of the modified ISO method for oysters and mussels could both reach 3.33 × 103 copies/g of digestive glands. Finally, the modified ISO method has been successfully applied in commercial oysters (14/27, 51.85 %) and mussels (15/23, 65.22 %), and the results indicated a significant difference in NoV recovery rates between two shellfish (p < 0.05, one-way analysis of variance). In summary, the modified ISO method showed higher virus recovery rates than the standard ISO method, which would be used as an essential tool for NoV detection in oysters and mussels.

GII.17[P17] and GII.8[P8] noroviruses showed different RdRp activities associated with their epidemic characteristics.

Norovirus is the primary foodborne pathogenic agent causing viral acute gastroenteritis. It possesses broad genetic diversity and the prevalence of different genotypes varies substantially. However, the differences in RNA-dependent RNA polymerase (RdRp) activity among different genotypes of noroviruses remain unclear. In this study, the molecular mechanism of RdRp activity difference between the epidemic strain GII.17[P17] and the non-epidemic strain GII.8[P8] was characterized. By evaluating the evolutionary history of RdRp sequences with Markov Chain Monte Carlo method, the evolution rate of GII.17[P17] variants was higher than that of GII.8[P8] variants (1.22 × 10-3 nucleotide substitutions/site/year to 9.31 × 10-4 nucleotide substitutions/site/year, respectively). The enzyme catalytic reaction demonstrated that the Vmax value of GII.17[P17] RdRp was 2.5 times than that of GII.8[P8] RdRp. And the Km of GII.17[P17] and GII.8[P8] RdRp were 0.01 and 0.15 mmol/L, respectively. Then, GII.8[P8] RdRp fragment mutants (A-F) were designed, among which GII.8[P8]-A/B containing the conserved motif G/F were found to have significant effects on improving RdRp activity. The Km values of GII.8[P8]-A/B reached 0.07 and 0.06 mmol/L, respectively. And their Vmax values were 1.34 times than that of GII.8[P8] RdRp. In summary, our results suggested that RdRp activities were correlated with their epidemic characteristics. These findings will ultimately provide a better understanding in replication mechanism of noroviruses and development of antiviral drugs.

A systematic review and meta-analysis indicates a substantial burden of human noroviruses in shellfish worldwide, with GII.4 and GII.2 being the predominant genotypes.

Human noroviruses (HuNoVs) have been found as the leading cause of acute gastroenteritis outbreaks in all age groups and are significantly correlated with the consumption of shellfish. In this study, the contamination of HuNoVs in shellfish was estimated through a systematic review and meta-analysis. Studies on the contamination of HuNoVs in shellfish were searched from PubMed, Web of Science, Embase, and Cochrane Library from January 2000 to August 2021. A total of 75 studies were included, and the pooled HuNoVs prevalence in shellfish was 29% (95% CI: 23-35) worldwide. As revealed by the results of the subgroup meta-analysis, the prevalence of dominant genogroup was variable, and 4% (95% CI: 3-6), 13% (95% CI: 10-17), with 7% (95% CI: 4-11) of the samples, respectively, contaminated by GI alone, GII alone, and GI&GII. The HuNoVs prevalence of shellfish in Europe, America, and Asia was 33% (95% CI: 24-43), 24% (95% CI: 7-47), and 27% (95% CI: 18-35), respectively, while only 10% (95% CI: 5-17) in Africa. Furthermore, the prevalence of HuNoVs in shellfish was the highest in spring (35%, 95% CI: 23-49) and winter (35%, 95% CI: 22-50), and the lowest in summer (11%, 95% CI: 5-18). Oysters, clams, and mussels had comparable HuNoVs prevalence of 28% (95% CI: 20-37), 27% (95% CI: 16-39) and 24% (95% CI: 17-32), respectively. The prevalence of HuNoVs in shellfish from harvest areas and markets was 30% (95% CI: 23-38) and 30% (95% CI: 19-41), respectively. The results of this study suggest a substantial burden of HuNoVs in shellfish worldwide, with GII.4 (92.86%) and GII.2 (46.43%) as the predominant genotypes. This study provides information regarding the contamination of HuNoVs in shellfish worldwide, which will contribute to the development of appropriate control measures to prevent shellfish-related HuNoVs gastroenteritis.

Ru(II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma.

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.

Epochal coevolution of minor capsid protein in norovirus GII.4 variants with major capsid protein based on their interactions over the last five decades.

Norovirus is a leading cause of viral gastroenteritis outbreaks worldwide, with GII.4 responsible for the majority of infections. Minor capsid protein VP2 has been found to have functions such as stabilizing virus particles, and VP2 is one of the highly variable proteins of norovirus, similar to major capsid protein VP1. However, whether the variation of VP2 is functionally driven still remains unclear. In this study, VP2 showed a higher evolutionary rate (2.642×10-3 substitutions/site/year) than VP1 (1.587×10-3 substitutions/site/year), and a hypervariable region in VP2 in a serial of norovirus GII.4 over the past 50 years had been observed. Notably, the high variation of VP2 was not haphazard. The evolutionary process of VP2 is similar to that of VP1 with comparable topologies when the phylogenetic trees were constructed. Moreover, VP2 was found to interact with VP1 among epidemic variants of GII.4 using the yeast two-hybrid experiments. The results of interactions were grouped into time-adjacent (e.g. Ancestral-VP1 plus US95-VP2) and non-adjacent (e.g. Ancestral-VP1 plus Sydney-VP2) according to the epochal chronologically based prevalence of GII.4 norovirus. Interestingly, the interaction of the former group was significantly stronger than that of the latter group (P=0.0001). Furthermore, the interaction regions on VP2 (residues 131-160 and 171-180) were mapped to the hypervariable region. And these interaction regions did show an important role in the evolutionary process of VP2, which was consistent with that of VP1. In summary, the minor capsid protein VP2 of GII.4 noroviruses had shown the epochal coevolution with VP1 based on their interactions over the past 50 years. The findings of this study provided valuable information for further understanding and completing the evolutionary mechanism of norovirus.

The VP2 protein exhibits cross-interaction to the VP1 protein in norovirus GII.17.

Norovirus is a major cause of acute gastroenteritis worldwide. Like the major capsid protein (VP1), the minor capsid protein (VP2) also contains a hypervariable domain. Generally, a hypervariable domain is functionally driven. However, many functions of VP2 remain unknown and worth exploring. Without sufficient sequences and an available crystallographic model, it is difficult to explore VP2's mysteries. As a helper of stabilizing and coordinating the formation of virus-like particles (VLPs), we asked whether VP2 interacted with the major capsid protein (VP1) in GII.17 and if so, what the key interaction residues were. Here, we reported cross-interaction among four strains represented four clusters of GII.17, and the VP1 interaction domain of VP2 (174-179aa) was found. However, the VP1 interaction domain of VP2 was not universal in different clusters of GII.17. VP2 might evolve in a different pattern from VP1. Additionally, in contrast to previous reports, we found that VP2 localized in the cytoplasm. More possibilities of VP2 should be further explored.

Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis.

Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-ß signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.

Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice.

Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in TERC KO mice. TERC KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the Trp53-/- allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated AEC1) in AEC2 of the late generation of TERC KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.

Association of fucosyltransferase 2 gene with norovirus infection: A systematic review and meta-analysis.

BACKGROUND: Norovirus is a leading cause of viral gastroenteritis outbreaks worldwide. Histo-blood group antigens (HBGAs) are important host attachment factors in susceptibility to norovirus. In this study, the association of FUT2 gene, which participates in the biosynthesis of HBGAs, with norovirus infection has been investigated. METHODS: All relevant studies on the associations of FUT2 gene with norovirus were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Odds ratios (ORs) and 95% confidence interval (CI) were used to analyze the extracted data. I2 statistic, sensitivity analysis and publication bias analysis were used to confirm the findings. Subgroup analyses were performed for races, genotypes, development degree of the countries, publication years, age and setting when heterogeneity was recorded. RESULTS: Twenty studies including 4066 participants were included for the meta-analysis. This analysis showed that there is a significant association between FUT2 gene and norovirus infection (OR = 3.02, 95%CI = 2.00-4.55, P < 0.001). Additionally, the ORs of norovirus infection among Chinese (OR = 4.49, 95%CI = 2.37-8.50, P < 0.001) were higher than those among Caucasian (OR = 3.23, 95%CI = 2.20-4.74, P < 0.001). CONCLUSIONS: The meta-analysis suggested that FUT2 gene is associated with susceptibility to norovirus infection.

Global prevalence of norovirus in cases of acute gastroenteritis from 1997 to 2021: An updated systematic review and meta-analysis.

BACKGROUND: The worldwide response towards the acute gastroenteritis epidemic was well known, but the absence of an updated systematic review of global norovirus epidemiology in cases of gastroenteritis existed. We aimed to conduct and update a systematic review and meta-analysis of studies assessing norovirus prevalence among gastroenteritis patients worldwide. METHODS: Four databases (PubMed, EMBASE, Cochrane Library, and Web of Science) were searched for epidemiological papers from 2014 to 2021 which applied the PCR method to access the prevalence of norovirus in acute gastroenteritis patients more than a full year. Statistical analysis was conducted using R-4.0.0 software. RESULTS: A total of 405 records with 842, 926 cases were included. The pooled prevalence of norovirus was 16% (95%CI 15, 17). Children under 5 years old were at a higher risk with norovirus. A higher prevalence was seen in South America (22%, 95% CI 18, 27), while other continents showed a similar result with the overall prevalence of norovirus. No association was found between national income level and norovirus prevalence. A gradient of decreasing prevalence was noticed from community (20%, 95% CI 16, 24) to outpatients (18%, 95% CI 16, 20) to hospital setting (included both in- and outpatients, 17%, 95% CI 16, 19) to inpatients (15%, 95% CI 13, 17). CONCLUSION: Norovirus were associated with 16% acute gastroenteritis globally. To fully understand the prevalence of norovirus worldwide, the continual surveillance of norovirus epidemics was required.

Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination.

Telomere shortening results in cellular senescence and the regulatory mechanisms remain unclear. Here, we report that the sub-telomere regions facilitate telomere lengthening by homologous recombination, thereby attenuating senescence in yeast Saccharomyces cerevisiae. The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y' element recombination. Genetic disruption of SIR4 increases Y' element abundance and rescues telomere-shortening-induced senescence in a Rad51-dependent manner, indicating a sub-telomere regulatory switch in regulating organismal senescence by DNA recombination. Inhibition of the sub-telomere recombination requires Sir4 binding to perinuclear protein Mps3 for telomere perinuclear localization and transcriptional repression of the telomeric repeat-containing RNA TERRA. Furthermore, Sir4 repression of Y' element recombination is negatively regulated by Rif1 that mediates senescence-evasion induced by Sir4 deficiency. Thus, our results demonstrate a dual opposing control mechanism of sub-telomeric Y' element recombination by Sir3/4 and Rif1 in the regulation of telomere shortening and cell senescence.

Pulmonary alveolar stem cells undergo senescence, apoptosis and differentiation by p53-dependent and -independent mechanisms in telomerase deficient mice.

Pulmonary senescence and fibrosis occur with deoxyribonucleic acid (DNA) damage response in the lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that pulmonary alveolar epithelial type 2 cells (AEC2) (alveolar stem cells) undergo not only replicative senescence, but also apoptosis and differentiation in association with increased innate immune natural killer (NK) cells in telomerase knockout (KO) mice. Telomerase ribonucleic acid (RNA) component (TERC) deficiency results in increased senescence-associated heterochromatin foci marker HP1γ, p21, p16 and apoptosis-associated cleaved caspase-3 in AEC2. However, p53 deficiency in the Trp53-/- allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated alveolar epithelial type 1 cells [AEC1]) in AEC2 of the late generation of TERC KO mice. Collectively, our findings suggest that pulmonary senescence takes place in deficiency of telomerase RNA component with the alveolar stem cells undergoing p53-dependent senescence and apoptosis as well as p53-independent differentiation.

Simultaneous visualisation of the complete sets of telomeres from the MmeI generated terminal restriction fragments in yeasts.

Telomere length is measured using Southern blotting of the chromosomal terminal restriction fragments (TRFs) released by endonuclease digestion in cells from yeast to human. In the budding yeast Saccharomyces cerevisiae, XhoI or PstI is applied to cut the subtelomere Y' element and release TRFs from the 17 subtelomeres. However, telomeres from other 15 X-element-only subtelomeres are omitted from analysis. Here, we report a method for measuring all 32 telomeres in S. cerevisiae using the endonuclease MmeI. Based on analyses of the endonuclease cleavage sites, we found that the TRFs generated by MmeI displayed two distinguishable bands in the sizes of ~500 and ~700 bp comprising telomeres (300 bp) and subtelomeres (200-400 bp). The modified MmeI-restricted TRF (mTRF) method recapitulated telomere shortening and lengthening caused by deficiencies of YKu and Rif1 respectively in S. cerevisiae. Furthermore, we found that mTRF was also applicable to telomere length analysis in S. paradoxus strains. These results demonstrate a useful tool for simultaneous detection of telomeres from all chromosomal ends with both X-element-only and Y'-element subtelomeres in S. cerevisiae species.

RNA interference-mediated knockdown and virus-induced suppression of Troponin C gene adversely affect the behavior or fitness of the green rice leafhopper, Nephotettix cincticeps.

The green rice leafhopper, Nephotettix cincticeps, is a major rice pest in Southeast Asia and Southern China. Novel control strategies must be explored to control the rice pest. Behavior or fitness regulation of insect by modulating the Troponin C (TnC) may be a novel strategy in the comprehensive management of the insect pest. However, characterizations and functions of TnC, especially regarding effect of its RNA interference-mediated gene knockdown on the behavior or fitness of N. cincticeps remain unknown. Here, we successfully cloned and characterized TnC gene from N. cincticeps (Nc-TnC). We demonstrated that Nc-TnC ubiquitously transcribed at all development stages and special tissues in adult insects, with relative higher levels at the adult stage and in the intestinal canal. Microinjection- or oral membrane feeding-based transient knockdown of Nc-TnC adversely affected the performance or fitness, such as the decreased survival, feeding capacity, weight, and fecundity of N. cincticeps. Furthermore, we revealed that the expression of Nc-TnC was suppressed by its interaction with rice dwarf virus-encoded nonstructural protein 10, which ultimately affected detrimentally the corresponding parameters of the performance or fitness of N. cincticeps. In conclusion, our data deepen understanding of Nc-TnC functions during the development of and viral infection in N. cincticeps. It imply Nc-TnC may serve as a potential target for N. cincticeps control in future.

A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans.

Renal agenesis (RA) is one of the more extreme examples of congenital anomalies of the kidney and urinary tract (CAKUT). Bilateral renal agenesis is almost invariably fatal at birth, and unilateral renal agenesis can lead to future health issues including end-stage renal disease. Genetic investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we carried out whole exome sequence analysis of two families showing inheritance of an RA phenotype, and in both identified a single candidate gene, GREB1L Analysis of a zebrafish greb1l loss-of-function mutant revealed defects in the pronephric kidney just prior to death, and F0 CRISPR/Cas9 mutagenesis of Greb1l in the mouse revealed kidney agenesis phenotypes, implicating Greb1l in this disorder. GREB1L resides in a chromatin complex with RAR members, and our data implicate GREB1L as a coactivator for RARs. This study is the first to associate a component of the RAR pathway with renal agenesis in humans.