Search

Background Cervical cancer (CC) has become the fourth most common cancer among women and cause a larger number of deaths in worldwide. Screening at the early stage of CC is an effective precaution. Discovery of the new hallmark of CC will provide a guidance for CC screening. Kinesin family member 4A (KIF4A) expressed in a variety of tissues and also contributed to development of several cancers, however its function in CC remains unclear.Methods we download and analyzed the clinical information and mRNA profile of cervical cancer patients from TCGA and GTEx database. After normalization process, the expression values of KIF4A were calculated according to TCGA and GTEx data. We collected CC patient tissue samples from the Second Hospital of Anhui Medical University and detected KIF4A expression by IHC and WB. The immune cell infiltration analysis is preformed in the online analysis tool TIMER 2.0 (http://timer.cistrome.org/).Results The high-expression of KIF4A was demonstrated in the CC patients according to the bioinformatics analysis and clinical test. Additionally, loss-function of KIF4A with shRNA abrogated cervical cell proliferation, migration and invasion. We also found that the difference expression genes were identified between KIF4A− high and KIF4A− low CC patients among with abundant mutation of several genes occurred in the CC progression. Finally, we also proved that KIF4A was involved in the immune cell infiltration in the CC patients by clinical information analysis. These demonstrated that the dys-expression of KIF4A may be used for the CC screening and clinical therapy.

This letter presents a novel superstrate composed of multilayer metasurface (MM), which is characterized by wideband monostatic and bistatic radar cross section reduction (RCSR) for Fabry–Perot (FP) antenna with magnetoelectric (ME) dipole-fed. The proposed MM consists of four layers, the top three layers form a polarization-selective absorber (PSA), and the bottom layer is a polarization conversion metasurface (PCM). The copolarized incident waves are absorbed by the PSA, while the cross-polarized waves pass through with a low insertion loss. Then, it is reflected by the PCM with 90° polarization rotation and absorbed by the upper PSA. Additionally, the bottom layer of the PCM unit is an improved pattern instead of the ground plane. It is capable of polarization conversion and partial reflection. Therefore, the MM and ME dipole are respectively utilized as the partially reflecting surface (PRS) and the primary source to construct an FP antenna. Simulation and measurement results show that the bandwidth of monostatic RCSR is more than 80%. The FP antenna also achieves a high aperture efficiency of 51%, which is due to the benefit from the widebeam characteristics of the ME dipole.

Mixed-lineage leukemia 1 (MLL1), which exerts its H3K4 methyltransferase activity by interacting with WDR5, ASH2L, and RBBP5, plays a pivotal role in regulating hematopoietic stem cell homeostasis. Disrupting the integrity of MLL1-complex has been reported to be associated with acute leukemia. However, the exact role of MLL1-complex in myeloid cells is unknown. In this study, microarray analysis revealed that the core components of the Mll1-complex, Wdr5, Ash2l, and Mll1, were concurrently downregulated by tumor-secreted factors as well as GM-CSF + IL-6 during the accumulation and activation of murine myeloid-derived suppressor cells (MDSCs). These changes were further validated by quantitative RT-PCR and Western blotting both in vitro and in vivo. The expression levels of WDR5 and ASH2L were also significantly decreased in bone marrow MDSCs of lung cancer patients compared with that of healthy controls. Functionally, ectopic expression of Wdr5, Ash2l, and Mll1 (C terminus) reversed the accumulation and function of GM-CSF + IL-6–induced as well as tumor-cocultured polymorphonuclear MDSCs (PMN-MDSCs) by promoting them to differentiate into mature neutrophil-like cells. Mechanistically, GM-CSF + IL-6–activated Stat3 and Cebpβ synergistically induced the expression of miR-21a, miR-21b, and miR-181b, and thus inhibited the expression of Wdr5, Ash2l, and Mll1 by targeting to their 3′ untranslated regions, respectively. Furthermore, knockdown of these microRNAs also suppressed the expansion and function of GM-CSF + IL-6–induced PMN-MDSCs. Taken together, our findings indicate that the Stat3/Cebpβ–miR-21a/b/181b–Mll1-complex axis may play a critical role in PMN-MDSC expansion, activation, and differentiation, and this axis may provide an effectively immunological therapeutic approach for patients with cancer or other immunological diseases.

Azide, the most used photo-crosslinking group, facilitates the analysis of protein structure and function. This group is particularly useful when photochemically label antibodies and examine protein-protein interactions. The use of the expanded genetic code technique allows the special labeling of the functional azide group in proteins by adding the unnatural amino acid (UAA), p-azido-l-phenylalanine (AzF), in response to the amber codon during translation. However, a low UAA uptake rate due to mass transfer resistance in the cell membrane may lead to the early termination of the full-length protein. This study reports a general method for the efficient in vivo incorporation of AzF into the target protein by improving cell permeability using organic solvents. As expected, the yield of the full-length protein was significantly increased, which indicated that the AzF uptake was greatly improved due to the addition of organic solvents. Our method can serve as a good reference for improving the genetic incorporation of other kinds of UAAs into proteins.

Hippo signalling plays key role in tissue growth and homeostasis, and its dysregulation is implicated in various human diseases. Expanded (Ex) is an important upstream activator of Hippo signalling; however, how Ex activates Hippo signalling is still poorly understood. Here, we demonstrate that Ex forms a homodimer via C-terminal interaction, and that the ExC2 region (912-1164 aa) is sufficient and essential for Ex dimerization. Functional analysis shows that ExC2 is required for Ex to promote the phosphorylation and inactivation of Yki in Drosophila cells. Further in vivo analysis shows that ExC2 is important for Ex to control Drosophila tissue growth. Our study, thus, uncovers a novel mechanism whereby Ex homodimerization mediates its full activation to promote Hippo signalling in growth control.

Alzheimer's disease (AD) is the most prevalent form of dementia in the old adult and characterized by progressive cognitive decline and neuronal damage. The mammalian Ste20-like kinase1/2 (MST1/2) is a core component in Hippo signaling, which regulates neural stem cell proliferation, neuronal death and neuroinflammation. However, whether MST1/2 is involved in the occurrence and development of AD remains unknown. In this study we reported that the activity of MST1 was increased with Aβ accumulation in the hippocampus of 5xFAD mice. Overexpression of MST1 induced AD-like phenotype in normal mice and accelerated cognitive decline, synaptic plasticity damage and neuronal apoptosis in 2-month-old 5xFAD mice, but did not significantly affect Aβ levels. Mechanistically, MST1 associated with p53 and promoted neuronal apoptosis by phosphorylation and activation of p53, while p53 knockout largely reversed MST1-induced AD-like cognitive deficits. Importantly, either genetic knockdown or chemical inactivation of MST1 could significantly improve cognitive deficits and neuronal apoptosis in 7-month-old 5xFAD mice. Our results support the idea that MST1-mediated neuronal apoptosis is an essential mechanism of cognitive deficits and neuronal loss for AD, and manipulating the MST1 activity as a potential strategy will shed light on clinical treatment for AD or other diseases caused by neuronal injury.

As the most primordial signaling pathway in animal physiology, the Hippo pathway and innate immunity play crucial roles not only in sensing cellular conditions or infections, but also in various metabolite homeostasis and tumorigenesis. However, the correlation between cellular homeostasis and antiviral defense is not well understood. The core kinase LATS1/2, could either enhance or inhibit the anti-tumor immunity in different cellular contexts. In this study, we found that LATS2 can interact with PQBP1, the co-factor of cGAS, thus enhanced the cGAS-STING mediated innate immune response to HIV-1 challenge. LATS2 was observed to upregulate type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA and inhibited HIV-1 infection. Due to the involvement of PQBP1, the function of LATS2 in regulating cGAS activity is not relying on the downstream YAP/TAZ as that in the canonical Hippo pathway. The related kinase activity of LATS2 was verified, and the potential phosphorylation site of PQBP1 was identified. Our study established a novel connection between Hippo signaling and innate immunity, thus may provide new potential intervention target on antiviral therapeutics.

A Fabry-Perot (FP) antenna with enhanced bandwidth and wideband RCS reduction based on polarization conversion metasurface (PCM) is presented in this paper. The wide impedance bandwidth benefits from the two parasitic mushroom-shaped patches loaded on the radiating edges of source antenna to excite a new resonant mode (quasi-TM30 mode), and high gain-bandwidth is also achieved by using an irregular ground plane. The PCM units are arranged in chessboard configuration to form a superstrate, which is placed on the antenna to obtain good scattering characteristics.

A compact double-layer power divider with high isolation between output ports based on the groove gap waveguide (GGW) is presented in this paper. A five-port 1-to-2 power divider is designed base on the gap waveguide technology. Then a 1-to-8 power divider is built up by connecting seven 1-to-2 five-port power dividers. To achieve a compact size, the 1-to-8 power divider adopts a double-layer structure. The top layer is the feeding structure of the power divider, and the bottom layer contains the loads. The simulated results show that the proposed power divider exhibits the impedance matching bandwidth for the reflection coefficient below -15 dB is from 23.7 GHz to 30.3 GHz, and isolations between the output ports is more than 18 dB.

The Hippo signaling pathway is an evolutionarily conserved regulator that plays important roles in organ size control, homeostasis, and tumorigenesis. As the key effector of the Hippo pathway, Yorkie (Yki) binds to transcription factor Scalloped (Sd) and promotes the expression of target genes, leading to cell proliferation and inhibition of apoptosis. Thus, it is of great significance to understand the regulatory mechanism for Yki protein turnover. Here, we provide evidence that the deubiquitinating enzyme ubiquitin-specific protease 10 (Usp10) binds Yki to counteract Yki ubiquitination and stabilize Yki protein in Drosophila S2 cells. The results in Drosophila wing discs indicate that silence of Usp10 decreases the transcription of target genes of the Hippo pathway by reducing Yki protein. In vivo functional analysis ulteriorly showed that Usp10 upregulates the Yki activity in Drosophila eyes. These findings uncover Usp10 as a novel Hippo pathway modulator and provide a new insight into the regulation of Yki protein stability and activity.

Summary Commensal microbes are necessary for a healthy gut immune system. However, the mechanism involving these microbes that establish and maintain gut immune responses is largely unknown. Here, we have found that the gut immune receptor leucine-rich repeat (LRR) C19 is involved in host-microbiota interactions. LRRC19 deficiency not only impairs the gut immune system but also reduces inflammatory responses in gut tissues. We demonstrate that the LRRC19-associated chemokines CCL6, CCL9, CXCL9, and CXCL10 play a critical role in immune cell recruitment and intestinal inflammation. The expression of these chemokines is associated with regenerating islet-derived (REG) protein-mediated microbiotas. We also found that the expression of REGs may be regulated by gut Lactobacillus through LRRC19-mediated activation of NF-κB. Therefore, our study establishes a regulatory axis of LRRC19, REGs, altered microbiotas, and chemokines for the recruitment of immune cells and the regulation of intestinal inflammation., Graphical Abstract, Highlights • The gut immune receptor LRRC19 is involved in host-microbiota interactions • LRRC19-associated chemokines control immune cell recruitment and gut inflammation • Chemokines are regulated by REG protein-mediated gut microbiotas • Lactobacillus may modulate the expression of REG proteins through LRRC19, Cao et al. found that the gut epithelial receptor LRRC19 is involved in gut host-microbiota interactions and that it plays a critical role in promoting the recruitment of immune cells and intestinal inflammation.

We here found that intestinal epithelial Paneth cells secrete FABP4, adipsin and adiponectin in both mice and human. Deletion of Paneth cell results in the decrease of FABP4, adipsin and adiponectin not only in intestinal crypt cells but also in sera, suggesting that they may influence the state of the whole body. We also demonstrate that expression of FABP4, adipsin and adiponectin may be modulated by specific gut microbiota. In germ-free (GF) mice, the expression of FABP4, adipsin and adiponectin were lower or difficult to be detected. Feces transplantation promoted the expression of FABP4, adipsin and adiponectin in gut epithelial Paneth cells. We have found that Lactobacillus NK6 colony, which has the highest similarity with Lactobacillus taiwanensis strain BCRC 17755, may induce the expression of FABP4, adipsin and adiponectin through TRAF2 and TRAF6 ubiquitination mediated NF-κB signaling. Taken together, our findings set up a novel mechanism for FABP4, adipsin and adiponectin through gut microbiota mediating expression in gut Paneth cells.