Molecular characterization, expression and antibacterial function of a macin, HdMac, from Haliotis discus hannai.

Macins are a family of antimicrobial peptides, which play multiple roles in the elimination of invading pathogens. In the present study, a macin was cloned and characterized from Pacific abalone Haliotis discus hannai (Designated as HdMac). Analysis of the conserved domain suggested that HdMac was a new member of the macin family. In non-stimulated abalones, HdMac transcripts were constitutively expressed in all five tested tissues, especially in hemocytes. After Vibrio harveyi stimulation, the expression of HdMac mRNA in hemocytes was significantly up-regulated at 12 hr (P < 0.01). RNAi-mediated knockdown of HdMac transcripts affected the survival rates of abalone against V. harveyi. Moreover, recombinant protein of HdMac (rHdMac) exhibited high antibacterial activities against invading bacteria, especially for Vibrio anguillarum. In addition, rHdMac possessed binding activities towards glucan, lipopolysaccharides (LPS), and peptidoglycan (PGN), but not chitin in vitro. Membrane integrity analysis revealed that rHdMac could increase the membrane permeability of bacteria. Meanwhile, both the phagocytosis and chemotaxis ability of hemocytes could be significantly enhanced by rHdMac. Overall, the results showed that HdMac could function as a versatile molecule involved in immune responses of H. discus hannai.

Complete remission in a pretreated, microsatellite-stable, KRAS-mutated colon cancer patient after treatment with sintilimab and bevacizumab and platinum-based chemotherapy: a case report and literature review.

Metastatic colon cancer remains an incurable disease, and it is difficult for existing treatments to achieve the desired clinical outcome, especially for colon cancer patients who have received first-line treatment. Although immune checkpoint inhibitors (ICIs) have demonstrated durable clinical efficacy in a variety of solid tumors, their response requires an inflammatory tumor microenvironment. However, microsatellite-stable (MSS) colon cancer, which accounts for the majority of colorectal cancers, is a cold tumor that does not respond well to ICIs. Combination regimens open the door to the utility of ICIs in cold tumors. Although combination therapies have shown their advantage even for MSS colon cancer, it remains unclear whether combination therapies show their advantage in patients with pretreated metastatic colon cancer. We report a patient who has achieved complete remission and good tolerance with sintilimab plus bevacizumab and platinum-based chemotherapy after postoperative recurrence. The patient had KRAS mutation and MSS-type colon cancer, and his PD-1+CD8+ and CD3-CD19-CD14+CD16-HLA-DR were both positive. He has achieved a progression-free survival of 43 months and is still being followed up at our center. The above results suggest that this therapeutic regimen is a promising treatment modality for the management of pretreated, MSS-type and KRAS-mutated metastatic colorectal cancer although its application to the general public still needs to be validated in clinical trials.

Phase fluctuations-induced bit error ratio of deep-space optical communication systems during superior solar conjunction.

Deep-space optical communication has garnered increasing attention for its high data transfer rate, wide bandwidth, and high transmission speed. However, coronal plasma turbulence severely degrades optical signals during superior solar conjunction. In this study, we introduce the models for plasma density and generalized non-Kolmogorov turbulence power spectrum. Based on these models, we derive the variance of the phase fluctuations with the assistance of the Rytov theory in the weak turbulence regime involving various variables, such as turbulence outer scale, spectral index, relative fluctuation factor, and wavelength. Subsequently, we evaluate the bit error ratio (BER) performance of the deep-space optical communication system, considering phase fluctuations and intensity scintillations, under binary phase shift keying modulation. Numerical calculations reveal that small heliocentric distance, large relative fluctuation factor and spectral index, could induce severe phase fluctuations and high BER. Fortunately, the effects of the plasma irregularities on the BER performance can be mitigated by short optical wavelength under large outer scale.

Identifying chemical markers in wine-processed Salvia miltiorrhiza using ultrahigh-performance liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry.

To find the chemical markers of wine-processed Salvia miltiorrhiza (WSM), 76 constituents, including diterpenoid quinones and phenolic acids in Salvia miltiorrhiza (SM) and WSM, were profiled using ultrahigh-performance liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS/MS) in positive- and the negative-ion modes. Thirty compounds were screened out as candidate differential components using chemometrics analysis, and the concentration of most compounds increased after processing with wine. Seven compounds, namely tanshinone IIA, magnesium lithospermate B, salvianolic acid G, cryptotanshinone, isocryptotanshinone, salvianolic acid B, and rosmarinic acid, were selected as chemical markers of WSM using variable importance of the project. This study revealed the chemical markers of WSM and confirmed that WSM can improve the extraction and solubility effect of chemical constituents.

Evidence for non-Arrhenius behavior of EPDM rubber by combining Arrhenius and time-temperature superposition (TTS) extrapolations.

Studying the non-Arrhenius behavior of rubber is crucial to ensure appropriate lifetime prediction and reduce ineffective acceleration experiments. In this paper, accelerated thermal aging from 70 °C to 130 °C is conducted on an ethylene propylene diene monomer (EPDM) rubber and the tensile characteristics of the rubber are tested. Further, the popular Mooney-Rivlin equation is employed to analyze the influence of aging temperature and time on the effective crosslink densities. The enormous increase in the physical crosslinking density when the aging temperature reaches 115 °C demonstrates that the activation energy varied during the degradation process. By combining the Arrhenius extrapolation with the time-temperature superposition (TTS) extrapolation, a novel method to prove the non-Arrhenius behavior of EPDM rubber is provided. Based on the method proposed in this study, the activation energies for the high- and low-temperature processing of rubber can be determined.

Metastable gallium hydride mediates propane dehydrogenation on H2 co-feeding.

In heterogeneous catalysis, the catalytic dehydrogenation reactions of hydrocarbons often exhibit a negative pressure dependence on hydrogen due to the competitive chemisorption of hydrocarbons and hydrogen. However, some catalysts show a positive pressure dependence for propane dehydrogenation, an important reaction for propylene production. Here we show that the positive activity dependence on H2 partial pressure of gallium oxide-based catalysts arises from metastable hydride mediation. Through in situ spectroscopic, kinetic and computational analyses, we demonstrate that under reaction conditions with H2 co-feeding, the dissociative adsorption of H2 on a partially reduced gallium oxide surface produces H atoms chemically bonded to coordinatively unsaturated Ga atoms. These metastable gallium hydride species promote C-H bond activation while inhibiting deep dehydrogenation. We found that the surface coverage of gallium hydride determines the catalytic performance. Accordingly, benefiting from proper H2 co-feeding, the alumina-supported, trace additive-modified gallium oxide catalyst GaOx-Ir-K/Al2O3 exhibited high activity and selectivity at high propane concentrations.

Oxophilic Ce single atoms-triggered active sites reverse for superior alkaline hydrogen evolution.

The state-of-the-art alkaline hydrogen evolution catalyst of united ruthenium single atoms and small ruthenium nanoparticles has sparked considerable research interest. However, it remains a serious problem that hydrogen evolution primarily proceeds on the less active ruthenium single atoms instead of the more efficient small ruthenium nanoparticles in the catalyst, hence largely falling short of its full activity potential. Here, we report that by combining highly oxophilic cerium single atoms and fully-exposed ruthenium nanoclusters on a nitrogen functionalized carbon support, the alkaline hydrogen evolution centers are facilely reversed to the more active ruthenium nanoclusters driven by the strong oxophilicity of cerium, which significantly improves the hydrogen evolution activity of the catalyst with its mass activity up to -10.1 A mg-1 at -0.05 V. This finding is expected to shed new light on developing more efficient alkaline hydrogen evolution catalyst by rational regulation of the active centers for hydrogen evolution.

Alkaline-earth ion stabilized sub-nano-platinum tin clusters for propane dehydrogenation.

The strong promotion effects of alkali/alkaline earth metals are frequently reported for heterogeneous catalytic processes such as propane dehydrogenation (PDH), but their functioning principles remain elusive. This paper describes the effect of the addition of calcium (Ca) on reducing the deactivation rate of platinum-tin (Pt-Sn) catalyzed PDH from 0.04 h-1 to 0.0098 h-1 at 873 K under a WHSV of 16.5 h-1 of propane. The Pt-Sn-Ca catalyst shows a high propylene selectivity of >96% with a propylene production rate of 41 molC3H6 (gPt h)-1 and ∼1% activity loss after regeneration. The combination of characterization and DFT simulations reveals that Ca acts as a structural promoter favoring the transition of Snn+ in the parent catalyst to Sn0 during reduction, and the latter is an electron donor that increases the electron density of Pt. This greatly suppresses coke formation from deep dehydrogenation. Moreover, it was found that Ca promotes the formation of a highly reactive and sintering-resistant sub-nano Pt-Sn alloy with a diameter of approximately 0.8 nm. These lead to high activity and selectivity for the Pt-Sn-Ca catalyst for PDH.

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Palladium-Catalyzed Deuteration of Arylketone Oxime Ethers.

We report herein the development of palladium-catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel-Crafts acylation and subsequent deacylative deuteration. Vicinal meta-C-H bond functionalization (including fluorination, arylation, and alkylation) and para-C-H bond deuteration of electro-rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration.

Biocompatibility and osteogenic potential of choline phosphate chitosan-coated biodegradable Zn1Mg.

Zinc alloys have demonstrated considerable potentials as implant materials for biodegradable vascular and orthopedic applications. However, the high initial release of Zn2+ can trigger intense immune responses that impede tissue healing. To address this challenge and enhance the osteogenic capacity of zinc alloys, the surface of Zn1Mg was subjected to CO2 plasma modification (Zn1Mg-PP) followed by grafting with choline phosphate chitosan (Zn1Mg-PP-PCCs). This study aims to investigate the in vitro and in vivo biocompatibility of the surface-modified Zn1Mg. The effect of the surface modification on the inflammatory response and osteogenic repair process was investigated. Compared with unmodified Zn1Mg, the degradation rate of Zn1Mg-PP-PCCs was significantly decreased, avoiding the cytotoxicity triggered by the release of large amounts of Zn2+. Moreover, PCCs significantly enhanced the cell-material adhesion, promoted the proliferation of osteoblasts (MC3T3-E1) and upregulated the expression of key osteogenic factors in vitro. Notably, the in vivo experiments revealed that the surface modification of Zn1Mg suppressed inhibited the expression of inflammatory cytokines, promoting the secretion of anti-inflammatory factors, thereby reducing inflammation and promoting bone tissue repair. Furthermore, histological analysis of tissue sections exhibited strong integration between the material and the bone, along with well-defined new bone formation and reduced osteoclast aggregation on the surface. This was attributed to the improved immune microenvironment by PCCs, which promoted osteogenic differentiation of osteoblasts. These findings highlight that the preparation of PCCs coatings on zinc alloy surfaces effectively inhibited ion release and modulated the immune environment to promote bone tissue repair. STATEMENT OF SIGNIFICANCE: Surface modification of biodegradable Zn alloys facilitates the suppression of intense immune responses caused by excessive ion release concentrations from implants. We modified the surface of Zn1Mg with choline phosphate chitosan (PCCs) and investigated the effects of surface modification on the inflammatory response and osteogenic repair process. In vitro results showed that the PCCs coating effectively reduced the degradation rate of Zn1Mg to avoid cytotoxicity caused by high Zn2+ concentration, favoring the proliferation of osteoblasts. In addition, in vivo results indicated that Zn1Mg-PP-PCCs attenuated inflammation to promote bone repair by modulating the release of inflammation-related factors. The surface-modified Zn1Mg implants demonstrated strong osseointegration, indicating that the PCCs coating effectively modulated the immune microenvironment and promoted bone healing.

Effects of Zr Addition on the Microstructural Evolution, Mechanical Properties, and Corrosion Behavior of Novel Biomedical Ti-Zr-Mo-Mn Alloys.

ß-Type Ti alloys have been widely investigated as implant materials owing to their excellent mechanical properties, corrosion resistance, and biocompatibility. In the present work, the effects of Zr on the microstructure, mechanical properties, and corrosion behaviors of Ti-Zr-Mo-Mn alloys were systematically studied. With the increase of Zr content, the phase composition gradually changed from intragranular-α + ß of (TZ)5:1MM alloy to grain-boundary-α + ß of (TZ)2:1MM alloy and finally transferred to a single ß phase structure of (TZ)1:1MM alloy. The (TZ)1:1MM alloy exhibited a good mechanical combination with a yield strength of 750.8 MPa, an elastic modulus of 61.3 GPa, and a tensile ductility of 14.6%. Moreover, the addition of Zr can effectively stabilize the passivation film and reduce the sensitivity of microgalvanic corrosion in simulated body fluid, leading to enhanced corrosion resistance in the TZMM alloys. X-ray photoelectron spectroscopy analysis together with the ion-sputtering technique revealed that the passivation films formed on TZMM alloys possessed a bilayered structure (outer Ti+Zr mixed-oxide layer and inner Zr-oxide-rich layer), in which the inner Zr oxide layer plays an important role in the corrosion resistance of the TZMM alloys. In vitro biocompatibility evaluations demonstrated that the TZMM alloys can support cell adhesion and proliferation with high biocompatibility comparable to that of CP-Ti, while in vivo biocompatibility evaluations validated the bone osteointegration ability of TZMM alloys after long-term implantation. The above results indicate that novel TZMM alloys are promising candidates for implant material.

Single-cell and bulk RNA sequencing reveals Anoikis related genes to guide prognosis and immunotherapy in osteosarcoma.

Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan-Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.

CircPTP4A2 Promotes Microglia Polarization in Cerebral Ischemic Stroke via miR-20b-5p/YTHDF1/TIMP2 Axis.

Activated microglia play dual roles in ischemic stroke (IS) according to its polarization states. Herein, we investigated the function of circPTP4A2 in regulating microglia polarization in IS. IS models were established by MACO/R and OGD/R treatment. TTC staining was employed to detect cerebral infarct size. Cell vitality was measured using CCK-8 assay. CD16 and CD206 levels were examined using flow cytometry. The interactions between circPTP4A2, miR-20b-5p, and YTHDF1 were analyzed by dual-luciferase reporter gene, RIP, or RNA pull-down assays. circPTP4A2 was upregulated in IS patients. circPTP4A2 knockdown alleviated MCAO/R-induced cerebral injury in mice. circPTP4A2 knockdown promoted microglia M2 polarization after OGD/R. circPTP4A2 promoted YTHDF1 expression by sponging miR-20b-5p. The promoting effect of circPTP4A2 knockdown on microglia M2 polarization was abrogated by miR-20b-5p inhibition. YTHDF1 activated the NF-κB pathway by increasing TIMP2 mRNA stability and expression. circPTP4A2 downregulation promoted microglia M2 polarization to inhibit IS development by regulating the miR-20b-5p/YTHDF1/TIMP2/NF-κB axis.

SLC38A5 aggravates DC-mediated psoriasiform skin inflammation via potentiating lysosomal acidification.

Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1ß from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Supramolecular assemblies with spatio-temporal sequential drug delivery capability treat spinal cord injury via neuroprotection and immunoregulation.

Spinal cord injury (SCI) can result in irreversible motor and sensory deficits. However, up to data, clinical first-line drugs have ambiguous benefits and debilitating side effects, mainly due to the insufficient accumulation, poor physiological barrier penetration, and lack of spatio-temporal controlled release at lesion tissue. Herein, we proposed a supramolecular assemblies composed of hyperbranched polymer-formed core/shell structure through host-guest interactions. Such HPAA-BM@CD-HPG-C assemblies co-loaded with p38 inhibitor (SB203580) and insulin-like growth factor 1(IGF-1) are able to achieve time- and space-programmed sequential delivery benefiting from their cascaded responsiveness. The core-shell disassembly of HPAA-BM@CD-HPG-C occurs in acidic micro-environment around lesion, achieving preferentially the burst release of IGF-1 to protect survival neurons. Subsequently, the HPAA-BM cores containing SB203580 are endocytosed by the recruited macrophages and degraded by intracellular GSH, accelerating the release of SB203580 to promote the conversion from M1 to M2 macrophage. Hence, the successive synergy of neuroprotection and immunoregulation effects contribute to subsequent nerve repair and locomotor recovery as demonstrated in vitro and in vivo studies. Thus, our fabrication provides a strategy that multiple drugs co-delivery in a spatio-temporal selective manner adapting to the disease progression through self-cascaded disintegration, are expected to realize multidimensional precise treatment of SCI.

Tandem propane dehydrogenation and surface oxidation catalysts for selective propylene synthesis.

Direct propane dehydrogenation (PDH) to propylene is a desirable commercial reaction but is highly endothermic and severely limited by thermodynamic equilibrium. Routes that oxidatively remove hydrogen as water have safety and cost challenges. We coupled chemical looping-selective hydrogen (H2) combustion and PDH with multifunctional ferric vanadate-vanadium oxide (FeVO4-VOx) redox catalysts. Well-dispersed VOx supported on aluminum oxide (Al2O3) provides dehydrogenation sites, and adjacent nanoscale FeVO4 acts as an oxygen carrier for subsequent H2 combustion. We achieved an integral performance of 81.3% propylene selectivity at 42.7% propane conversion at 550°C for 200 chemical looping cycles for the reoxidization of FeVO4. Based on catalytic experiments, spectroscopic characterization, and theory calculations, we propose a hydrogen spillover-mediated coupling mechanism. The hydrogen species generated at the VOx sites migrated to adjacent FeVO4 for combustion, which shifted PDH toward propylene. This mechanism is favored by the proximity between the dehydrogenation and combustion sites.

Characteristics of glucose and lipid metabolism and the interaction between gut microbiota and colonic mucosal immunity in pigs during cold exposure.

BACKGROUND: Cold regions have long autumn and winter seasons and low ambient temperatures. When pigs are unable to adjust to the cold, oxidative damage and inflammation may develop. However, the differences between cold and non-cold adaptation regarding glucose and lipid metabolism, gut microbiota and colonic mucosal immunological features in pigs are unknown. This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation. Moreover, the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs. RESULTS: Cold and non-cold-adapted models were established by Min and Yorkshire pigs. Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models (Yorkshire pigs), decreasing plasma glucose concentrations. In this case, cold exposure enhanced the ATGL and CPT-1α expression to promote liver lipolysis and fatty acid oxidation. Meanwhile, the two probiotics (Collinsella and Bifidobacterium) depletion and the enrichment of two pathogens (Sutterella and Escherichia-Shigella) in colonic microbiota are not conducive to colonic mucosal immunity. However, glucagon-mediated hepatic glycogenolysis in cold-adapted pig models (Min pigs) maintained the stability of glucose homeostasis during cold exposure. It contributed to the gut microbiota (including the enrichment of the Rikenellaceae RC9 gut group, [Eubacterium] coprostanoligenes group and WCHB1-41) that favored cold-adapted metabolism. CONCLUSIONS: The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa. During non-cold adaptation, cold-induced glucose overconsumption promotes thermogenesis through lipolysis, but interferes with the gut microbiome and colonic mucosal immunity. Furthermore, glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.

Circular RNA hsa_circ_0064559 affects tumor cell growth and progression of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally. It is essential to identify new CRC-associated therapeutic targets and diagnostic biomarkers. Previous studies have demonstrated that a series of circular RNAs (circRNAs) play a crucial role in CRC pathogenesis. This study assessed the potential of hsa_circ_0064559 in tumor cell growth and progression of CRC. METHODS: Six pairs of matched CRC and normal colorectal tissue samples were sequenced using the Affymetrix Clariom D array. Using RNA interference, the expression of thirteen circRNAs was knocked down in CRC cells. The proliferation of CRC cell lines (RKO and SW620 cells) was detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Apoptosis and cell cycle were determined by flow-cytometric analysis. An in vivo study uses nude mice to establish a CRC mouse model. The differentially expressed genes were analyzed using Affymetrix primeview human GeneChip array and verified by polymerase chain reaction. RESULTS: Affymetrix Clariom D array analysis revealed that thirteen circRNAs were upregulated in CRC. The proliferation of CRC cell lines was decreased, while the proportion of apoptotic and G1 phase cells was higher after hsa_circ_0064559 knockdown. In vivo xenograft nude mice model revealed that the volume and weight of the tumor were reduced by hsa_circ_0064559 knockdown. In Affymetrix primeview human GeneChip array, we found six upregulated genes (STAT1, ATF2, TNFRSF10B, TGFBR2, BAX, and SQSTM1) and two downregulated genes (SLC4A7 and CD274) related to apoptosis and proliferation of colorectal cancer cells after hsa_circ_0064559 knockdown. CONCLUSIONS: The hsa_circ_0064559 knockdown could inhibit the proliferation, promote apoptosis in CRC cell lines in vitro, and inhibit the development of CRC tumors in vivo. The mechanism may be related to activating a wide range of signaling pathways. The hsa_circ_0064559 may be a potential biomarker for early diagnosis or prognosis of CRC and a novel drug target for CRC therapy.

Transcription factor TOX maintains the expression of Mst1 in controlling the early mouse NK cell development.

Rationale: TOX is a DNA-binding factor required for the development of multiple immune cells and the formation of lymph nodes. However, the temporal regulation mode of TOX on NK cell development and function needs to be further explored. Methods: To investigate the role of TOX in NK cells at distinct developmental phases, we deleted TOX at the hematopoietic stem cell stage (Vav-Cre), NK cell precursor (CD122-Cre) stage and late NK cell developmental stage (Ncr1-Cre), respectively. Flow cytometry was used to detect the development and functional changes of NK cell when deletion of TOX. RNA-seq was used to assess the differences in transcriptional expression profile of WT and TOX-deficient NK cells. Published Chip-seq data was exploited to search for the proteins directly interact with TOX in NK cells. Results: The deficiency of TOX at the hematopoietic stem cell stage severely retarded NK cell development. To a less extent, TOX also played an essential role in the physiological process of NKp cells differentiation into mature NK cells. Furthermore, the deletion of TOX at NKp stage severely impaired the immune surveillance function of NK cells, accompanied by down-regulation of IFN-γ and CD107a expression. However, TOX is dispensable for mature NK cell development and function. Mechanistically, by combining RNA-seq data with published TOX ChIP-seq data, we found that the inactivation of TOX at NKp stage directly repressed the expression of Mst1, an important intermediate kinase in Hippo signaling pathway. Mst1 deficient at NKp stage gained the similar phenotype with Toxfl/flCD122Cre mice. Conclusion: In our study, we conclude that TOX coordinates the early mouse NK cell development at NKp stage by maintaining the expression of Mst1. Moreover, we clarify the different dependence of the transcription factor TOX in NK cells biology.