Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome.

NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.

A mouse model to distinguish NLRP6-mediated inflammasome-dependent and -independent functions.

The NOD-like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome-dependent and inflammasome-independent manners. However, there is no tool to distinguish the contribution of individual NLRP6-mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for ASC recruitment and inflammasome activation, but are not important for the RNA binding and PYD-independent NLRP6 oligomerization. We further generated the Nlrp6R39E&W50E mutant mice, which showed reduced inflammasome activation in either steady state intestine or during viral infection. However, the type I IFN production in cells or intestine tissue from Nlrp6R39E&W50E mutant mice remain normal. Interestingly, NLRP6-mediated inflammasome activation or the IFN-I production seems to play distinct roles in the defense responses against different types of RNA viruses. Our work generated a useful tool to study the inflammasome-dependent role of NLRP6 in vivo, which might help to understand the complexity of multiple pathways mediated by NLRP6 in response to the complicated and dynamic environmental cues in the intestine.

[Treatment of chronic prostatitis with Xiongji Formula based on the concept of "brain-heart-kidney-essence chamber" axis of medication].

Chronic prostatitis is a process of kidney deficiency and blood stasis mixed with various pathological factors involving the essence chamber, which is manifested as kidney deficiency and blood stasis. Based on the concept of the "brain-heart-kidney-essence chamber" axis of medication, Xiongji Formula is applied to the treatment of chronic prostatitis, due to its "simultaneous holistic and local action" and effects of tonifying the kidney yang and assisting the systemic yang, acting on the brain, heart and kidney as a whole, and meanwhile activating blood circulation, eliminating blood stasis and restoring the function of the essence chamber. This paper discusses the etiology and pathogenesis of chronic prostatitis with kidney deficiency and blood stasis in Chinese medicine, expounds the significance of "brain-heart-kidney-essence chamber" axis of medication, and explores the specific value and clinical application of Xiongji Formula.

Orderly Assembled, Self-Powered FRET Flares for MicroRNA Imaging in Live Cells.

Signal amplification provides unparalleled opportunities for visualizing low-abundance targets in living cells. However, self-powered signal amplification has not been achieved because of the lack of "fuel" in living cells. Thus, the aim of this work was to develop an integrated amplification platform for the detection of intracellular miRNA by itself. This system, termed self-powered FRET flares (SPF), was first established by self-assembly to form a DNA nanostructure, and then the FRET flares and fuel DNA as the driving force were precisely and orderly loaded on it, which was able to power target recycle and realize signal amplification without any auxiliary additives under the trigger of intracellular miRNA-21. In addition, it employed AS1411 aptamer to target specific cancer cells and facilitated cell internalization of assembly DNA nanostructures. As a proof of concept, we demonstrated that SPF enabled rapid response to miRNA-21 and improvement of the detection sensitivity compared to previously proposed FRET flares without amplification. This strategy is promising for advancing integrated and self-powered nanomachines to execute diverse tasks, facilitating their biological and medical application.

Lmod3 promotes myoblast differentiation and proliferation via the AKT and ERK pathways.

Mutations in the Lmod3 gene have been identified as a genetic cause of nemaline myopathy. However, the mechanism underlying this disease and the function of Lmod3 remain largely unknown. In this study, we found that Lmod3 knockdown in C2C12 cells impaired myoblast differentiation, whereas enforced Lmod3 expression enhanced such differentiation. We also discovered that myoblast proliferation was promoted by Lmod3 overexpression but impeded by its knockdown. Additionally, knockdown of Lmod3 led to apoptosis in myoblasts. Concurrently, forced Lmod3 expression in C2C12 cells contributed to activation of the AKT and ERK pathways during myoblast differentiation and proliferation, respectively. Conversely, knockdown of Lmod3 in C2C12 cells produced the opposite results. Furthermore, administration of IGF-1, a booster of both AKT and ERK pathways, partially rescued the inhibitory effect of Lmod3 knockdown on both differentiation and proliferation of C2C12 cells. These results suggest that Lmod3 promotes differentiation and proliferation of myoblasts through the AKT and ERK pathways, respectively.

Paediatric acute kidney injury induced by vancomycin monotherapy versus combined vancomycin and meropenem.

WHAT IS KNOWN AND OBJECTIVE: Increasing reports of the combined use of vancomycin (VAN) and piperacillin/tazobactam leading to higher nephrotoxicity have led to carbapenems being recommended as an alternative option to combine with VAN when nephrotoxicity is a major concern. However, whether carbapenems also increase the nephrotoxicity of VAN is unclear. This study aimed to determine whether meropenem is a suitable drug to combine with VAN based on whether meropenem enhances the nephrotoxicity of VAN. METHODS: This retrospective cohort study enrolled hospitalized children ranging in age from 1 month to 18 years at two tertiary hospitals from 1 February 2017 to 1 February 2018. Patients treated with either VAN or combined VAN and meropenem (VM) for more than 48 hours were eligible for inclusion. Those with underlying kidney diseases or abnormal age-adjusted baseline serum creatinine (SCr) at admission were excluded. Propensity score matching (PSM) was applied to the patients to balance factors associated with acute kidney injury (AKI). In addition, VAN trough concentrations were also compared. AKI was defined as an increase in SCr by ≥50% from baseline or by ≥0.3 mg/dL sustained over at least two consecutive measurements ranging from the time of initiation until 72 hours after the completion of VAN therapy. RESULTS AND DISCUSSION: The eligibility criteria were met by 183 of 243 identified patients: 101 patients received VAN alone and 82 received VM. PSM resulted in 154 hospitalized children being included (77 patients in each group). The incidence of AKI was 10.7% (8/77) in both of the compared groups, while the VAN trough concentration was significantly higher in the VM group (9.0 mg/L) than in the VAN group (6.6 mg/L, P = 0.007) after controlling for confounders. WHAT IS NEW AND CONCLUSION: Despite the elevated VAN trough concentration, meropenem did not increase the nephrotoxicity of VAN and might therefore be an acceptable antibiotic to combine with VAN when necessary.

Effect of kaolin on floc properties for reactive orange removal in continuous coagulation process.

Magnesium hydroxide was used as a coagulant for treating reactive orange wastewater in a real continuous process. Effects of kaolin on coagulation performance and floc properties were investigated with controlled experiments through floc size distribution, zeta potential, scanning electron microscopy and Fourier transform infrared spectroscopy. Kaolin had significant influence on magnesium hydroxide-reactive orange floc formation and growth. The results showed that average floc size reached 16.31, 12.88 and 20.50 µm, respectively, in the rapid mixer, flocculation basin and sedimentation tank when kaolin concentration was 10 mg/L and reactive orange initial concentration was 0.25 g/L. The floc size tended to increase with the increase of kaolin suspension to 10 mg/L. All of the flocs under investigation showed that floc breakage led to decreased average floc size and remained stable in the flocculation basin. Reactive orange and kaolin could be removed effectively in the continuous coagulation process. Reactive orange was adsorbed in the surface of magnesium hydroxide through charge neutralization and adsorption.

Analysis of friction between articular cartilage and polyvinyl alcohol hydrogel artificial cartilage.

Many biomaterials are being used to repair damaged articular cartilage. In particular, poly vinyl alcohol hydrogel has similar mechanical properties to natural cartilage under compressive and shearing loading. Here, three-factor and two-level friction experiments and long-term tests were conducted to better evaluate its tribological properties. The friction coefficient between articular cartilage and the poly vinyl alcohol hydrogel depended primarily on the three factors of load, speed, and lubrication. When the speed increased from 10 to 20 mm/s under a load of 10 N, the friction coefficient increased from 0.12 to 0.147. When the lubricant was changed from Ringer's solution to a hyaluronic acid solution, the friction coefficient decreased to 0.084 with loads as high as 22 N. The poly vinyl alcohol hydrogel was severely damaged and lost its top surface layers, which were transferred to the articular cartilage surface. Wear was observed in the surface morphologies, which indicated the occurrence of surface adhesion of bovine cartilage. Surface fatigue and adhesive wear was the dominant wear mechanism.

Impact of Graphitization Degree on the Electrochemical and Thermal Properties of Coal.

Coal-based cryptocrystalline graphite is an intermediate phase formed during the transformation of highly metamorphic anthracite into crystalline graphite. In order to explore the relationship between the graphitization degree of coal-based cryptocrystalline graphite and its physical properties from macromolecular structure to provide a theoretical basis for industrial application, samples were tested by X-ray diffraction, electrochemistry, and thermal conductivity and compared with standard graphite (SG) and artificial thermal simulation graphitized samples. The results show that with the increase of graphitization degree and the growth of microcrystalline structure, the electrical impedance of cryptocrystalline graphite decreases, the conductivity increases, the specific capacity of initial discharge increases, and the thermal conductivity increases, which gradually approach the electrical and thermal properties of crystalline graphite. The linear equations between impedance and La and Lc are y = -0.42x + 70.44 and y = -1.87x + 70.62, and the correlation coefficients are 0.93 and 0.88. The linear equations between thermal conductivity and the horizontal extension length (La) and vertical stacking thickness (Lc) are y = 0.09x + 1.36 and y = 0.4x + 0.76, the correlation coefficients are 0.82 and 0.84., and the reduction of microcrystalline parameters d002 and the increase of La and Lc lead to a direct improvement of physical properties. Artificial thermal simulation samples also show the same regularity, but their physical properties are lower than those of natural evolution samples. Short-term high-temperature simulation is different from long-term magma heat and pressure, and the growth of graphite microcrystals is more complete under long-term geological conditions, resulting in better physical properties.

Hsa_circ_0000092 up-regulates IL24 by SMC1A to induce macrophages M2 polarization.

Introduction: Hepatocellular carcinoma (HCC) as the malignant cancers with high morbidity. The EMT of HCC has closely linked to the metastasis and recurrence. Moreover, tumor-associated macrophages (TAMs) can interact with HCC cells in the immune microenvironment; the M2 polarization of TAMs enhance the HCC cells EMT. The mechanism between HCC cells and TAMs is still unclear and our study was aimed to uncover it. Methods: We performed RT-qPCR and western to detach the RNA and protein expression. The relationship among has_circ_0000092, U2AF2, SMC1A and IL24 were revealed through mechanism experiments. Rescue assays were implemented to determine how circ_0000092 modulates M2 polarization of TAMs. Results: As detected by RT-qPCR, has_circ_0000092 was with high expression in HCC cells and could recruit U2AF2 to promote transcription of SMC1A. Moreover, circ_0000092 could control macrophage M2 polarization via promoting IL24 expression in HCC cells. Conclusion: To conclude, hsa_circ_0000092 can up-regulates IL24 by SMC1A to induce macrophages M2 polarization.

Acute murine cytomegalovirus infection boosts cell-type specific response and lipid metabolism changes in the liver of infant mice.

Introduction: Human cytomegalovirus (HCMV) infection in infants can lead to severe diseases, including neonatal hepatitis. The single-cell dimensional changes in immune cells after the initial CMV infection remain elusive, as do the effects of CMV infection on hepatic lipid metabolism. Methods: We employed single-cell RNA-sequencing to investigate the changes in liver cell types and immune responses in infant mice following murine CMV (MCMV) infection. Additionally, we examined alterations in protein expression profiles related to lipid metabolism in hepatocytes and the role of the key transcription factor PPAR-γ in hepatocytes during CMV infection. Results: Our study revealed that MCMV infects most liver cell types in infant mice, leading to an increase in the proportion of proliferating CD8 effector T cells and a subset of Nos2+ monocytes, potentially playing an essential role in early anti-viral responses. Furthermore, MCMV infection resulted in altered protein expression of lipid metabolism in hepatocytes. Knocking down the transcription factor PPAR-γ in hepatocytes effectively inhibited CMV infection. Discussion: Our findings underscore the immune system's response to early-stage MCMV infection and the subsequent impact on hepatic lipid metabolism in infant mice. This research provides new insights into the mechanisms of CMV infection and could pave the way for novel therapeutic strategies.

Experimental Investigation on the Impact of Coal Fines Migration on Pores and Permeability of Cataclastic Coal.

During the production process of coalbed methane, the generation and migration of coal fines can obstruct fractures in coal reservoirs and reduce their permeability. In order to investigate the effects of coal fines migration on the porosity and permeability of coal reservoirs, we conducted core water flooding experiments, low-field nuclear magnetic resonance (NMR), and low-temperature N2 adsorption experiments to study the variations in porosity and permeability of cataclastic coal during coal fines migration and the impact of coal fines migration on porosity and permeability. The experimental results reveal that the initial porosity ratio of cataclastic coal exhibits the characteristics of micropore > macropore > transitional pore > mesopore, with the pore types being predominantly fissured. The porosity of pores larger than 1000 nm and those larger than 10,000 nm exhibit consistent trends before and after water flooding, indicating that the blockage or unblocking of pores with radius larger than 10,000 nm by coal fines can also cause blockage or unblocking of some interconnected macropore. The early stage of flooding is the main period for coal fines migration and production in cataclastic coal, during which the mass concentration of coal fines production is higher and some macropores and fractures become blocked, resulting in a larger decrease in porosity. The higher the initial permeability of cataclastic coal samples with a larger end-face fracture density, the more similar the variations in porosity and permeability of pores larger than 10,000 nm during the flooding experiment, indicating that coal fines mainly block interconnected pores and fractures with radius larger than 10,000 nm through migration, thereby reducing permeability. This study provides a theoretical basis for the efficient production of coalbed methane.

Effects of Functional Groups in Coal with Different Vitrinite/Inertinite Ratios on Pyrolysis Products.

Maceral composition is one of the key factors affecting the liquefaction and gasification of coal, which has attracted extensive attention of researchers working on coal chemical industry. To elucidate the impact of vitrinite and inertinite in coal on pyrolysis products, vitrinite and inertinite were extracted from a single coal sample and mixed to create six samples with varying vitrinite/inertinite ratios. The samples were subjected to thermogravimetry coupled online with mass spectrometry (TG-MS) experiments, and the Fourier transform infrared spectrometry (FITR) experiment was used to determine the macromolecular structures before and after the TG-MS experiments. The results show that the maximum mass loss rate is proportional to the vitrinite content and inversely proportional to the inertinite content, and increased vitrinite content accelerates the pyrolysis process and shifts the pyrolysis peak to low temperatures. Based on FTIR experiments, the sample's CH2/CH3 content, representing the length of aliphatic side chains, decreases significantly after pyrolysis, and the greater the loss of CH2/CH3, the greater the intensity of organic molecule production, indicating that aliphatic side chains are likely to yield organic molecule products. The aromatic degree (I) of samples rises sharply and steadily with increasing inertinite content. After high-temperature pyrolysis, the polycondensation degree of aromatic rings (DOC) and relative abundance of aromatic and aliphatic hydrogen (Har/Hal) within the sample increased significantly, indicating the thermal degradation rate of aromatic hydrogen content is much lower than that of aliphatic hydrogen. When the pyrolysis temperature is lower than 400 °C, the higher the inertinite content, the easier it is to produce CO2, whereas an increase in vitrinite leads to an increase in CO production. At this stage, the "-C-O-" functional group is pyrolyzed to produce CO and CO2. When the temperature exceeds 400 °C, the CO2 output intensity of vitrinite-rich samples is much higher than that of inertinite-rich samples, while the CO output intensity of vitrinite-rich samples is lower, and the higher the vitrinite content, the higher the peak temperature of CO gas production of samples, indicating that when the temperature exceeds 400 °C, the increase of vitrinite inhibits CO production and promotes CO2 production. At this stage, the reduction of each sample's "-C-O-" functional group after pyrolysis is positively correlated with the maximum CO gas production intensity, and the reduction of each sample's "-C=O" functional group after pyrolysis is positively correlated with the maximum CO2 gas production intensity. As a result, the "-C-O-" functional group is more likely to produce CO, whereas the "-C=O" functional group is more likely to be pyrolyzed to CO2. Hydrogen is primarily produced during the polycondensation and aromatization processes, and its production is proportional to the dynamic DOC values after pyrolysis. The higher the I value after pyrolysis, the lower the maximum gas production peak intensity of CH4 and C2H6, which indicates that increasing the aromatic proportion is detrimental to CH4 and C2H6 production. This work is expected to provide theoretical support of the liquefaction and gasification of coal with different vitrinite/inertinite ratios.

Efficacy of acupuncture for psychogenic erectile dysfunction: a randomized, sham-controlled trial.

BACKGROUND: Psychogenic erectile dysfunction (pED) is a common sexual dysfunction often accompanied by psychosomatic factors. Its treatment includes oral medications, psychotherapy, and behavioral therapy. Acupuncture's effect on erectile function in pED patients remains to be investigated. This randomized study evaluated the effects of acupuncture and sham acupuncture in pED patients. Altogether, 66 men with pED were randomized to the acupuncture (n = 33) or sham acupuncture group (n = 33). Both groups have a 6-week treatment with 18 sessions. Primary outcome was the International Index of Erectile Function-5 (IIEF-5) at 6 weeks. Secondary outcomes were IIEF-5 (weeks 2, 4, and 10), erection hardness score (EHS), sexual encounter profile-2 (SEP-2), SEP-3, self-rating anxiety scale (SAS), and self-rating depression scale (SDS). RESULTS: Among the 66 participants, 64 completed the outcome measurements at week 10. Both acupuncture and sham acupuncture groups had improved IIEF-5 and EHS and decreased SAS and SDS post-treatment (p < 0.05). The acupuncture group had significantly better improvement in IIEF-5, EHS, and SEP-3 and significantly reduced SAS and SDS than the sham acupuncture group (p < 0.05). The improvement in SEP-2 post-treatment was not significantly different between the two groups (p > 0.05). There were no serious adverse events. CONCLUSIONS: The 6-week acupuncture treatment significantly improved the erectile capacity and psychosomatic status of pED patients. TRIAL REGISTRATION: ChiCTR2200064345 (Chinese Clinical Trial Registry) ( https://www.chictr.org.cn/showproj.html?proj=174873 ).

RéSUMé: CONTEXTE: La dysfonction érectile psychogène (DEp) est une dysfonction sexuelle courante, souvent accompagnée de facteurs psychosomatiques. Son traitement comprend des médicaments par voie orale, une psychothérapie, et une thérapie comportementale. L'effet de l'acupuncture sur la fonction érectile chez les patients atteints de DEp reste à étudier. Cette étude randomisée a évalué les effets de l'acupuncture et de l'acupuncture simulée chez les patients atteints de DEp. Au total, 66 hommes atteints de DEp ont été répartis par randomisation dans le groupe d'acupuncture (n = 33) ou d'acupuncture simulée (n = 33). Les deux groupes ont eu un traitement de 6 semaines avec 18 séances. Le critère de jugement principal était l'indice international de la fonction érectile-5 (IIEF-5) à six semaines. Les critères de jugement secondaires étaient l'IIEF-5 (semaines 2, 4 et 10), le score dedureté de l'érection (EHS), le profil de rencontre sexuelle-2 (SEP-2), le SEP-3, l'échelle d'auto-évaluation de l'anxiété (SAS) et l'échelle d'auto-évaluation de la dépression (SDS). RéSULTATS: Parmi les 66 participants, 64 ont complété les mesures souhaitées à la semaine 10. Les groupes d'acupuncture et d'acupuncture simulée présentaient une amélioration de l'IIEF-5 et de l'EHS et une diminution du SAS et du SDS après le traitement (p < 0,05). Le groupe d'acupuncture a eu une amélioration significativement meilleure de l'IIEF-5, de l'EHS et du SEP-3 et une réduction significative de la SAS et de la SDS par rapport au groupe d'acupuncture simulée (p < 0,05). L'amélioration post-traitement du SEP-2 n'était pas significativement différente entre les deux groupes (p > 0,05). Il n'y a pas eu d'effets indésirables graves. CONCLUSIONS: Le traitement par acupuncture de six semaines a significativement amélioré la capacité érectile et l'état psychosomatique des patients atteints de dysfonction érectile psychogène (DEp). NUMéRO D'ENREGISTREMENT DE L'ESSAI: ChiCTR2200064345 (Registre chinois des essais cliniques) ( https://www.chictr.org.cn/showproj.html?proj=174873 ) Date d'inscription : 3 octobre 2022. MOTS-CLéS: Acupuncture; psychogène; Dysfonction érectile; Acupuncture simulée; Dysfonction sexuelle.

Nucleic DHX9 cooperates with STAT1 to transcribe interferon-stimulated genes.

RNA helicase DHX9 has been extensively characterized as a transcriptional regulator, which is consistent with its mostly nucleic localization. It is also involved in recognizing RNA viruses in the cytoplasm. However, there is no in vivo data to support the antiviral role of DHX9; meanwhile, as a nuclear protein, if and how nucleic DHX9 promotes antiviral immunity remains largely unknown. Here, we generated myeloid-specific and hepatocyte-specific DHX9 knockout mice and confirmed that DHX9 is crucial for host resistance to RNA virus infections in vivo. By additional knockout MAVS or STAT1 in DHX9-deficient mice, we demonstrated that nucleic DHX9 plays a positive role in regulating interferon-stimulated gene (ISG) expression downstream of type I interferon. Mechanistically, upon interferon stimulation, DHX9 is directly bound to STAT1 and recruits Pol II to the ISG promoter region to participate in STAT1-mediated transcription of ISGs. Collectively, these findings uncover an important role for nucleic DHX9 in antiviral immunity.

Floc formation and growth mechanism during magnesium hydroxide and polyacrylamide coagulation process for reactive orange removal.

Magnesium hydroxide is commonly used as a coagulant for treating reactive dyes wastewater. However, the flocs are relatively small and coagulation process needs longer sedimentation time. Large flocs and short operation time are important for good coagulation performance. Coagulation floc formation and growth processes using magnesium hydroxide and polyacrylamide (PAM) dual-coagulant were investigated with controlled experiments through flocculation index (FI), floc size distribution, zeta potential, scanning electron microscopy and Fourier transform infrared spectroscopy. The final average floc size reached 58.5 and 4.96 µm with and absence of PAM addition during slow mixing periods. PAM feeding time and magnesium hydroxide formation time can affect the floc formation and growth processes. The results showed that floc formed rapidly during magnesium hydroxide generation within 90 s and flocs aggregated together by PAM bridging function. Reactive orange removal efficiency reached 99.3% with rapid mixing 250 rpm at 90 s during 100 mg/L magnesium ion addition, then adding 6 mg/L PAM at the beginning of slow mixing period in dual-coagulant system.

Analysis of the Global Disease Burden of Down Syndrome Using YLDs, YLLs, and DALYs Based on the Global Burden of Disease 2019 Data.

Purpose: This study aimed to determine Down syndrome (DS) burden using years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life years (DALYs), and the trends in these parameters. Methods: We obtained the annual YLDs, YLLs, DALYs, and age-standardized rates (ASRs) of DS from 2010 to 2019 using the Global Health Data Exchange tool. The estimated annual percentage changes (EAPCs) in ASR were used to quantify and evaluate DS burden trends. Gaussian-process regression and Pearson's correlation coefficient were used to assess the relationship between DS burden and socio-demographic index (SDI). Results: Global DALYs decreased by 2.68% from 2010 to 2019 but the ASR was stable, which was mostly explained by the stability in the ASR for YLLs. The ASR of YLDs showed an increasing trend (EAPC = 1.07, 95% CI = 0.45 to 1.69). There was notable regional imbalance, with most of the DALYs or ASRs in areas with relatively low SDI. The DALY rates of DS were mostly from the YLLs of children younger than 1 year. Lower SDI areas tended to have higher DS burdens (ρ = -0.3, p < 0.001). Conclusion: This systematic analysis of the global disease burden of DS from 2010 to 2019 revealed that although the global DS DALY and YLL rate is stable, the YLD rate is increasing. And the DS burden varies significantly differences among regions or countries. The present results suggest that future strategies should focus on DS-related deaths in children younger than 1 year and the DS burden in low-SDI regions or countries, since this may be effective in further reducing DS burden.

m6A modifications regulate intestinal immunity and rotavirus infection.

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (Mettl3ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as one of the primary m6A targets during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3ΔIEC mice. Moreover, the global m6A modification on mRNA transcripts declined with age in mice, with a significant drop from 2 weeks to 3 weeks post birth, which likely has broad implications for the development of intestinal immune system against enteric viruses early in life. Collectively, we demonstrated a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.

SNHG17 Serves as an Oncogenic lncRNA by Regulating the miR-361-3p/STC2 Axis in Rectal Cancer.

Long noncoding RNA (lncRNA) have been reported to be crucial regulators for carcinogenesis, including rectal cancer. This work aimed to explore the roles and associated mechanisms of small nucleolar RNA host gene 17 (SNHG17) in rectal cancer. A quantitative real-time polymerase chain reaction was performed to measure the expression level of SNHG17 in rectal cancer tissues and cells. Cell counting kit-8 (CCK-8) assay and flow cytometry assay were conducted to measure the biological roles of SNHG17 in rectal cancer. In addition, luciferase activity reporter assay, RNA immunoprecipitation (RIP) assay, and rescue experiments were conducted to explore the mechanisms of SNHG17 in rectal cancer. The upregulation status of SNHG17 was identified in rectal cancer tissues and cells. Functionally, knockdown the expression of SNHG17 inhibits rectal cancer cell proliferation via stimulating cell apoptosis. In vivo assay showed that the knockdown of SNHG17 inhibits tumor growth. Furthermore, we showed that microRNA-361-3p (miR-361-3p) has decreased expression in tumor tissues and cells, and SNHG17 functions as a sponge for miR-361-3p. The upregulation status of stanniocalcin 2 (STC2) was also found in rectal cancer, and the knockdown of STC2 hinders cancer progression. In conclusion, lncRNA SNHG17 functions as an oncogenic lncRNA in rectal cancer by regulating the miR-361-3p/STC2 axis.

lncRNA MAGI2-AS3 Exerts Antioncogenic Roles in Hepatocellular Carcinoma via Regulating the miR-519c-3p/TXNIP Axis.

INTRODUCTION: Our work was aimed to explore the mechanisms of MAGI2 antisense RNA 3 (MAGI2-AS3) in regulating hepatocellular carcinoma (HCC) carcinogenesis. METHODS: MAGI2-AS3, microRNA-519c-3p (miR-519c-3p), and thioredoxin interacting protein (TXNIP) levels in HCC were detected by the RT-qPCR method. Cell proliferation and apoptosis rate were measured using Cell Counting Kit-8 assay and flow cytometry assay. Relationship between MAGI2-AS3, TXNIP, and miR-519c-3p were analyzed via luciferase activity assay, RNA pull-down assay, and RNA immunoprecipitation assay. Mouse xenograft models of HCC were conducted to explore the roles of MAGI2-AS3 in vivo. RESULTS: MAGI2-AS3 levels were elevated, and miR-519c-3p decreased in HCC. MAGI2-AS3 overexpression inhibits while its knockdown stimulates HCC cell growth through miR-519c-3p. Moreover, miR-519c-3p overexpression stimulates HCC cell growth. MAGI2-AS3 serves as competing endogenous RNA (ceRNA) of miR-519c-3p to regulate TXNIP in HCC. And, TXNIP upregulation weakened the influence of MAGI2-AS3 knockdown on HCC cell behaviors. Additionally, MAGI2-AS3 overexpression suppressed HCC tumor growth in vivo. CONCLUSION: MAGI2-AS3 inhibits HCC tumorigenesis through miR-519c-3p/TXNIP axis in vitro and in vivo, indicating MAGI2-AS3 plays a crucial role in HCC development.