A Study on the Growth and Physiological Toxicity Effects of the Combined Exposure of Microplastics and Cadmium on the Vicia faba L. Seedlings.

To investigate the toxicological effects of polystyrene microplastics (PS-MPs), cadmium (Cd), and their combined contamination on the growth and physiological responses of V. faba seedlings, this experiment employed a hydroponic method. The Hoagland nutrient solution served as the control, changes in root growth, physiological and biochemical indicators of V. faba seedlings under different concentrations of PS-MPs (10, 100 mg/L) alone and combined with 0.5 mg/L Cd. The results demonstrated that the root biomass, root vitality, generation rate of superoxide radicals (O2·-), malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity increased with increasing concentration under the influence of PS-MPs alone, while the soluble sugar content and peroxidase (POD) activity decreased. In the combined treatment with Cd, the trends of these indicators are generally similar to the PS-MPs alone treatment group. However, root vitality and SOD activity showed an inverse relationship with the concentration of PS-MPs. Furthermore, laser confocal and electron microscopy scanning revealed that the green fluorescent polystyrene microspheres entered the root tips of the V. faba and underwent agglomeration in the treatment group with a low concentration of PS-MPs alone and a high concentration of composite PS-MPs with Cd.

The effects of daily fasting hours on shaping gut microbiota in mice.

BACKGROUND: It has recently been reported that intermittent fasting shapes the gut microbiota to benefit health, but this effect may be influenced to the exact fasting protocols. The purpose of this study was to assess the effects of different daily fasting hours on shaping the gut microbiota in mice. Healthy C57BL/6 J male mice were subjected to 12, 16 or 20 h fasting per day for 1 month, and then fed ad libitum for an extended month. Gut microbiota was analyzed by 16S rRNA gene-based sequencing and food intake was recorded as well. RESULTS: We found that cumulative food intake was not changed in the group with 12 h daily fasting, but significantly decreased in the 16 and 20 h fasting groups. The composition of gut microbiota was altered by all these types of intermittent fasting. At genus level, 16 h fasting led to increased level of Akkermansia and decreased level of Alistipes, but these effects disappeared after the cessation of fasting. No taxonomic differences were identified in the other two groups. CONCLUSIONS: These data indicated that intermittent fasting shapes gut microbiota in healthy mice, and the length of daily fasting interval may influence the outcome of intermittent fasting.

The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Hepatitis E virus (HEV), as an emerging zoonotic pathogen, is a leading cause of acute viral hepatitis worldwide, with a high risk of developing chronic infection in immunocompromised patients. However, the global epidemiology of HEV infection has not been comprehensively assessed. This study aims to map the global prevalence and identify the risk factors of HEV infection by performing a systematic review and meta-analysis. METHODS: A systematic searching of articles published in Medline, Embase, Web of science, Cochrane and Google scholar databases till July 2019 was conducted to identify studies with HEV prevalence data. Pooled prevalence among different countries and continents was estimated. HEV IgG seroprevalence of subgroups was compared and risk factors for HEV infection were evaluated using odd ratios (OR). RESULTS: We identified 419 related studies which comprised of 1 519 872 individuals. A total of 1 099 717 participants pooled from 287 studies of general population estimated a global anti-HEV IgG seroprevalence of 12.47% (95% CI 10.42-14.67; I2  = 100%). Notably, the use of ELISA kits from different manufacturers has a substantial impact on the global estimation of anti-HEV IgG seroprevalence. The pooled estimate of anti-HEV IgM seroprevalence based on 98 studies is 1.47% (95% CI 1.14-1.85; I2  = 99%). The overall estimate of HEV viral RNA-positive rate in general population is 0.20% (95% CI 0.15-0.25; I2  = 98%). Consumption of raw meat (P = .0001), exposure to soil (P < .0001), blood transfusion (P = .0138), travelling to endemic areas (P = .0244), contacting with dogs (P = .0416), living in rural areas (P = .0349) and receiving education less than elementary school (P < .0001) were identified as risk factors for anti-HEV IgG positivity. CONCLUSIONS: Globally, approximately 939 million corresponding to 1 in 8 individuals have ever experienced HEV infection. 15-110 million individuals have recent or ongoing HEV infection. Our study highlights the substantial burden of HEV infection and calls for increasing routine screening and preventive measures.

Roll angle measurement system based on differential plane mirror interferometer.

A precision roll angle measurement system based on differential plane mirror interferometer (DPMI) is proposed and the measurement principle has been analyzed theoretically in detail. This system uses DPMI with wedgy angle prism and wedgy angle reflector to produce diagonal symmetry of the two frequency beams. The residual of nanopositioning stage and roll angle system is less than 1 µrad, which has verified the correctness of the measuring principle. As result, the stability of the roll angle measurement system is satisfactory, and the average deviation of measurement experiments is less than 5 µrad.

Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication.

Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.

Coupling efficiency model for spectral beam combining of high-power fiber lasers calculated from spectrum.

We utilize the spectral broadening of Yb-doped fiber lasers in the spectral beam combining scheme to develop an analytical model of the coupling efficiency, which forms a critical factor in evaluating the practicality of the beam combination system. The simulation results predict a trend similar to the measured ones. Via increasing the number of simulating lasers, the model can be extended to calculate the combining efficiency of the resulting multiple-beam-combination system and estimate the optimal output power and combining efficiency. Moreover, the analytical model is suitable to investigate key parameters of Yb-doped lasers and filters, which is beneficial in enhancing the combining efficiency.

[A New Method for Measurement of Laser-Induced Damage Threshold].

With the development of the laser towards high-power and high energy, laser-induced damage threshold of optics becomes one of the important parameters to evaluate the laser damage resistance of optics. Therefore, accurately measuring of the laser-induced damage threshold optics become the focal point studied. And the key to accurately measuring of the laser-induced damage threshold is whether the laser-induced damage can be accurately identified when it occurs. In order to solve low accuracy, long testing time, narrow scope of applications and complex operation of the common damage identification methods, a new testing method to diagnose the laser-induced damage of optics, called plasma diagnosis, is proposed in this paper. Based on this new method, the testing platform was set up, and the spectrum obtained by fiber spectrometer was analyzed under laser radiation by different laser energies. Take whether the spectral lines of the feature element contained in the measured optics occur as standard. The laser-induced damage threshold of K9 glass has been tested, and the test result was compared to that measured by the plasma flash method and the microscope method. The results show that, the plasma diagnosis method proposed in this paper has high-accurate judgment, high- testing speed, simple testing equipment, and easy to realization, which can greatly improve the testing efficiency of the laser-induced damage threshold of optics.

Research on Ground-Based LWIR Hyperspectral Imaging Remote Gas Detection.

The new progress of ground-based long-wave infrared remote sensing is presented, which describes the windowing spatial and temporal modulation Fourier spectroscopy imaging in details. The prototype forms the interference fringes based on the corner-cube of spatial modulation of Michelson interferometer, using cooled long-wave infrared photovoltaic staring FPA (focal plane array) detector. The LWIR hyperspectral imaging is achieved by the process of collection, reorganization, correction, apodization, FFT etc. from data cube. Noise equivalent spectral radiance (NESR), which is the sensitivity index of CHIPED-1 LWIR hyperspectral imaging prototype, can reach 5.6 x 10⁻8 W · (cm⁻¹ · sr · cm²)⁻¹ at single sampling. The data is the same as commercial temporal modulation hyperspectral imaging spectrometer. It can prove the advantage of this technique. This technique still has space to be improved. For instance, spectral response range of CHIPED-1 LWIR hyperspectral imaging prototype can reach 11. 5 µm by testing the transmission curve of polypropylene film. In this article, choosing the results of outdoor high-rise and diethyl ether gas experiment as an example, the authors research on the detecting method of 2D distribution chemical gas VOC by infrared hyperspectral imaging. There is no observed diethyl ether gas from the infrared spectral slice of the same wave number in complicated background and low concentration. By doing the difference spectrum, the authors can see the space distribution of diethyl ether gas clearly. Hyperspectral imaging is used in the field of organic gas VOC infrared detection. Relative to wide band infrared imaging, it has some advantages. Such as, it has high sensitivity, the strong anti-interference ability, identify the variety, and so on.

mRNA vaccine development and applications: A special focus on tumors (Review).

Cancer is characterized by unlimited proliferation and metastasis, and traditional therapeutic strategies usually result in the acquisition of drug resistance, thus highlighting the need for more personalized treatment. mRNA vaccines transfer the gene sequences of exogenous target antigens into human cells through transcription and translation to stimulate the body to produce specific immune responses against the encoded proteins, so as to enable the body to obtain immune protection against said antigens; this approach may be adopted for personalized cancer therapy. Since the recent coronavirus pandemic, the development of mRNA vaccines has seen substantial progress and widespread adoption. In the present review, the development of mRNA vaccines, their mechanisms of action, factors influencing their function and the current clinical applications of the vaccine are discussed. A focus is placed on the application of mRNA vaccines in cancer, with the aim of highlighting unique advances and the remaining challenges of this novel and promising therapeutic approach.

A scalable thin-film defect quantify model under imbalanced regression and classification task based on computer vision.

Optical coating damage detection is a part of both industrial production and scientific research. Traditional methods require sophisticated expert systems or experienced front-line producers, and the cost of these methods rises dramatically when film types or inspection environments change. In practice, it has been found that customized expert systems imply a significant investment of time and money, and we expect to find a method that can perform this task automatically and quickly, while at the same time the method should be adaptable to the later addition of coating types and the ability to identify damage kinds. In this paper, we propose a deep neural network-based detection tool that splits the task into two parts: damage classification and damage degree regression. Introduces attention mechanisms and Embedding operations to enhance the performance of the model. It was found that the damage type detection accuracy of our model reached 93.65%, and the regression loss was kept within 10% on different data sets. We believe that deep neural networks have great potential to tackle industrial defect detection by significantly reducing the design cost and time of traditional expert systems, while gaining the ability to detect entirely new damage types at a fraction of the cost.

Body Weight Support Treadmill Training Combined With Sciatic Nerve Electrical Stimulation Ameliorating Motor Function by Enhancing PI3K/Akt Proteins Expression via BDNF/TrkB Signaling Pathway in Rats with Spinal Cord Injury.

OBJECTIVE: To investigate the effects of body weight support treadmill training (BWSTT) and sciatic nerve electrical stimulation (SNES) on motor function recovery in spinal cord injury (SCI) rats and its possible mechanism. METHODS: Modified Allen's method was utilized for T10 incomplete SCI. The Basso-Beattie-Bresnahan (BBB) score and modified Tarlov score were applied to assess motor function. Pathologic alterations of the spinal cord and muscles were observed by hematoxylin and eosin (HE) staining. The positive staining region of collagen fibers was assessed with Masson staining. Immunofluorescence was applied to count the positive cells of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). BDNF, TrkB, phosphatidylinositol-3-kinase (PI3K), and protein kinase B (Akt) relative mRNA and protein expressions were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: On the 21st day of the intervention, the motor scores in SNES and BWSTT + SNES groups were higher than that in SCI group (P < 0.05). Compared with SCI group, mRNA and protein expressions of BDNF/TrkB and PI3K/Akt were more significant on the 21st day of the intervention in SNES and BWSTT + SNES groups (P < 0.05), but there was no difference in BWSTT group (P > 0.05). CONCLUSIONS: This experiment demonstrated that BWSTT combined with SNES contributed to alleviating spinal cord tissue injury, delaying muscle atrophy and improving locomotion. One of the possible mechanisms may be related to the regulation of the BDNF/TrkB signaling pathway, which changes the expression of PI3K/Akt protein. Furthermore, it was discovered that the ultra-early BWSTT may not be conducive to recovery.

Investigating Ramadan Like Fasting Effects on the Gut Microbiome in BALB/c Mice.

Recently we reported that in healthy volunteer Ramadan-associated intermittent fasting (RAIF) remodels the gut microbiome and resulted in an increase in small chain fatty acid producing bacteria concomitant with improved metabolic parameters. As interpretation of these results is hampered by the possible psychological effects associated with the study, we now aim to investigate RAIF in experimental animals. To this end, 6-week male BALB/c mice were subjected to RAIF (30 days of a 16-h daily fasting; n = 8) or provided with feed ad libitum (n = 6). Fecal samples were collected before and the end of fasting and bacterial 16S rRNA sequencing was performed. We found that RAIF remodeled the composition of gut microbiota in BALB/c mice (p < 0.01) and especially provoked upregulation of butyrate acid-producing Lachnospireceae and Ruminococcaceae (p < 0.01), resembling the effects seen in human volunteers. Hence we conclude that the effects of RAIF on gut microbiome relate to the timing of food intake and are not likely related to psychological factors possibly at play during Ramadan.

Study of the Explosive Bridge Film Using Laser Shaping Technology.

Laser shaping technology and its applications have gained widespread attention in different fields. Using laser repair technology prolongs the service life of micro-explosive products and reduces the production cost, as well as enables the recycling of resources. Although most research mainly focuses on aspheric surface shaping and testing technology, only a few studies on repair technology for micro-explosive products using laser shaping have been reported. To promote the better application of laser shaping technology in the production and repair process of micro-explosive components, this work mainly studied the effect of laser shaping on the repair of an explosive bridge film to enhance the ignition performance and prevent damage. Different processes were used to repair the metal film using laser shaping and non-shaping, respectively. Furthermore, we investigated the similarities and differences of a laser-damaged film surface before and after shaping, and the influence of laser energy parameters on the microstructure and ignition properties of the repaired region. Additionally, we obtained a reasonable repair scheme by analyzing the temperature field variation from the simulation. The results show that the damage caused by the non-shaping and shaping lasers can be repaired using the heat flow and vaporization methods, respectively. By controlling the process parameters, the quality of repair can be improved and the production cost of the bridge film can be reduced.

Yak Gut Microbiota: A Systematic Review and Meta-Analysis.

The yak (Bos grunniens) is closely related to common cows (Bos taurus), but is clearly a distinct species. Yaks are of substantial importance to food and leather production in certain high-altitude regions of Asia. The animal is increasing elsewhere as well, mainly because of the perceived health benefits of its milk. Like all ruminants, the animal harbors a complex community of microbial cells in its gut, crucial for its physiology. Despite yaks being important domestic animals, the composition of its gut microbiota and how the composition is guided by its specific high-altitude environment remains largely uncategorized. Hence, online databases (Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar) were searched for articles on yak intestinal microbiota. The pooled taxonomic abundance was compared between regions, sexes, different age groups, and feeding patterns. The gut microbiota distribution across different yak intestinal segments was established through pooled average taxonomic abundance. A total of 34 studies met the inclusion criteria and yielded information on 982 unique yak gut microbiota samples. An analysis of overall pooled microbiota revealed a segmented microbial community composition of the yak gut. Yak rumen microbiota was significantly influenced by difference in region, sex, and feeding patterns, the latter factor being dominant in this respect. Yak microbiome is shaped by the feeding strategy and provides an obvious avenue for improving health and productivity of the animal. More generally, the current segmental description of physiological gut microbiome provides insight into how the microbiology of this animal has adapted itself to help comping yaks with its high-altitude habitat.

Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds.

Ghee is a traditional Tibetan dairy product with high-fat content, low yield, plasticity, caseation, and rich nutrition. In this study, we analyzed the diversity of microbial communities in yak milk and ghee samples at high and low altitudes, especially the Lactobacillus genus, and further used metabolomic techniques to compare the differences in metabolites in yak ghee at different altitudes. The results showed that the increase in altitude had a significant and generally inhibitory effect on the microbial community diversity in milk ghee, and yak milk at high altitude was abundant in nutrients, which could antagonize the negative impact of increased altitude. Using non-targeted metabolomics, we infer the composition of flavor compounds in ghee: nine kinds of carboxylic acids, 11 kinds of esters, six kinds of ketones, two kinds of alcohols, and four kinds of alkene compounds, among which the key flavor compounds are dl-2-(acetylamino)-3-phenylephrine acid, 1-(4-methoxyphenyl)-2-propanone, sebacic acid, Lysope 18:1, and uracil 1-beta-d-arabinofuranoside. These flavor substances are found in Lactococcus, Lactobacillus, and Streptococcus. With the participation of Lactobacillus, it is synthesized through biosynthesis of alkaloids derived from ornithine, lysine, and nicotine acid and glyoxylate and decarboxylate metabolism, among which Lactococcus plays a key role. In this study, a variety of lactic acid bacteria related to ghee fermentation were screened out, revealing the composition of volatile flavor compounds in Gannan yak milk ghee in the Qinghai-Tibet Plateau and providing a reference for further key volatile flavor compounds and the formation mechanism of flavor compounds.

Mapping codon usage of the translation initiation region in porcine reproductive and respiratory syndrome virus genome.

BACKGROUND: Porcine reproductive and respitatory syndrome virus (PRRSV) is a recently emerged pathogen and severely affects swine populations worldwide. The replication of PRRSV is tightly controlled by viral gene expression and the codon usage of translation initiation region within each gene could potentially regulate the translation rate. Therefore, a better understanding of the codon usage pattern of the initiation translation region would shed light on the regulation of PRRSV gene expression. RESULTS: In this study, the codon usage in the translation initiation region and in the whole coding sequence was compared in PRRSV ORF1a and ORFs2-7. To investigate the potential role of codon usage in affecting the translation initiation rate, we established a codon usage model for PRRSV translation initiation region. We observed that some non-preferential codons are preferentially used in the translation initiation region in particular ORFs. Although some positions vary with codons, they intend to use codons with negative CUB. Furthermore, our model of codon usage showed that the conserved pattern of CUB is not directly consensus with the conserved sequence, but shaped under the translation selection. CONCLUSIONS: The non-variation pattern with negative CUB in the PRRSV translation initiation region scanned by ribosomes is considered the rate-limiting step in the translation process.

Remodeling of the gut microbiome during Ramadan-associated intermittent fasting.

BACKGROUND: Intermittent fasting is a popular dietary intervention with perceived relatively easy compliance and is linked to various health benefits, including weight loss and improvement in blood glucose concentrations. The mechanistic explanations underlying the beneficial effects of intermittent fasting remain largely obscure but may involve alterations in the gut microbiota. OBJECTIVES: We sought to establish the effects of 1 mo of intermittent fasting on the gut microbiome. METHODS: We took advantage of intermittent fasting being voluntarily observed during the Islamic faith-associated Ramadan and sampled feces and blood, as well as collected longitudinal physiologic data in 2 cohorts, sampled in 2 different years. The fecal microbiome was determined by 16S sequencing. Results were contrasted to age- and body weight-matched controls and correlated to physiologic parameters (e.g., body mass and calorie intake). RESULTS: We observed that Ramadan-associated intermittent fasting increased microbiome diversity and was specifically associated with upregulation of the Clostridiales order-derived Lachnospiraceae [no fasting 24.6 ± 13.67 compared with fasting 39.7 ± 15.9 in relative abundance (%); linear discriminant analysis = 4.9, P < 0.001 by linear discriminant analysis coupled with effect size measurements] and Ruminococcaceae [no fasting 13.4 ± 6.9 compared with fasting 23.2 ± 12.9 in relative abundance (%); linear discriminant analysis = 4.7, P < 0.001 by linear discriminant analysis coupled with effect size measurements] bacterial families. Microbiome composition returned to baseline upon cessation of intermittent feeding. Furthermore, changes in Lachnospiraceae concentrations mirrored intermittent fasting-provoked changes in physiologic parameters. CONCLUSIONS: Intermittent fasting provokes substantial remodeling of the gut microbiome. The intermittent fasting-provoked upregulation of butyric acid-producing Lachnospiraceae provides an obvious possible mechanistic explanation for health effects associated with intermittent fasting.

Identification of Hub Genes and Their Correlation With Immune Infiltration Cells in Hepatocellular Carcinoma Based on GEO and TCGA Databases.

Hepatocellular carcinoma (HCC) is a primary liver cancer with extremely high mortality in worldwide. HCC is hard to diagnose and has a poor prognosis due to the less understanding of the molecular pathological mechanisms and the regulation mechanism on immune cell infiltration during hepatocarcinogenesis. Herein, by performing multiple bioinformatics analysis methods, including the RobustRankAggreg (RRA) rank analysis, weighted gene co-expression network analysis (WGCNA), and a devolution algorithm (CIBERSORT), we first identified 14 hub genes (NDC80, DLGAP5, BUB1B, KIF20A, KIF2C, KIF11, NCAPG, NUSAP1, PBK, ASPM, FOXM1, TPX2, UBE2C, and PRC1) in HCC, whose expression levels were significantly up-regulated and negatively correlated with overall survival time. Moreover, we found that the expression of these hub genes was significantly positively correlated with immune infiltration cells, including regulatory T cells (Treg), T follicular helper (TFH) cells, macrophages M0, but negatively correlated with immune infiltration cells including monocytes. Among these hub genes, KIF2C and UBE2C showed the most significant correlation and were associated with immune cell infiltration in HCC, which was speculated as the potential prognostic biomarker for guiding immunotherapy.

Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance.

BACKGROUND & AIMS: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment. METHODS: Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors. 3D co-culture models of tumor organoids with CAFs and Transwell culture systems were established in vitro. A xenograft model was used to investigate the cell-cell interactions in vivo. Gene expression analysis of CAF markers in our hepatocellular carcinoma cohort and an online liver cancer database indicated the clinical relevance of CAFs. RESULTS: To functionally investigate the interactions of liver cancer cells with CAFs, we successfully established murine and human 3D co-culture models of liver tumor organoids with CAFs. CAFs promoted tumor organoid growth in co-culture with direct cell-cell contact and in a Transwell system via paracrine signaling. Vice versa, cancer cells secrete paracrine factors regulating CAF physiology. Co-transplantation of CAFs with liver tumor organoids of mouse or human origin promoted tumor growth in xenograft models. Moreover, tumor organoids conferred resistance to clinically used anticancer drugs including sorafenib, regorafenib, and 5-fluorouracil in the presence of CAFs, or the conditioned medium of CAFs. CONCLUSIONS: We successfully established murine and human 3D co-culture models and have shown robust effects of CAFs in liver cancer nurturing and treatment resistance.

PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target.

Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.