IVIM parameters mapping with artificial neural network based on mean deviation prior.

BACKGROUND: The diffusion and perfusion parameters derived from intravoxel incoherent motion (IVIM) imaging provide promising biomarkers for noninvasively quantifying and managing various diseases. Nevertheless, due to the distribution gap between simulated and real datasets, the out-of-distribution (OOD) problem occurred in supervised learning-based methods degrades their performance and hinders their real applications. PURPOSE: To address the OOD problem in supervised methods and to further improve the accuracy and stability of IVIM parameter estimation, this work proposes a novel learning framework called IterANN, based on mean deviation prior (MDP) between training and estimated IVIM parameters on the test set. METHODS: Specifically, MDP indicates that the mean of the estimated IVIM parameters always locates between the mean of IVIM parameters in the test and train sets. In IterANN, we adopt a very simple artificial neural network (ANN) architecture of two hidden layers with 12 neurons per hidden layer, an input layer containing the signals acquired at multiple b-values and an output layer composed of three IVIM parameters ( D $D$ , F $F$ and D S t a r $DStar$ ). Inspired by MDP, the distribution of IVIM parameters in the training set (simulated data) is iteratively updated so that their mean gradually approaches the predicted values of the real data. This aims to achieve a strong correlation between the simulated data and the real data. To validate the effectiveness of IterANN, we compare it with several methods on both simulation and real acquisition datasets, including 21 healthy and 3 tumor subjects, in terms of residual errors of IVIM parameters or DW signals, the coefficients of variation (CV) of IVIM parameters, and the parameter contrast-to-noise ratio (PCNR) between normal and tumor tissues. RESULTS: On two simulation datasets, the proposed IterANN achieves the lowest residual error in IVIM parameters, especially in the case of low signal-to-noise ratio (SNR = 10), the residual error of D $D$ , F $F$ and D S t a r $DStar$ is decreased by 15.82 % / 14.92 % , 81.19 % / 74.04 % , 50.77 % / 1.549 % $15.82\%/14.92\%, 81.19\%/74.04\%, 50.77\%/1.549\%$ (Gaussian distribution /realistic distribution) respectively comparing to the suboptimal method. On real dataset, the IterANN achieves the highest PCNR when comparing the normal and tumor regions. Additionally, the proposed IterANN demonstrated better stability, with its CV being significantly lower than that of other methods in the vast majority of cases ( p < 0.01 $p<0.01$ , paired-sample Student's t-test). CONCLUSIONS: The superior performance of IterANN demonstrates that updating the distribution of the train set based on MDP can effectively solve the OOD problem, which allows us not only to improve the accuracy and stability of the estimated IVIM parameters, but also to increase the potential of IVIM in disease diagnosis.

Unilateral biportal endoscopy vs. open decompression for lumbar epidural lipomatosis-cohort study using a prospective registry.

Objective: This study aimed to compare the outcomes of unilateral biportal endoscopy, unilateral laminectomy bilateral decompression (UBE-ULBD), and open lumbar decompression (OLD) in patients with lumbar epidural lipomatosis (LEL). Methods: This prospective observational study was conducted from March 2019 to May 2022 and encompassed 33 patients with LEL who underwent lumbar decompression. The study included 15 cases of UBE-ULBD decompression and 18 cases of open decompression, which were followed up for 1 year. The baseline characteristics, initial clinical manifestations, and surgical details [including estimated blood loss (EBL) and preoperative complications] of all patients were recorded. Radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Clinical results were analyzed using the Short Form-36 Score (SF-36), the Numeric Pain Rating Scale (NRS) for lumbar and leg pain, creatine kinase, the Roland and Morris Disability Questionnaire (RMDQ), and the Oswestry Disability Index (ODI). Results: The dural sac CSA increased considerably at the 1-year postoperative follow-up in both groups (p < 0.001). The operative duration in the OLD group (48.2 ± 7.2 min) was shorter than that in the UBE-ULBD group (67.7 ± 6.3 min, p < 0.001). The OLD group (97.2 ± 19.8 mL) was associated with more EBL than the UBE-ULBD group (40.6 ± 13.6 mL, p < 0.001). The duration of hospitalization in the OLD group (5.4 ± 1.3 days) was significantly longer compared with the UBE-ULBD group (3.5 ± 1.2 days, p < 0.01). The SF-36, NRS, RMDQ, and ODI scores improved in both groups postoperatively (p < 0.001). Serum creatine kinase values in the UBE-ULBD group (101.7 ± 15.5) were significantly lower than those in the OLD group (330.8 ± 28.1 U/L) 1 day after surgery (p < 0.001). The degree of paraspinal muscle atrophy in the UBE-ULBD group (4.81 ± 1.94) was significantly lower than that in the OLD group (12.15 ± 6.99) at 1 year (p < 0.001). Conclusion: UBE-ULBD and OLD demonstrated comparable clinical outcomes in treating LEL. However, UBE-ULBD surgery was associated with shorter hospital stays, lower rates of incision infection, lighter paravertebral muscle injury, and lower EBL than OLD surgery. Consequently, UBE-ULBD can be recommended in patients with LEL if conservative treatment fails.

Ultrasensitive protein and exosome analysis based on a rolling circle amplification assisted-CRISPR/Cas12a strategy.

CRISPR/Cas12a system has attracted extensive concern in biosensing due to its high specificity and programmability. Nevertheless, existing Cas12a-based assays mainly focus on nucleic acid detection and have limitations in non-nucleic acid biomarker analysis. To broaden the application prospect of the CRISPR/Cas technology, a cascade Cas12a biosensing platform is reported by combining dual-functionalized gold nanoparticles (FGNPs)-assisted rolling circle amplification (RCA) and Cas12a trans-cleavage activity (GAR-Cas) for ultrasensitive protein and exosome analysis. FGNPs serve as a critical component in the transduction of protein or exosome recognition information into nucleic acid amplification events to produce Cas12a activators. In the GAR-Cas assay, by integrating the triple cascade amplification of FGNPs-assisted transduction, RCA, and Cas12a signal amplification, ultralow abundance of target molecules can arouse numerous concatemers to activate Cas12a trans-cleavage activity to release intense fluorescence, allowing the ultrasensitive detection of as low as 1 fg/mL (∼41 aM) cTnI and 5 exosomes per µL. Furthermore, the presented strategy can be applied to detect exosome levels from clinical samples, showing excellent performance in distinguishing cancer patients from healthy individuals. The GAR-Cas sensing platform exhibits great potential in clinical diagnosis and enlarges biosensing toolboxes based on CRISPR/Cas technology for non-nucleic acid target analysis.

Orientation Growth of N-Doped and Iron-Based Metal-Organic Framework and Its Application for Removal of Cr(VI) in Wastewater.

A series of NH2-functionalized nano-sized magnetic metal-organic frameworks (MOFs) were prepared in this study for Cr(VI) removal from wastewater. It was observed that not only the morphological, i.e., orientation growth of N-doped and iron-based metal-organic frameworks, but also the adsorption of magnetic MOFs is largely related to the used amount of ammonium hydroxide in preparation. For example, with increasing amounts of ammonium hydroxide used in preparation, the morphology of magnetic MOFs changed from spherical to cube and triangular cone. Moreover, the maximum adsorption capacity of spherical-magnetic MOFs, cubic-magnetic MOFs and triangular cone-magnetic MOFs could be up to 204.08 mg/g, 232.56 mg/g and 270.27 mg/g, respectively. Under optimal conditions, the adsorption process of magnetic MOFs for Cr(VI) was consistent with the pseudo-second-order rate equation (R2 = 1) and Langmuir isotherm model (R2 > 0.99). Therefore, magnetic MOFs developed in this work offered a viable option for the removal of Cr(VI) from wastewater.

Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.

The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.

Blue light stimulates light stress and phototactic behavior when received in the brain of Diaphorina citri.

Blue light with a wavelength of 400-470 nm is the composition of the visible light. However, in recent years, blue light contributed the most significance to light pollution due to the artificial light at night. Previously, we have demonstrated that the Asian citrus psyllid (ACP), Diaphorina citri, an important pest in citrus production, has significant positive phototaxis with a light-emitting diode light of 400 nm. In this study, ACP with positive phototactic behavior to 400 nm light (PH) and non-phototactic behavior to 400 nm light (NP) were collected, individually. Transcriptome dynamics of head tissues of PH and NP groups were captured by using RNA-sequencing technology, respectively. Forty-three to 46 million clean reads with high-quality values were obtained, and 1773 differential expressed genes (DEGs) were detected. Compared with the NP group, there were 841 up-regulated DEGs and 932 down-regulated DEGs in the PH group. Eight pathways were significantly enriched in the PH group in the KEGG database, while 43 up-regulated pathways and 25 down-regulated pathways were significantly enriched in the PH group in the GO database. The DGE approach was reliable validated by real time quantitative PCR. Results indicated that the blue light acted as an abiotic stress causing physiological and biochemical responses such as oxidative stress, protein denaturation, inflammation and tumor development in ACPs. Additionally, the light was absorbed by photoreceptors of ACPs, and converted into electrical signal to regulate neuromodulation. This study provides basic information for understanding the molecular mechanisms of ACP in response to blue light and provides a reference for further studies to elucidate phototactic behavior.

Treatment of Radiation Enteritis With Fecal Transplantation.

Radiation enteritis (RE) is a frequent complication in patients who undergo pelvic irradiation, and this condition has been increasingly diagnosed. Fecal microbiota transplantation (FMT) is being developed in recent years, and it has remarkable curative effect for the clostridium and inflammatory bowel disease. Herein, we present a case of recurrent RE in a 59-year-old woman with RE 18 years after radiotherapy for cervical carcinoma. Fecal microbiota transplantation therapy with intestinal flora from her 18-year-old son was applied and was successful in relieving the symptoms. To the best of our knowledge, this study is the first case report of FMT in a patient with RE.

Bio-photoelectrochemical degradation, and photocatalysis process by the fabrication of copper oxide/zinc cadmium sulfide heterojunction nanocomposites: Mechanism, microbial community and antifungal analysis.

In this work, the fabrication of the CuO on ZnCdS as a heterojunction nanocomposites were conducted by hydrothermal method and the synthesis method was confirmed by the XRD, XPS, EDS, UV-vis spectrum analysis. The CuO/ZnCdS was used as a photocathode in the bio-photoelectrochemical system (BPES) for tetracycline (TC) degradation under solar irradiation. The CuO/ZnCdS photocathode indicated substantial photocatalytic efficiency for TC degradation, due to the fast separation and transfer of photogenerated carriers. The ESR test evaluates the mechanism of degradation, and shows that ·OH, and ·O2- were contributed to TC degradation. The TC degradation was 1.59 times higher than the unilluminated process (98.72% vs 61.71). The photocatalysis test shows that the TC was degraded about 90.5% in 1.5 h. Then, the synthesized CuO/ZnCdS nanocomposites were studied for the biological application such as antifungal activities. CuO/ZnCdS nanocomposites depicted substantial antimicrobial activity versus Candida-albicans by in vitro process. Therefore, this study suggests the novel system for the antibiotics degradation, and as antifungal application.

Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death.

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.

Polypyrrole supported Pd/Fe bimetallic nanoparticles with enhanced catalytic activity for simultaneous removal of 4-chlorophenol and Cr(VI).

Nanoscale zerovalent iron (nZVI) represents a promising reduction technology for water remediation, but its broad application is largely hampered by the tendency of nZVI to aggregate and the low electron transferability due to the interfacial charge resistance. Herein, by combining the advantages of polypyrrole (PPY) and nZVI, we prepared a composite material (i.e., PPY supported palladium­iron bimetallic nanoparticles (Pd/Fe@PPY)) and applied it for the simultaneous removal of 4-chlorophenol (4-CP) and Cr(VI). Our results showed that this material had superior catalytic performances with a complete removal of 4-CP (50 mg·L-1) and Cr(VI) (10 mg·L-1) within 60 and 1 min, respectively. As opposed to the bare Pd/Fe nanoparticles, the reactivity of Pd/Fe@PPY with 4-CP was significantly enhanced by nearly 8 times. The enhanced catalytic activity of Pd/Fe@PPY was attributed to the distinctive properties of PPY as i) a good support that resulted in the formation of Pd/Fe nanoparticles with high dispersibility; ii) an adsorbent that increased the accessibility of 4-CP and Cr(VI) with electrons or active species (e.g., H*) on the particles surface; iii) an electron transfer carrier that facilitated the reactivity of Pd/Fe@PPY with contaminants by reducing the interfacial charge resistance. Moreover, by conducting cyclic voltammetry and quenching investigations, we showed that two mechanisms (i.e., direct and H*-mediated indirect electron transfer) were involved in the reductive dehalogenation of 4-CP, while catalytic hydrodechlorination played a dominant role. This work offers an alternative material for the efficient removal of 4-CP and Cr(VI) and provides better understanding of the relationship between structure and catalytic activity of nZVI.

Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.

It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics. Mice lacking NcDase have reduced cluster of differentiation (CD) 8αß+ T cells and interferon (IFN)-γ+ T cells and increased macrophages in the intestine and fail to clear bacteria after Citrobacter rodentium infection. Mechanistically, cellular NcDase or extracellular vesicle (EV)-related NcDase generates sphingosine, which promotes macrophage-driven Th1 immunity. Loss of NcDase influences sphingosine-controlled glycolytic metabolism in macrophages, which regulates the bactericidal activity of macrophages. Importantly, administration of dietary sphingomyelin and genetic deletion or pharmacological inhibition of SphK1 can protect against C. rodentium infection. Our findings demonstrate that sphingosine profoundly alters macrophage glycolytic metabolism, leading to intestinal macrophage activation and T cell polarization, which prevent pathogen colonization of the gut.

Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma.

RORγt is a master regulator of Th17 cells. Despite evidence linking RORγt deficiency/inhibition with metastatic thymic T cell lymphomas, the role of RORγt in lymphoma metabolism is unknown. Chronic alcohol consumption plays a causal role in many human cancers. The risk of T cell lymphoma remains unclear in humans with alcohol use disorders (AUD) after chronic RORγt inhibition. Here we demonstrated that alcohol consumption accelerates RORγt deficiency-induced lymphomagenesis. Loss of RORγt signaling in the thymus promotes aerobic glycolysis and glutaminolysis and increases allocation of glutamine carbon into lipids. Importantly, alcohol consumption results in a shift from aerobic glycolysis to glutaminolysis. Both RORγt deficiency- and alcohol-induced metabolic alterations are mediated by c-Myc, as silencing of c-Myc decreases the effects of alcohol consumption and RORγt deficiency on glutaminolysis, biosynthesis, and tumor growth in vivo. The ethanol-mediated c-Myc activation coupled with increased glutaminolysis underscore the critical role of RORγt-Myc signaling and translation in lymphoma.

Mesoporous ferrihydrite-supported Pd nanoparticles for enhanced catalytic dehalogenation of chlorinated environmental pollutant.

Organic chlorides are a group of ubiquitous environmental pollutants that have attracted wide attention because of their carcinogenetic effect on human. Catalytic hydrodechlorination represents one of the most promising methods for the removal of these contaminants, but it suffers from drawbacks such as catalytic inefficiency and/or instability, and the danger of using H2 as hydrogen source. The relationship between the catalyst structure and its dehalogenation activity has not been completely understood. By combining the advantages of Pd nanocatalyst and mesoporous ferrihydrite (Fh) with its distinctive structure, here we present a new composite material with Pd nanoparticles (NPs) supported onto the Fh (Pd/Fh), which has excellent catalytic dehalogenation performance with a rapid, complete dechlorination of chlorophenol (turnover frequency 25.2 min-1) and the ability to perform well over a wide range of pH and temperature. The superior catalytic property of Pd/Fh can be attributed to the three unique functions of Fh, including: 1) having abundant hydroxyl groups that provide interaction sites with metals for incorporating highly dispersed small Pd NPs; 2) facilitating the fast adsorption of chlorophenol onto the catalyst surface via hydrogen bonding and importantly, 3) working as an electron mediator to greatly enhance the electron transfer from iron or chemicals (e.g., NaBH4) to the catalyst, thereby achieving a synergistic effect between Pd catalyst and support, and an enhanced dechlorination activity. In essence, this work presents a promising catalyst for the efficient dehalogenation of chlorinated environmental pollutants and provides an insight into the relationship between catalyst structure and dehalogenation activity.

Conductive-polymer-supported palladium-iron bimetallic nanocatalyst for simultaneous 4-chlorophenol and Cr(VI) removal: Enhanced interfacial electron transfer and mechanism.

Nanoscale zerovalent iron (nZVI) reduction offers a wide range of applications in source-zone remediation, but the reactivity of nZVI is largely hampered due to its low electron-transfer ability and tendency to aggregate. Based on the dual function of conductive polymers (CPs) as support and electron transfer carrier, we combined CPs with nZVI and prepared a series of Pd/Fe bimetallic materials that successfully address the challenges of nZVI reduction. These Pd/Fe@CPs particles showed strong catalytic ability for the simultaneous removal of 4-chlorophenol (4-CP) and Cr(VI). The removal rate of 4-CP was significantly enhanced by 1.5-6.2 times after supporting Pd/Fe nanoparticles (NPs) with CPs. The enhanced reactivity of supported Pd/Fe NPs was attributed to their highly stabilized and dispersed state and the promoted electron transfer due to the synergistic effect between CPs and nZVI bimetallic particles. The various catalytic activity over Pd/Fe@CPs was attributed to the distinctive properties of CPs and their different interfacial electron transfer ability. Importantly, this study provides insights into distinguishing both mechanisms of direct electron transfer and atomic-hydrogen-mediated indirect electron transfer, and their quantitative relationship to the dehalogenation performance over Pd/Fe@CPs materials. This work provides better understanding of the remediation process and mechanisms of nZVI reduction.

[Unilateral vertebroplasty and kyphoplasty by digital subtraction angiography for the treatment of osteoporotic vertebral compression fractures].

OBJECTIVE: To explore the methods and efficacy of unilateral extra-pedicle precision puncture percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty(PKP) by digital subtraction angiography (DSA) for the treatment of osteoporotic vertebral compression fractures (OVCFs). METHODS: The clinical data of 68 patients with osteoporotic vertebral compression fractures treated from August 2015 to December 2018 were retrospectively analyzed. There were 20 males and 48 females, aged 56 to 90(73.5±8.0) years, 40 cases of double segments, 28 cases of three segments, a total of 168 vertebrae. All the patients were performed PVP orPKP through unilateral extra pedicle precision puncture under the guidance of DSA. The vertebrae were distributed in T1-T6(29 vertebrae), T6-T12(89 vertebrae), and L1-L5(50 vertebrae). Whether the puncture needle tip reached the midline of vertebral body was observed during operation, the leakage rate of bone cement was recorded after operation. The height of anterior edge and middle of the fractured vertebral body were measured after operation. Visual analogue scale (VAS) and the Oswestry Disability Index (ODI) were used to assess pain and lumbar function before operation, 3 days after operation and final follow-up time. RESULTS: All the punctures were successful in 68 patients. All the puncture needles reached the midline of vertebral body, and the bone cement was well dispersed in the vertebral body with symmetrical distribution. The operation time was 35 to 60 (41.6±3.2) minutes, and there was no puncture complications. The injection volume of bone cement was 3 to 5 (3.6±0.5) ml in each vertebra. There were 8 cases of bone cement leakage, with a leakage rate of 11.76%. All 68 patients were followed up from 12 to 27 (14.3±3.5) months in the study. VAS score and ODI at 3 days after surgery and at final follow-up time were significantly improved (P<0.05). The height of the anterior edge and the middle of vertebral body at 3 days after operation and at final were significantly recovered (P<0.05). CONCLUSION: PVP or PKP under the guidance of DSA via a unilateral extrapedicular approach with precision puncture can effectively relieve pain, restore vertebral body height and spinal function, which is a safe, fast and effective method in the treatment of osteoporotic vertebral compression fractures.

Is It Necessary to Approach the Severe Osteoporotic Vertebral Biconcave-Shaped Fracture Bilaterally During the Process of PKP?

PURPOSE: The goal of this study was to explore the outcomes of unilateral and bilateral approach percutaneous kyphoplasty (PKP) using CT-guidance in the treatment of severe osteoporotic single-level vertebral biconcave-shaped fracture. METHODS: We retrospectively reviewed 89 patients with severe osteoporotic single-level vertebral biconcave-shaped fracture who had undergone unilateral and bilateral PKP surgeries using CT-guidance at our hospital between June 2013 and June 2019, and followed for at least 1 year. All patients were divided into unilateral (the transverse process-pedicle approach, n = 49) and bilateral (the pedicle approach, n = 40) groups. We collected the clinical and radiological evaluation results during postoperative and last follow-up periods. RESULTS: Our findings revealed that the surgery time for the unilateral group was significantly shorter than that of the bilateral group at P < 0.05. The amount of bone cement and radiation exposure of the unilateral group were significantly lesser than that of the bilateral group (P < 0.05). Relative to preoperative data, the values of the VAS score and Oswestry disability index (ODI) were significantly improved at 1 day after surgery and the last follow-up in the two groups (P < 0.05). Notably, the median height of vertebra at 1 day after surgery and the last follow-up in the unilateral group was significantly restored than that of preoperative data (P < 0.05). However, the median height of vertebra at the same time intervals in the bilateral group showed no significant change compared with preoperative data (P > 0.05). Furthermore, the rate of bone cement leakage and incidence of adjacent-level vertebra fracture were not significantly different in the two groups (P > 0.05). Finally, both groups can obtain an asymmetrical distribution of bone cement in the vertebra. CONCLUSION: Compared to the bilateral PKP, unilateral PKP using CT-guidance in the treatment of the sOVBFs exhibits significantly shorter operation time, lesser radiation dose, and complications. Moreover, unilateral PKP can restore the median height of the vertebral body and eventually obtain a symmetrical distribution of bone cement in the vertebra.

Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12.

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.

Selective sphingosine-1-phosphate receptor 1 modulation ameliorates TBI-induced neurological deficit after CCI.

BACKGROUND AND PURPOSE: The inflammatory response after traumatic brain injury (TBI) can contribute to secondary brain injury. RP101075, a sphingosine-1-phosphate receptor modulator, can attenuate various inflammatory responses. Here, we hypothesized that consecutive administration of RP101075 over 3 days could broadly suppress the TBI-induced inflammatory response and ameliorate the outcomes of TBI. METHODS AND RESULTS: Young C57/BL6 mice were subjected to a controlled cortical impact (CCI) model. RP101075-treated mice exhibited significantly reduced scores on the modified neurological severity score (mNSS) test on days 3, 7, 14, and 21 after TBI, in comparison to TBI mice that received the vehicle. RP101075-treated mice had a remarkably decreased percentage of foot faults on the foot fault test on days 7, 14, and 21 after surgery, in comparison to TBI mice that received the vehicle. Using the wet brain weight/dry brain weight method, we found that RP101075 attenuated brain edema at 3 days post-TBI. According to the results of the Morris water maze (MWM), TBI mice treated with RP101075 exhibited reduced latency time and an increased percentage of target quadrant time from day 24 to day 25 after TBI, in comparison to TBI mice that received the vehicle. In addition, flow cytometry and immunohistochemistry showed that RP101075 markedly decreased the number of infiltrated T cells, B cells and NK cells at 3 days after TBI. Analysis of Western blot data showed that RP101075 lowered the expression of proinflammatory factors on day 3 after TBI. CONCLUSIONS: Our study demonstrated that consecutive administration of RP101075 over 3 days suppressed the TBI-induced inflammatory response and ameliorated neurological deficits after TBI. Thus, this procedure may be a potential treatment strategy for TBI in the clinical setting.

High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.

Proximal anal sinus resection as an alternative to fistulectomy and seton for reducing recurrence of anal fistulas: a retrospective study.

BACKGROUND: The recurrence rate of anal fistula following classic surgery is a common issue. The purpose of the present study was to compare the recurrence rate of anal fistula following classic surgery (fistulectomy or seton) and proximal anal sinus resection (PASR) in a cohort study. METHODS: From May 2016 to May 2018, 106 patients who did the anal fistula surgery (classic or PASR) were studied with 2 groups; 74 patients were allocated to the classic surgery group and 32 patients were allocated to the PASR group. Fifty-two patients were excluded because they did not meet the inclusion criteria. We analyzed the recurrence rate of anal fistula, wound healing time, surgical complications, and duration of pain. RESULTS: Patient characteristics, grouped by surgical approach, showed no significant difference. There was a significant difference in the recurrence rate between the classic surgery group and the PASR group (16.2% vs. 0%, P<0.05). There was no significant difference in the surgical complications in the 2 groups (P>0.05). The mean healing time in the 2 groups was not significantly different; 41.6 days in the classic group (P>0.05) and 40.8 days in the PASR group. Our results also found no significant difference in the duration of pain between the 2 groups; 5.1±1.5 days in the classic group and 5.0±1.0 days in the PASR group (P>0.05). CONCLUSIONS: PASR was found to have a lower recurrence rate of anal fistula and did not increase the risk of complications. Therefore, PASR should be considered as a first line of treatment for patients at risk of anal fistula recurrence.