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Background and objectivesDepression is a common comorbidity of dementia and may be a risk factor for dementia. Accumulating evidence has suggested that the cholinergic system plays a central role in dementia and depression, and the loss of cholinergic neurons is associated with memory decline in aging and Alzheimer’s patients. A specific loss of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) is correlated with depression and dysfunction of cognition in mice. In this study, we examined the potential regenerative mechanisms of knockdown the RNA-binding protein polypyrimidine tract binding protein (PTB) in reversing depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons.MethodsWe lesioned cholinergic neurons in mice induced by injection of 192 IgG-saporin into HDB; then, we injected either antisense oligonucleotides or adeno-associated virus-shRNA (GFAP promoter) into the injured area of HDB to deplete PTB followed by a broad range of methodologies including behavioral examinations, Western blot, RT-qPCR and immunofluorescence.ResultsWe found that the conversion of astrocytes to newborn neurons by using antisense oligonucleotides on PTB in vitro, and depletion of PTB using either antisense oligonucleotides or adeno-associated virus-shRNA into the injured area of HDB could specifically transform astrocytes into cholinergic neurons. Meanwhile, knockdown of PTB by both approaches could relieve the depression-like behaviors shown by sucrose preference, forced swimming or tail-suspension tests, and alleviate cognitive impairment such as fear conditioning and novel object recognition in mice with lesioned cholinergic neurons.ConclusionThese findings suggest that supplementing cholinergic neurons after PTB knockdown may be a promising therapeutic strategy to revert depression-like behaviors and cognitive impairment.

IntroductionDespite recent developments in our comprehension of how the gut microbiota and systemic lupus erythematosus (SLE) are related. The mycobiome: which is a small but crucial part of the gut microbiota and is involved in hosts’ homeostasis and physiological processes, remained unexplored in SLE.MethodsWe profiled the gut fungal mycobiota based on internal transcribed spacer region 1 (ITS1) sequencing for the gut microbial DNA from the SLE individuals with lupus nephritis (LN) (n = 23), SLE without LN (n = 26) and healthy controls (n = 14) enrolled in Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School.ResultsThe ITS sequencing generated a total of 4.63 million valid tags which were stratified into 4,488 operational taxonomic units (OTUs) and identified about 13 phyla and 262 genera. Patients with SLE were characterized with unique fungal flora feature. The fungal microbiomes of the three groups displayed distinct beta diversity from each other. Compared with HC group, the abundance of fungal dysbiosis was reflected in a higher ratio of opportunistic fungi in SLE or LN group, as well as the loss of Rhizopus and Malassezia. The main principal components of the flora between the SLE and LN group were generally consistent. The relative abundance of Vanrija in the fecal fungal community was higher in LN group, while the relative abundance of Fusarium was higher in SLE group. Moreover, our data revealed superior diagnostic accuracy for SLE with the fungal species (e.g. Candida, Meyerozyma). Correlations between gut fungi and clinical parameters were identified by Spearman’s correlation analysis. Interestingly, Aspergillus in SLE patients was positively correlated with ACR, 24 h proteinuria, proteinuria, anti-dsDNA, ANA, and SLEDAI, while Rhizopus was negatively correlated with lymphocytes and Hb. Finally, we successfully cultured the fungi and identified it as Candida glabrata by microscopic observation and mass spectrometry.DiscussionWe first explored the highly significant gut fungal dysbiosis and ecology in patients with SLE, and demonstrated the applicability of fungal species as SLE diagnostic tools, signifying that the gut fungal mycobiome-host interplay can potentially contribute in disease pathogenesis.

Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.

Horticultural crops are greatly disturbed by severe abiotic stress conditions. This is considered one of the major threats to the healthy lives of the human population. Salicylic acid (SA) is famous as one of the multifunctional phytohormones that are widely found in plants. It is also an important bio-stimulator involved in the regulation of growth and the developmental stages of horticultural crops. The productivity of horticultural crops has been improved with the supplemental use of even small amounts of SA. It has good capability to reduce oxidative injuries that occur from the over-production of reactive oxygen species (ROS), potentially elevated photosynthesis, chlorophyll pigments, and stomatal regulation. Physiological and biochemical processes have revealed that SA enhances signaling molecules, enzymatic and non-enzymatic antioxidants, osmolytes, and secondary metabolites activities within the cell compartments of plants. Numerous genomic approaches have also explored that SA regulates transcriptions profiling, transcriptional apprehensions, genomic expression, and metabolism of stress-related genes. Many plant biologists have been working on SA and its functioning in plants; however, its involvement in the enhancement of tolerance against abiotic stress in horticultural crops is still unidentified and needs more attention. Therefore, the current review is focused on a detailed exploration of SA in physiological and biochemical processes in horticultural crops subjected to abiotic stress. The current information is comprehensive and aims to be more supportive of the development of higher-yielding germplasm against abiotic stress.

ObjectiveLupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). Early identification of renal disease in SLE is important. Renal biopsy is currently recognized as the gold standard for diagnosing LN, however, it is invasive and inconvenient for dynamic monitoring. Urine has been considered more promising and valuable than blood in identifying inflamed kidney tissue. Here, we determine whether the signatures of tRNA-derived small noncoding RNA (tsRNA) in urinary exosomes can serve as novel biomarkers for the diagnosis of LN.MethodstsRNA sequencing was performed in exosome extracted from pooled urine of 20 LN patients and 20 SLE without LN, and the top 10 upregulated tsRNAs were screened as candidate markers of LN. The candidate urinary exosomal tsRNAs were primarily elected by TaqMan probe-based quantitative reverse transcription-PCR (RT-PCR) in 40 samples (20 LN and 20 SLE without LN) in the training phase. In the validation phase, selected tsRNAs from the training phase were further confirmed in a larger cohort (54 LN patients and 39 SLE without LN). Receiver operating characteristic curve (ROC) analysis was conducted to evaluate the diagnostic efficacy.ResultsUpregulated levels of tRF3-Ile-AAT-1 and tiRNA5-Lys-CTT-1 in the urinary exosomes were observed in LN compared with SLE without LN (P < 0.0001 and P < 0.001) and healthy controls (P < 0.01 and P < 0.01), with the area under the curve (AUC) of 0.777 (95% CI: 0.681-0.874, sensitivity 79.63%, specificity 66.69%) and 0.715 (95% CI: 0.610-0.820, sensitivity 66.96%, specificity 76.92%) for discriminating LN from SLE without LN patients. SLE patients with mild activity and moderate to severe activity had higher levels of urinary exosome derived tRF3-Ile AAT-1 (P = 0.035 and P < 0.001) and tiRNA5-Lys-CTT-1 (P = 0.021 and P < 0.001) compared with patients with no activity. Moreover, bioinformatics analysis revealed that both of the tsRNAs regulate the immune process by modulating metabolism and signal pathway.ConclusionIn this study, we demonstrated that urinary exosome tsRNAs can be served as noninvasive biomarkers for the efficient diagnosis and prediction of nephritis in SLE.

COVID-19 has been affecting the world unprecedentedly and will remain widely prevalent due to its elusive pathophysiological mechanism and the continuous emergence of new variants. Critically ill patients with COVID-19 are commonly associated with cytokine storm, multiple organ dysfunction, and high mortality. To date, growing evidence has shown that extracorporeal hemoadsorption can exert its adjuvant effect to standard of care by regulating immune homeostasis, reducing viremia, and decreasing endotoxin activity in critically ill COVID-19 cases. However, the selection of various hemofilters, timing of initiation and termination of hemoadsorption therapy, anticoagulation management of extracorporeal circuits, identification of target subgroups, and ultimate survival benefit remain controversial. The purpose of this narrative review is to comprehensively summarize the rationale for the use of hemoadsorption in critically ill patients with COVID-19 and to gather the latest clinical evidence in this field.

Immunotherapy has greatly enhanced the effectiveness of cancer treatments, but the efficacy of many current immunotherapies is still limited by the tumor-suppressive immune microenvironment. Multiple studies have shown that activating the stimulation of IFN genes (STING) pathway and inducing innate immunity can significantly impact the tumor immune microenvironment and improve antitumor therapy. While natural or synthetic STING agonists have been identified or developed for preclinical and clinical use, small molecule agonists have limited utility due to degradation and lack of targeting. As such, the delivery and release of STING agonists into tumor tissue is a major challenge that must be addressed in order to further advance the use of STING agonists. To address this challenge, various nanomedicines have been developed. In this paper, we concisely review the antitumor immunotherapeutic mechanisms of STING agonists, highlighting the latest developments in STING agonists and the current progress of nanomedicines for activating STING. We classify the different nanomedicines according to the STING agonists they utilize in order to facilitate understanding of recent advances in this field. Finally, we also discuss the prospects and challenges of this field.

The high incidence and mortality of idiopathic pulmonary fibrosis (IPF) have led to the widespread use of antifibrotic drugs such as pirfenidone; however, the associated adverse reactions greatly vary among individuals and the dose is not fixed. To date, no reliable blood concentration range of pirfenidone is available to monitor adverse reactions and clinical efficacy. This real study assessed the efficacy and safety of different plasma concentrations of pirfenidone in patients with IPF. The study included 99 patients with IPF orally treated with pirfenidone capsules for at least 52 weeks. Ultra-performance liquid chromatography–mass spectrometry was used to analyze drug plasma concentrations. The annual rate of forced vital capacity (FVC) decline, assessed at week 52, was set as the primary end point. Secondary end points were the change from the baseline in the 6-min walk distance (6 MWD) and the time to the first acute exacerbation of IPF, both of which evaluated over 52 weeks. In the total population, the annual FVC decline in the high-concentration group was −90.0 ml per year versus −260.0 ml per year in the low-concentration group, for a between-group difference of 190.3 ml per year. The proportion of patients treated with high plasma concentrations of pirfenidone who showed an absolute decline of ≥10% in FVC% predicted, with a 6 MWD reduction of ≥50 m, or died, was lower than that of patients treated with low plasma concentrations of pirfenidone. High concentrations of pirfenidone reduced the risk of acute exacerbation in patients with IPF. Considerable differences were not observed for the total St. George’s Respiratory Questionnaire score or the rates of death between the high- and low-concentration groups. Mild to moderate adverse events, mainly involving the gastrointestinal system and the skin, were more common in the high-concentration group than in the low-concentration group but did not lead to termination of treatment in most cases. Our results suggest that treatment of IPF with high blood concentration of pirfenidone is both safe and effective. In the case of tolerable adverse reactions, patients with IPF may benefit from high concentrations of pirfenidone.

Deep vein thrombosis is a common clinical peripheral vascular disease that occurs frequently in orthopaedic patients and may lead to pulmonary embolism (PE) if the thrombus is dislodged. pulmonary embolism can be prevented by placing an inferior vena cava filter (IVCF) to intercept the dislodged thrombus. Thus, IVCFs play an important role in orthopaedics. However, the occurrence of complications after inferior vena cava filter placement, particularly recurrent thromboembolism, makes it necessary to carefully assess the risk-benefit of filter placement. There is no accepted statement as to whether IVCF should be placed in orthopaedic patients. Based on the problems currently displayed in the use of IVCFs, an ideal IVCF is proposed that does not affect the vessel wall and haemodynamics and intercepts thrombi well. The biodegradable filters that currently exist come close to the description of an ideal filter that can reduce the occurrence of various complications. Currently available biodegradable IVCFs consist of various organic polymeric materials. Biodegradable metals have shown good performance in making biodegradable IVCFs. However, among the available experimental studies on degradable filters, there are no experimental studies on filters made of degradable metals. This article reviews the use of IVCFs in orthopaedics, the current status of filters and the progress of research into biodegradable vena cava filters and suggests possible future developments based on the published literature by an electronic search of PubMed and Medline databases for articles related to IVCFs searchable by October 2022 and a manual search for citations to relevant studies.

The purpose of this study was to investigate changes in functional connectivity and regional brain activity between and within the default mode network (DMN), salience network (SN), and executive control network (ECN) among individuals with disorders of consciousness (DOC) in the conditions of minimally conscious state (MCS) and vegetative-state/unresponsive wakefulness syndrome (VS/UWS). Twenty-five VS/UWS patients, 14 MCS patients, and 30 healthy individuals as normal control, completed resting-state fMRI scans. ROI-wise functional connectivity and fractional amplitude of low-frequency fluctuation (fALFF) were implemented to examine group differences. All ROI-wise and fALFF analyses masks were identified from the triple-network model. ROI-wise analyses indicated significantly decreased functional connectivity between posterior cingulate cortex (DMN)-left anterior insula (SN), right anterior insula (SN)-left dorsolateral prefrontal cortex (ECN), and right anterior insula (SN)-right amygdala (SN) in VS/UWS patients compared to MCS patients. Moreover, fALFF were observed reduced in the triple-network across all DOC patients, and as the clinical manifestations of DOC deteriorated from MCS to VS/UWS, fALFF in dorsal DMN, anterior/posterior SN, and left ECN became significantly reduced. Moreover, a positive correlation between fALFF of the left ECN and Coma Recovery Scale-Revised (CRS-R) total scores was found across all DOC patients. These findings contribute to a better understanding of the underlying neural mechanism of functional connectivity and regional brain activity in DOC patients, and this triple-network model provides new connectivity pattern changes that may be integrated in future diagnostic tools based on the neural signatures of conscious states.

Eucalyptus, as an economically important species for wood and paper industries, still remains a challenge to genetic improvement by transgenic technology owing to the deficiency of a highly efficient and stable genetic transformation system, especially in cultivated superior clones.Eucalyptus urophylla×Eucalyptus grandisclone DH32-29 is most widely planted in southern China, but it is relatively recalcitrant to adventitious bud regeneration, which blocks the establishment of a genetic transformation system. Here, an efficient adventitious bud regeneration and transformation system ofEucalyptuswas established usingE. urophylla×E. grandisDH32-29 as material. Thein vitroleaves from microshoots that were subcultured for 20–25 days were immersed into liquid Woody Plant Medium supplemented with 0.02 mg·L−1of α-naphthaleneacetic acid (NAA) and 0.24 mg·L−1of forchlorfenuron (callus-inducing medium (CIM)). After 15 days, explants were transferred to a medium containing 0.10 mg·L−1of NAA and 0.50 mg·L−1of 6-benzyladenine (shoot-inducing medium (SIM)) for adventitious bud induction. The highest regeneration efficiency of adventitious buds was 76.5%. Therefore, anAgrobacterium tumefaciens-mediated genetic transformation system was optimized. The leaves were precultured for 7 days and infected for 30 min withA. tumefaciensstrain EHA105 grown to a bacterial density of 0.3 (OD600). After 72 h of cocultivation in the dark, leaves were transferred to CIM supplemented with 100 mg·L−1of cefotaxime (Cef), 100 mg·L−1of timentin, and 15 mg·L−1of kanamycin (Kan) for 15 days to induce calluses. Then, the explants were transferred to SIM supplemented with the same concentration of antibiotics, and the fresh medium was replaced every 15 days until resistant adventitious buds appeared. After induction of roots in root-inducing medium supplemented with 200 mg·L−1of Cef and 75 mg·L−1of Kan, completely transgenic plants were obtained. With the use of the aforementioned method, the transformation frequency can reach 1.9%. This provides a powerful approach for genetic improvement ofE. urophylla×E. grandisDH32-29 and gene function analysis inEucalyptus.

Autoimmune diseases a group of disorders elicited by unexpected outcome of lymphocytes self-tolerance failure, and the common members of which include multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, and type 1 diabetes mellitus, etc. The pathogenesis of autoimmune diseases is not fully understood and the current therapeutic regimen’s inefficacy in certain cases coupled with low rates of success, exorbitant financial burden, as well as numerous side effects, which do open new avenues for the role of natural products as novel therapeutic agents for auto-inflammatory disorders. Scutellaria baicalensis Georgi is a well-known and widely-recognized herbal medicine with certain ameliorative effect on diverse inflammation-involved dysfunction. Though recent advances do highlight its potential to be applied in the fight against autoimmune diseases, the specific mechanism and the related opinion on the exploring possibility are still limited which hampered the further progress. Here in this timeline review, we traced and collected the evidence of how Scutellaria baicalensis Georgi and its bioactive contents, namely baicalin, baicalein, wogonoside and wogonin affect autoimmune diseases. Moreover, we also discussed the clinical implications and therapeutic potential of Scutellaria baicalensis Georgi and its bioactive contents in autoimmune diseases treatment.

BackgroundRecent years have witnessed a gradual increase in the number of female methamphetamine users. Meanwhile, female methamphetamine users are more likely to have psychological problems than male methamphetamine users. The association between diet and psychological problems have been found among non-methamphetamine user. The present study aims to investigate the relationship between dietary intake frequency and psychological problems in female methamphetamine users.Materials and MethodsA total of 109 female methamphetamine users, collected from a Compulsory Isolated Drug Rehabilitation Centre in northern China, participated in the study. All participants completed the Symptom Checklist 90 (SCL-90) questionnaire to assess psychological status. The relation of dietary intake frequency with the SCL-90 score was tested in partial correlation analysis. Multivariable regression models were used to calculate odds ratios to evaluate the association of dietary intake frequency with psychological problems.ResultsOf the current female methamphetamine population, 33 participants were diagnosed with psychological problems using SCL-90. In the terms of dietary intake frequency, the frequency of nut intake in the psychiatric symptom group was significantly lower than that in the asymptomatic group. However, there was no difference in the frequency of other food intakes between the two groups. The frequency of nut intake was negatively correlated with the total score of SCL-90 and 8 different symptom clusters of psychopathologies on SCL-90. Logistic regression analysis indicated that the increased frequency of nut intake was associated with a lower risk of psychological problems.ConclusionIn the female methamphetamine population, increasing the frequency of nut intake may reduce the risk of psychological problems for female methamphetamine users.

Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

Calf thymus polypeptide (CTP), with a molecular mass of Apcem1Cin(MinC)/Gpt (ApcMin/+) mice. CTP hampered tumor development and enhanced the ratio of CD3e−NK1.1+ cells by 113.0% and CD3e+CD28+ cells by 84.7% in the peripheral blood of ApcMin/+ mice. CTP improved the richness, diversity, and evenness of the intestinal microbiota of ApcMin/+ mice, particularly by regulating the abundance of immune-related microorganisms. CTP effectively regulated the expression of immune-related cytokines, such as interleukin (IL)-2 (15.19% increment), IL-12 (17.47% increment), and transforming growth factor (TGF)-β (11.19% reduction). Additionally, it enhanced the levels of CD4 and CD8, as well as the ratio of helper T lymphocytes (Th)1/Th2 in the spleen and tumors of ApcMin/+ mice. In CTP-treated mice, reduced levels of programmed death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), activated nuclear factor of activated T cells 1 (NFAT1), and nuclear factor κB (NF-κB) p65 signaling were noted. Collectively, the anti-CRC effect of CTP is related to the modulation of intestinal microbiota-mediated immune function, which provides a reference for CTP as a therapeutic drug or a combination drug used in CRC treatment in a clinical setting.

BackgroundMild cognitive impairment (MCI) is known as the prodromal stage of the Alzheimer’s disease (AD) spectrum. The recent studies have advised that functional alterations in the dorsal attention network (DAN) could be used as a sensitive marker to forecast the progression from MCI to AD. Therefore, our aim was to investigate specific functional alterations in the DAN in MCI.MethodsWe systematically searched PubMed, EMBASE, and Web of Science and chose relevant articles based on the three functional indicators, the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in the DAN in MCI. Based on the activation likelihood estimation, we accomplished the aggregation of specific coordinates and the analysis of functional alterations.ResultsA total of 38 studies were involved in our meta-analysis. By summing up included articles, we acquired specific brain region alterations in the DAN mainly in the superior temporal gyrus (STG), middle temporal gyrus (MTG), superior frontal gyrus (SFG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), precentral gyrus (preCG), inferior parietal lobule (IPL), superior parietal lobule (SPL). At the same time, the key area that shows anti-interaction with default mode network included the IPL in the DAN. The one showing interactions with executive control network was mainly in the MFG. Finally, the frontoparietal network showed a close connection with DAN especially in the IPL and IFG.ConclusionThis study demonstrated abnormal functional markers in the DAN and its interactions with other networks in MCI group, respectively. It provided the foundation for future targeted interventions in preventing the progression of AD.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021287958].

Bacterial soft rot is one of the most destructive diseases of taro (Colocasia esculenta) worldwide. In recent years, frequent outbreaks of soft rot disease have seriously affected taro production and became a major constraint to the development of taro planting in China. However, little is known about the causal agents of this disease, and the only reported pathogens are two Dickeya species and P. carotovorum. In this study, we report taro soft rot caused by two novel Pectobacterium strains, LJ1 and LJ2, isolated from taro corms in Ruyuan County, Shaoguan City, Guangdong Province, China. We showed that LJ1 and LJ2 fulfill Koch’s postulates for taro soft rot. The two pathogens can infect taro both individually and simultaneously, and neither synergistic nor antagonistic interaction was observed between the two pathogens. Genome sequencing of the two strains indicated that LJ1 represents a novel species of the genus Pectobacterium, for which the name “Pectobacterium colocasium sp. nov.” is proposed, while LJ2 belongs to Pectobacterium aroidearum. Pan-genome analysis revealed multiple pathogenicity-related differences between LJ1, LJ2, and other Pectobacterium species, including unique virulence factors, variation in the copy number and organization of Type III, IV, and VI secretion systems, and differential production of plant cell wall degrading enzymes. This study identifies two new soft rot Pectobacteriaceae (SRP) pathogens causing taro soft rot in China, reports a new case of co-infection of plant pathogens, and provides valuable resources for further investigation of the pathogenic mechanisms of SRP.

Purpose: To explore pharmacological mechanisms of Pulsatilla decoction (PD) against Crohn’s disease (CD) via network pharmacology analysis followed by experimental validation.Methods: Public databases were searched to identify bioactive compounds and related targets of PD as well as related genes in patients with CD. Analyses using the drug–compound–target–disease network, the protein–protein interaction (PPI) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the core targets and pathways of PD against CD. Colon tissue resected from patients with CD and tissue samples from a mouse model of CD fibrosis treated with PD were assessed to verify the major targets of PD in CD predicted by network pharmacologic analysis.Results: A search of the targets of bioactive compounds in PD and targets in CD identified 134 intersection targets. The target HSP90AA1, which was common to the drug–compound–target–disease and PPI networks, was used to simulate molecular docking with the corresponding bioactive compound. GO and KEGG enrichment analyses showed that multiple targets in the antifibrotic pathway were enriched and could be experimentally validated in CD patients and in a mouse model of CD fibrosis. Assays of colon tissues from CD patients showed that intestinal fibrosis was greater in stenoses than in nonstenoses, with upregulation of p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, p-PKC, and PKC targets. Treatment of CD fibrosis mice with PD reduced the degree of fibrosis, with downregulation of the p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, and PKC targets.Conclusion: Network pharmacology analysis was able to predict bioactive compounds in PD and their potential targets in CD. Several of these targets were validated experimentally, providing insight into the pharmacological mechanisms underlying the biological activities of PD in patients with CD.

BackgroundCellular immunotherapy has become a new and promising treatment for patients with liver tumor. However, as most immune cells are delivered by intravenous injection, the effect is limited and is likely to produce systemic toxicity. Here, the objective was to investigate the efficacy and safety of cellular immunotherapy by local infusion, which seems to be a promising approach and has not been well-studied.MethodsThe PubMed, Web of Science, Embase, and Cochrane Library databases were searched to obtain literature. The overall response rate (ORR), overall survival (OS) rates, and adverse events were investigated to evaluate the effectiveness and safety of locoregional therapy. The methodological quality of the articles was assessed using the methodological index for non-randomized studies (MINORS) score. The meta-analysis was performed using Stata 15.0.ResultsThe eligible 17 studies involved a total of 318 patients. The random-effects model demonstrated that the ORR of local cell infusion therapy was 48% (95% confidence interval [CI]: 26%–70%). The pooled OS rate was 94% (95% CI: 83%–100%) at 6 months, 87% (95% CI: 74%–96%) at 12 months, and 42% (95% CI: 16%–70%) at 24 months. Subgroup analyses suggested that minimally invasive treatment and absence of metastasis were significantly associated with better ORR. Fourteen studies reported a variety of adverse events related to cell therapy by local perfusion. The most common complications after regional infusion of immune cells were myelosuppression (66%), fever (50%), gastrointestinal toxicity (22%), hepatic dysfunction (15%), and pleural effusion and/or ascites (14%).ConclusionsImmune cell therapy through local perfusion is effective for patients with liver cancer, with manageable toxicity. It demonstrates better prognosis when combined with minimally invasive therapy. Considering the potential limitations, more randomized controlled trials are needed to provide solid evidence for our findings.

Dickeya zeae, a plant soft-rot pathogen, possesses a type III secretion system (T3SS) as one of the major virulence factors, infecting a wide variety of monocotyledonous and dicotyledonous plants and causing serious losses to the production of economic crops. In order to alleviate the problem of pesticide resistance during bacterial disease treatment, compounds targeting at T3SS have been screened using a hrpA-gfp bioreporter. After screening by Multifunctional Microplate Reader and determining by flow cytometer, five compounds including salicylic acid (SA), p-hydroxybenzoic acid (PHBA), cinnamyl alcohol (CA), p-coumaric acid (PCA), and hydrocinnamic acid (HA) significantly inhibiting hrpA promoter activity without affecting bacterial growth have been screened out. All the five compounds reduced hypersensitive response (HR) on non-host tobacco leaves and downregulated the expression of T3SS, especially the master regulator encoding gene hrpL. Inhibition efficacy of the five compounds against soft rot were also evaluated and results confirmed that the above compounds significantly lessened the soft-rot symptoms caused by Dickeya dadantii 3937 on potato, Dickeya fangzhongdai CL3 on taro, Dickeya oryzae EC1 on rice, and D. zeae MS2 on banana seedlings. Findings in this study provide potential biocontrol agents for prevention of soft-rot disease caused by Dickeya spp.

Soft rot Pectobacteriaceae (SRP), typical of Pectobacterium and Dickeya, are a class of Gram-negative bacterial pathogens that cause devastating diseases on a wide range of crops and ornamental plants worldwide. Quorum sensing (QS) is a cell-cell communication mechanism regulating the expression of specific genes by releasing QS signal molecules associated with cell density, in most cases, involving in the vital process of virulence and infection. In recent years, several types of QS systems have been uncovered in Dickeya pathogens to control diverse biological behaviors, especially bacterial pathogenicity and transkingdom interactions. This review depicts an integral QS regulation network of Dickeya, elaborates in detail the regulation of specific QS system on different biological functions of the pathogens and hosts, aiming at providing a systematic overview of Dickeya pathogenicity and interactions with hosts, and, finally, expects the future prospective of effectively controlling the bacterial soft rot disease caused by Dickeya by quenching the key QS signal.

BackgroundTo characterize the clinical and pathological features and survival of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer in China.MethodsThe China National Cancer Center database was used to identify 1,433 metastatic breast cancer patients with HER2-negative disease diagnosed between 2005 and 2015. Clinicopathological features, survival, and prognosis information were extracted. Overall survival (OS) was estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95% CI).ResultsThere were 618 (43.1%) and 815 (56.9%) HER2-low and HER2-zero tumors out of 1,433 tumors, respectively. The proportion of hormone receptor (HR)-positive tumors was significantly higher in HER2-low tumors than in those with HER2-zero tumors (77.8% vs. 69.2%, p < 0.001). Patients with HER2-low tumors survived significantly longer than those with HER2-zero tumors in the overall population (48.5 months vs. 43.0 months, p = 0.004) and HR-positive subgroup (54.9 months vs. 48.1 months, p = 0.011), but not in the HR-negative subgroup (29.5 months vs. 29.9 months, p = 0.718). Multivariate regression analysis revealed that HER2-low tumors were independently associated with increased OS in HER2-negative population (HR: 0.85, 95% CI: 0.73–0.98, p = 0.026).ConclusionOur findings demonstrate that HER2-low tumors could be identified as a more distinct clinical entity from HER2-zero tumors, especially for the HR-positive subgroup. A more complex molecular landscape of HER2-low breast cancer might exist, and more precise diagnostic algorithms for HER2 testing could be investigated, thus offering new therapeutic targets for breast cancer treatment.

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

Background: Ultrasound is ideal for displaying intracranial great vessels but not intracranial microvessels and terminal vessels. Even with contrast agents, the imaging effect is still unsatisfactory. In recent years, significant theoretical advances have been achieved in super-resolution imaging. The latest commonly used ultrafast plane-wave ultrasound Doppler imaging of the brain and microbubble-based super-resolution ultrasound imaging have been applied to the imaging of cerebral microvessels and blood flow in small animals such as mice but have not been applied to in vivo imaging of the cerebral microvessels in monkeys and larger animals. In China, preliminary research results have been obtained using super-resolution imaging in certain fields but rarely in fundamental and clinical experiments on large animals. In recent years, we have conducted a joint study with the Xi'an Jiaotong University to explore the application and performance of this new technique in the diagnosis of cerebrovascular diseases in large animals.Objective: To explore the characteristics and advantages of microbubble-based super-resolution ultrasound imaging of intracranial vessels in rhesus monkeys compared with conventional transcranial ultrasound.Methods: First, the effectiveness and feasibility of the super-resolution imaging technique were verified by modular simulation experiments. Then, the imaging parameters were adjusted based on in vitro experiments. Finally, two rhesus monkeys were used for in vivo experiments of intracranial microvessel imaging.Results: Compared with conventional plane-wave imaging, super-resolution imaging could measure the inner diameters of cerebral microvessels at a resolution of 1 mm or even 0.7 mm and extract blood flow information. In addition, it has a better signal-to-noise ratio (5.625 dB higher) and higher resolution (~30-fold higher). The results of the experiments with rhesus monkeys showed that microbubble-based super-resolution ultrasound imaging can achieve an optimal resolution at the micron level and an imaging depth >35 mm.Conclusion: Super-resolution imaging can realize the monitoring imaging of high-resolution and fast calculation of microbubbles in the process of tissue damage, providing an important experimental basis for the clinical application of non-invasive transcranial ultrasound.

Ipomoea aquatica is a leafy vegetable widely cultivated in tropical Asia, Africa, and Oceania. Bacterial leaf canker disease has been attacking the planting fields and seriously affecting the quality of I. aquatica in epidemic areas in China. This study examined the microbial composition of I. aquatica leaves with classical symptoms of spot disease. The results showed that Xanthomonas was overwhelmingly dominant in all four diseased leaf samples but rarely present in rhizospheric soil or irrigation water samples. In addition, Pantoea was also detected in two of the diseased leaf samples. Pathogen isolation, identification, and inoculation revealed that both Xanthomonas sp. TC2-1 and P. ananatis were pathogenic to the leaves of I. aquatic, causing crater-shaped ulcerative spots and yellowing with big brown rot lesions on leaves, respectively. We further sequenced the whole genome of strain TC2-1 and showed that it is a member of X. perforans. Overall, this study identified X. perforans as the causal pathogen of I. aquatica bacterial leaf canker, and P. ananatis as a companion pathogen causing yellowing and brown rot on leaves. The correct identification of the pathogens will provide important basis for future efforts to formulate targeted application strategy for bacterial disease control.

Histone deacetylases (HDACs) play crucial roles nearly in all aspects of plant biology, including stress responses, development and growth, and regulation of secondary metabolite biosynthesis. The molecular functions of HDACs have been explored in depth in Arabidopsis thaliana, while little research has been reported in the medicinal plant Cannabis sativa L. Here, we excavated 14 CsHDAC genes of C. sativa L that were divided into three relatively conserved subfamilies, including RPD3/HDA1 (10 genes), SIR2 (2 genes), and HD2 (2 genes). Genes associated with the biosynthesis of bioactive constituents were identified by combining the distribution of cannabinoids with the expression pattern of HDAC genes in various organs. Using qRT-PCR and transcription group analysis, we verified the expression of candidate genes in different tissues. We found that the histone inhibitor Trichostatin A (TSA) affected the expression of key genes in the cannabinoid metabolism pathway and the accumulation of synthetic precursors, which indirectly indicates that histone inhibitor may regulate the synthesis of active substances in C. sativa L.

Background: The six-minute walk (6MW) test is a validated assessment method in Multiple Sclerosis (MS) research. While the total distance covered during six minutes (6MWTD) is often used as the standard measurement of gait capacity (i.e., the maximum distance one can achieve), we hypothesize that endurance (i.e., ability to maintain speed over a prolonged time) can be inferred by the gait speed trajectory (GST) during the 6MW test (6MWGST).Objective: To characterize group differences in 6MWGST between MS patients and healthy controls (HCs), and to assess information added by 6MWGST for discerning between MS patients and HCs.Methods: We performed a secondary data analysis on a cross-sectional cohort of 40 MS and 20 HC subjects with three repeated 6MW tests. We modeled 6MWGST using a linear mixed-effects model with time in minutes and replicated walks nested within individuals. We compared the discernibility of 6MWGST with that of conventional metrics using likelihood ratio tests and receiver operating characteristic (ROC) analysis on logistic regression models.Results: MS subjects showed a concave, quadratic GST during 6MW tests, slowing down more than the HC subjects, especially at the beginning of 6MW tests. Despite accelerating at the end of the 6MW, MS subjects were unable to attain or surpass their initial 6MW gait speeds. 6MWGST added useful information (p = 0.002) to the conventional metrics (e.g., 6MWTD) for discerning between MS and HC subjects, and increased the area under the ROC curve from 0.83 to 0.93 (p = 0.037).Conclusions: The distinctive 6MWGST pattern of MS patients provided increased discernibility compared with currently used gait metrics. Both gait capacity measured by the 6MWTD, and gait endurance measured by parameters of 6MWGST, are significant functional indicators for the MS population.

Small intestine injury is an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) that urgently needs to be addressed for their safe application. Although pure total flavonoids from citrus (PTFC) have been marketed for the treatment of digestive diseases, their effects on small intestine injury and the underlying mechanism of action remain unknown. This study aimed to investigate the potential role of autophagy in the mechanism of NSAID (diclofenac)-induced intestinal injury in vivo and in vitro and to demonstrate the protective effects of PTFC against NSAID-induced small intestine disease. The results of qRT-PCR, western blotting, and immunohistochemistry showed that the expression levels of autophagy-related 5 (Atg5), light chain 3 (LC3)-II, and tight junction (TJ) proteins ZO-1, claudin-1, and occludin were decreased in rats with NSAID-induced small intestine injury and diclofenac-treated IEC-6 cells compared with the control groups. In the PTFC group, Atg5 and LC3-II expression, TJ protein expression, and the LC3-II/LC3-I ratio increased. Furthermore, the mechanism by which PTFC promotes autophagy in vivo and in vitro was evaluated by western blotting. Expression levels of p-PI3K and p-Akt increased in the intestine disease-induced rat model group compared with the control, but decreased in the PTFC group. Autophagy of IEC-6 cells was upregulated after treatment with a PI3K inhibitor, and the upregulation was significantly more after PTFC treatment, suggesting PTFC promoted autophagy through the PI3K/Akt signaling pathway. In conclusion, PTFC protected intestinal barrier integrity by promoting autophagy, which demonstrates its potential as a therapeutic candidate for NSAID-induced small intestine injury.

IntroductionCutaneous angiosarcoma (cAS) is an aggressive vascular tumor that originates from vascular or lymphatic epithelial cells. To date, the cAS literature has been limited in a small number with single-center experiences or reports due to its rarity and the optimal treatment strategy is still in dispute. This study aimed to conduct a systematic review and compare the effect of available treatments retrieved from observational studies and Surveillance, Epidemiology, and End Results (SEER) program.MethodsThe authors performed a systematic review in the PubMed, Embase and MEDLINE database identifying the researches assessing the treatment for cAS patients. Clinical and treatment information of patients who had been diagnosed with a primary cAS were also obtained from the SEER program.ResultsThirty-two studies were eligible but only 5 of which with 276 patients were included in meta-analysis since the unclear or unavailable information. The risk ratio of 5-year death for surgery, surgery with radiotherapy and surgery with chemotherapy were 0.84, 0.96, and 0.69. Meanwhile, in SEER database, there are 291 metastatic and 437 localized patients with cAS. The localized patients receiving surgery showed a significantly worse overall survival result when compared with the surgery combined with RT: hazard ratio: 1.6, 95% confidential interval: 1.05, 2.42, P = 0.03.ConclusionIn conclusion, our study provided a detailed picture of the effectiveness of present treatments for localized and metastatic cAS patients. The CT could be inappropriate in localized patients. For metastatic patients, the surgery combined RT was recommended compared with surgery alone since its enhanced OS prognosis. Yet, more novel-designed clinical trials with specific targeted populations and rigorous conducting are needed for a solid conclusion on which would be a better treatment strategy.

Purpose: Coronavirus disease 2019 (COVID-19) has been associated with acute liver injury in reports worldwide. But no studies to date have described hypoxic hepatitis (HH) in patients with COVID-19. We aim to identify the prevalence of and possible mechanisms of HH in COVID-19 patients in the Intensive Care Unit (ICU).Methods: This retrospective study was conducted on 51 patients with confirmed SARS-CoV-2 infection in the ICU at Zhongnan Hospital of Wuhan University from December 21, 2019, to March 11, 2020. Information on clinical features of enrolled patients was collected for analysis.Results: HH was observed in 5.88% of the ICU patients with SARS-CoV-2 infection. All HH patients were progressing to respiratory failure and peak alanine aminotransferase (ALT) values were 1665, 1414, and 1140 U/L during hospitalization, respectively. All patients with HH died as a result of the deterioration of multiple organ failure (MOF). The dynamic changes of ALT, aspartate transaminase (AST), and total bilirubin (TBIL) levels were more dramatic in HH groups. Levels of TBIL, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6(IL-6) showed statistically significant elevation in HH cases compared with that in non-HH cases (P < 0.001). Besides, the median survival time of the HH group was significantly shorter than the non-HH group (P < 0.05).Conclusions: In ICU, HH was not a rare condition in patients with severe COVID-19 and has a high mortality. The main causes of HH are respiratory and cardiac failure and may be associated with the immune-mediated inflammatory response. Clinicians should search for any underlying hemodynamic or respiratory instability even in patients with normal ALT levels on admission.

Achlorophyllous plants are full mycoheterotrophic plants with no chlorophyll and they obtain their nutrients from soil fungi. Gastrodia elata is a perennial, achlorophyllous orchid that displays distinctive evolutionary strategy of adaptation to the non-photosynthetic lifestyle. Here in this study, the genome of G. elata was assembled to 1.12 Gb with a contig N50 size of 110 kb and a scaffold N50 size of 1.64 Mb so that it helped unveil the genetic basics of those adaptive changes. Based on the genomic data, key genes related to photosynthesis, leaf development, and plastid division pathways were found to be lost or under relaxed selection during the course of evolution. Thus, the genome sequence of G. elata provides a good resource for future investigations of the evolution of orchids and other achlorophyllous plants.

Background: The literature reports conflicting results regarding the effect of human papillomavirus (HPV) genotype 16 (HPV-16)/18 (HPV-18) positivity on cervical cancer (CC) prognosis. Aim: To conduct a meta-analysis to examine the effect of HPV-16/18 positivity on the prognosis of patients with CC. Methods: PubMed, Embase, and the Cochrane Library were searched for available papers published up to March 2020. The main outcome was the hazard ratio (HR) of overall survival (OS) or disease-free survival (DFS) comparing HPV-16 or HPV-18 positivity and negativity. The random-effects model was used for synthesizing survival outcomes. Results: Nine studies and 2,028 patients were included. Four studies reported OS in HPV-16 positivity, and no association was found between HPV-16 positivity and OS to CC (HR = 0.79, 95% CI: 0.26–2.39, P = 0.675). Three studies reported DFS in HPV-16 positivity, and no association was found between HPV-16 positivity and DFS to CC (HR = 0.80, 95% CI: 0.30–2.11, P = 0.654). Two studies reported DFS in HPV-18 positivity, and no association was found between HPV-18 positivity and DFS to CC (HR = 0.99, 95% CI: 0.55–1.78, P = 0.984). One study reported progression-free survival (PFS) in HPV-18 positivity, and an association was observed between HPV-18 positivity and PFS to CC (HR = 2.66, 95% CI: 1.44–4.94, P = 0.002). The sensitivity analyses showed that one study biased the analysis of the association between HPV-16 and OS, and another study biased the association between HPV-16 and DFS. Conclusion: The presence of HPV-16 and HPV-18 positivity appears to have no significant association with prognosis in CC in either OS or PFS. The presence of HPV-16 or HPV-18 positivity has no significant association with prognosis in CC in either OS or PFS.