Search

Colorectal cancer (CRC) is one of the most common malignant tumors in the world, and most colorectal cancer is transformed from colorectal adenoma (CRA). Identifying biomarkers for the early prediction of colorectal cancer would be an important finding. Circular RNA (circRNA) plays a key role in the occurrence and development of tumors, and its biological characteristics make it a potential biomarker for the early diagnosis of diseases. Therefore, we explored the relationship between circRNA and the malignant transformation from colorectal adenoma to colorectal cancer. We constructed inflammation-based tumorigenesis mouse models and performed high-throughput RNA sequencing to determine the expression profile of circRNAs in tissues at different stages of disease. Subsequent STEM analysis showed that with the development of the disease, 30 circRNAs were significantly downregulated, and 10 circRNAs were significantly upregulated. After qRT-PCR and Fish analysis verification, it was clear that mmu_circ_0008035 and mmu_circ_0000420 were significantly and continuously overexpressed in the development of colorectal cancer in our mouse model. Next, through homology analysis of circRNA in human and mouse and validation of clinical normal tissues, adenoma tissues and CRC tissues, we found biomarkers of has_circ0101338 ahashsa_circ0022426 that could predict the malignant transformation of human colorectal inflammation into CRC and have certain diagnostic value. In conclusion, our results may shed light on the mechanism of progression from precancerous adenoma to cancer and provide biomarkers that may be used in the early diagnosis of CRC.

There are about 10 million people with epilepsy (PWE) in China. In addition to therapies approved by the National Medical Products Administration, the use of complementary and alternative medicine (CAM) is prevalent in Chines PWE. These CAM therapies mainly comprise traditional Chinese medicine herbs (TCMHs), acupuncture, and music. A retrospective literature search was performed to summarize the updates of CAM in China in the past ten years, and sixty-two papers were finally included. In this following review, we listed the animal and clinical studies to summarize the antiepileptic mechanisms and clinical efficacy of CAM in Chines PWE. The main mechanisms of TCMHs and acupuncture included regulation of neurotransmitters and receptors, voltage-gated ion channels modulation, expression of apoptosis-related genes, antioxidant response, and anti-inflammation. Although there were enormous clinical studies on them, the current available clinical trials were small, short-term, heterogeneous, and had a high risk of bias. With regard to music, a few studies conducted by Chinese scholars suggested that it was beneficial for PWE as an add-on therapy, which was consistent with the results of foreign studies. Further randomized clinical trials in large populations are required to prove the effectiveness and safety of CAM.

Nowadays, human beings are exposed to Cu in varieties of environmental mediums, resulting in health risks needing urgent attention. Our research found that Cu shortened lifespan and induced aging-related phenotypes of Caenorhabditis elegans (C. elegans). Transcriptomics data showed differential expression genes induced by Cu were mainly involved in regulation of metabolism and longevity, especially in fatty acid metabolism. Quantitative detection of free fatty acid by GC/MS further found that Cu upregulated free fatty acids of C. elegans. A mechanism study confirmed that Cu promoted the fat accumulation in nematodes, which was owing to disorder of fatty acid desaturase and CoA synthetase, endoplasmic reticulum unfolded protein response (UPRER), mitochondrial membrane potential, and unfolded protein response (UPRmt). In addition, Cu activated oxidative stress and prevented DAF-16 translocating into nuclear with a concomitant reduction in the expression of environmental stress-related genes. Taken together, the research suggested that Cu promoted aging and induced fat deposition and oxidative damage.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved treatment. The natural compound silybin (SLN) has versatile hepatoprotective efficacy with negligible adverse effects; however, poor absorption limits its clinical applications. Gut microbiota has been proposed to play a crucial role in the pathophysiology of NAFLD and targeted for disease control. Cyclodextrins, the cyclic oligosaccharides, were documented to have various health benefits with potential prebiotic properties. This study aimed to develop a silybin-2-hydroxypropyl-β-cyclodextrin inclusion (SHβCD) to improve the therapeutic efficacy of SLN and elucidate the mechanisms of improvement. The results showed that SLN formed a 1:1 stoichiometric inclusion complex with HP-β-CD. The solubility of SLN was increased by generating SHβCD, resulting in improved drug permeability and bioavailability. In high-fat diet (HFD)-fed hamsters, SHβCD modulated gut health by restoring the gut microbiota and intestinal integrity. SHβCD showed superior anti-lipid accumulation, antioxidant, and anti-inflammatory effects compared with SLN alone. Transcriptome analysis in the liver tissue implied that the improved inflammation and/or energy homeostasis was the potential mechanism. Therefore, SHβCD may be a promising alternative for the treatment of NAFLD, attributing to the dual functions of HβCD on drug absorption and gut microbial homeostasis.

Patients with persistent or de novo left ventricular (LV) dilation and/or reduced ejection fraction (EF) after correction for primary aortic (AR) or mitral (MR) regurgitation (i.e. residual LV remodelling) have not been well studied with regard to guideline-directed medical therapy after successful aetiology-reversing surgery. We aim to (i) compare the effectiveness of sacubitril/valsartan vs. valsartan in promoting LV reverse remodelling and (ii) explore the safety of medication withdrawal after LV recovery.The ReReRe study is a multicentre, randomized, open-label, parallel trial that consists of two consecutive parts. A total of 371 patients with an LV end-diastolic diameter (LVEDD) 60 mm or LVEF 50%, assessed by transthoracic echocardiography (TTE) 7-14 days after valve surgery for significant AR or primary MR will be enrolled. The 1The ReReRe study will provide new evidence for the treatment of patients with residual LV remodelling after curable unloaded surgery, as well as the duration of treatment. The study results will fill the gap in identifying an appropriate medical therapy regimen for this group of patients and perhaps for those with reversible aetiologies of heart failure.

Flexible wearable sensors based on conductive hydrogels are attracting increasing interest. To meet the urgent demands of sustainability and eco-friendliness, biopolymer-based physically crosslinked hydrogels have drawn great attention. Starch has a great potential due to its renewability, biocompatibility, nontoxicity and low cost. However, poor mechanical property, low conductivity and lack of versatility are seriously limiting the applications of starch-based hydrogels in wearable sensors. Moreover, the development of starch hydrogel-based wearable sensors in harsh conditions remains a challenge. Herein, multifunctional and physical crosslinking hydrogels were developed by introducing ionic liquid (1-ethyl-3-methyl imidazolium acetate) and metal salt (AlCl

Oxysterol metabolism plays an important role in the initiation and development of various tumors. However, little is known that the metabolic alternation can promote the metastasis of hepatocellular carcinoma (HCC). In this study, we identify the sulfotransferase family 2A member 1 (SULT2A1) to 27-hydroxycholesterol (27-OHC) metabolic axis as playing a critical role in HCC metastasis. The level of 27-OHC closely corresponded with HCC metastasis instead of proliferation in vitro and in vivo. Also, the expression of SULT2A1 is extremely downregulated in human HCC tissues and is correlated with poor prognosis and tumor metastasis. Gain- and loss-of-function studies reveal that SULT2A1 suppresses the metastasis of HCC by regulating the level of 27-OHC. Further mechanistic studies indicated that SULT2A1-dependent alternation of 27-OHC activates the nuclear factor-κB signaling pathway and promotes HCC metastasis by enhancing Twist1 expression and epithelial-mesenchymal transition. In conclusion, our findings indicate the relationship between the metabolism of 27-OHC and the metastasis of HCC. Moreover, SULT2A1 could act as a potential prognostic biomarker and a therapeutic target for preventing HCC metastasis.

Numerous studies have demonstrated the ubiquitous of phthalates in materials of food and food packaging, and the effects of regular eating takeaway food for a long time on human health and phthalate exposure levels were not fully investigated. A total of 288 college students who love eating takeaway food were recruited to explore phthalate exposure and oxidative stress, by measuring metabolites of traditional or alternative phthalates and 8-hydroxydeoxyguanosine (8-OHdG, a biomarker of DNA oxidative damage) in their urine samples. Both traditional and alternative phthalates were highly detected. Based on weekly frequency of takeaway eating collecting from questionnaire, the students were divided into four groups including level 1 (L1, 3 times), level 2 (L2, 3-7 times), level 3 (L3, 8-12 times) and level 4 (L4, 12 times). The total concentrations of all phthalate metabolites were 42.5-893 ng/mL in all students, which were significantly different among four groups, with the lowest level in L1 (p 0.05). Checking with the generalized linear model (L1 as the reference), the concentrations of most phthalate metabolites increased 12.0-144% in L2 and L3 compared with those in L1. For each group increase, the concentrations of total metabolites, and metabolites of high and low molecular weight phthalates will increase by 0.156%, 0.128%, and 0.142%, respectively. Besides, levels of 8-OHdG (0.639-33.7 ng/mL) were positively correlated with phthalate daily exposure doses. The each increase of a percentage unit of daily exposure of phthalates, the concentrations of 8-OHdG will increase by 0.258-0.405%. However, levels of 8-OHdG were not significantly different among the four groups. The alternative phthalates have already entered the body of Chinese young people. Our results indicated the regular consumption of takeaway food (e.g., more than three times per week) may increase the chance of exposure to certain phthalates, and may not significantly increase the levels of DNA oxidative damage, unless exposed to other pollutants such as phthalates.

Pancreatic cancer (PC) is one of the most fatal cancers with a very poor prognosis. Here, we found that N(6)-methyladenosine (m(6)A) RNA demethylase fat mass and obesity-related protein (FTO) promote the growth, migration and invasion of PC. FTO expression level is increased in human PC and is associated with poor prognosis of PC patients. Knockdown of FTO increases m(6)A methylation of TFPI-2 mRNA in PC cells, thereby increasing mRNA stability via the m(6)A reader YTHDF1, resulting in up-regulation of TFPI-2 expression, and inhibits PC proliferation, colony formation, sphere formation, migration and invasion in vitro, as well as tumour growth in vivo. Rescue assay further confirms that FTO facilitates cancer progression by reducing the expression of TFPI-2. Mechanistically, FTO promotes the progression of PC at least partially through reducing m(6)A/YTHDF1 mediated TFPI-2 mRNA stability. Our findings reveal that FTO, as an m(6)A demethylase, plays a critical role in promoting PC growth, migration and invasion, suggesting that FTO may be a potential therapeutic target for treating PC.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a threat to human health. 3C-like proteinase (3CLpro) plays an important role in the viral life cycle. Hence, it is considered an attractive antiviral target protein. Whole-genome sequencing showed that the sequence homology between SARS-CoV-2 3CLpro and SARS-CoV 3CLpro is 96.08%, with high similarity in the substrate-binding region. Thus, assessing peptidomimetic inhibitors of SARS-CoV 3CLpro could accelerate the development of peptidomimetic inhibitors for SARS-CoV-2 3CLpro. Accordingly, we herein discuss progress on SARS-CoV-2 3CLpro peptidomimetic inhibitors. Inflammation plays a major role in the pathophysiological process of COVID-19. Small-molecule compounds targeting 3CLpro with both antiviral and anti-inflammatory effects are also briefly discussed in this paper.

Major depressive disorder is the most common mental disorder with significant economic burden and limited treatments. Acupuncture has emerged as a promising non-pharmacological treatment for reducing depressive symptoms. However, the potential mechanisms and clinical effectiveness of acupuncture are not fully understood. This review aimed to: (1) summarize the available evidence on the mechanisms and clinical effectiveness of acupuncture for depression, and then (2) compare with pharmacological interventions, guiding future studies. Studies with animal models of depression and patients have shown that acupuncture could increase hippocampal and network neuroplasticity and decrease brain inflammation, potentially to alleviating depressive disorders. Overall clinical studies indicated that acupuncture could relieve primary depression, particularly milder cases, and was helpful in the management of post-stroke depression, pain-related depression, and postpartum depression both as an isolated and adjunct treatment. It was emphasized that acupuncture combined with antidepressant pharmacological treatment not only enhanced the improvement of primary and secondary depressive symptoms but also reduced the side effects of the medical treatment, which is the main cause for high dropout rates with drug treatment. In summary, substantial evidence from animal and human researches supported the beneficial effect of acupuncture in depression. However, most clinical trials of acupuncture were small, and it is unclear whether their findings can be generalized, so more studies are needed.

The engineering of patient T-cells for adoptive cell therapies has revolutionised the treatment of several cancer types(1). However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T-cell functions(2-1) and raise safety concerns due to permanent genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). The top-ranked genes increased primary human CD4+ and CD8+ T-cell proliferation, activation, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface antigens in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in myeloid cells but absent in lymphocytes. When overexpressed in T-cells, LTBR induced profound transcriptional and epigenomic remodelling, increasing T-cell effector functions, as well as resistance to exhaustion in chronic stimulation settings, via constitutive activation of the canonical NF-κB pathway. LTBR and other top-ranked genes improved antigen-specific chimeric antigen receptor (CAR) T-cell and γδ T-cell responses, highlighting their potential for future cancer-agnostic therapies(5). Our results provide several strategies for improving next generation T-cell therapies via induction of new synthetic cell programmes.

Objectives To map travel policies implemented due to COVID-19 during 2020, and conduct a mixed-methods systematic review of health effects of such policies, and related contextual factors. Design Policy mapping and systematic review. Data sources and Eligibility Criteria for the policy mapping, we searched websites of relevant government bodies and used data from the Oxford COVID-19 Government Response Tracker for a convenient sample of 31 countries across different regions. For the systematic review, we searched Medline (Ovid), PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and COVID-19 specific databases. We included randomized controlled trial, non-randomized studies, modeling studies, and qualitative studies. Two independent reviewers selected studies, abstracted data and assessed risk of bias. Results Most countries adopted a total border closure at the start of the pandemic. For the remainder of the year, partial border closure banning arrivals from some countries or regions was the most widely adopted measure, followed by mandatory quarantine and screening of travelers. The systematic search identified 69 eligible studies, including 50 modeling studies. Both observational and modeling evidence suggest that border closure may reduce the number of COVID-19 cases, disease spread across countries and between regions, and slow the progression of the outbreak. These effects are likely to be enhanced when implemented early, and when combined with measures reducing transmission rates in the community. Quarantine of travelers may decrease the number of COVID-19 cases but its effectiveness depends on compliance and enforcement and is more effective if followed by testing, especially when less than 14 day-quarantine is considered. Screening at departure and/or arrival is unlikely to detect a large proportion of cases or to delay an outbreak. Effectiveness of screening may be improved with increased sensitivity of screening tests, awareness of travelers, asymptomatic screening, and exit screening at country source. While four studies on contextual evidence found that the majority of the public is supportive of travel restrictions, they uncovered concerns about the unintended harms of those policies. Conclusion Most countries adopted full or partial border closure in response to COVID-19 in 2020. Evidence suggests positive effects on controlling the COVID-19 pandemic for border closure (particularly when implemented early), as well as quarantine of travelers (particularly with higher levels of compliance). While these positive effects are enhanced when implemented in combination with other public health measures, they are associated with concerns by the public regarding some unintended effects.

Background. Long noncoding RNAs (lncRNAs) play an important role in many cancer progression. The aim of this study was to evaluate the expression level and clinical significance of the lncRNA, proliferating cell nuclear antigen pseudogene 1 (PCNAP1), in cancer tissue and the plasma of patients with hepatocellular carcinoma (HCC). Methods. Quantitative real-time polymerase chain reaction was used to detect the expression of PCNAP1 in HCC tissue, adjacent tissue, and plasma. Spearman’s rank correlation analysis was performed to assess relationships among cancer tissue, plasma PCNAP1, and plasma AFP. Kaplan–Meier analysis was used to assess survival of HCC patient with high and low expression of PCNAP1. The survival difference was compared by the log-rank test. The use of plasma levels PCNAP1 for diagnosing HCC was evaluated by receiver operating characteristic curve analysis. Results. The expression of PCNAP1 in HCC tissue was significantly higher than in adjacent tissue ( P < 0.01 ). The PCNAP1 levels were related to the TNM stage, lymph node metastasis, and tumor maximum diameter ( P < 0.05 ) but were not related to gender and age ( P = 0.459 and 0.656). Patients with greater levels of PCNAP1 had poorer survival than patients with lower levels of expression ( P < 0.01 ). Compared to the healthy control group, a gastric cancer group, and a colorectal cancer group, HCC patient plasma levels of PCNAP1 were significantly greater ( P < 0.01 ). The area under the curve (AUC) of plasma PCNAP1 in HCC patients was 0.83 (95% CI: 0.78-0.88). With a cut-off value of plasma PCNAP1 at 1.27, an HCC diagnostic sensitivity of 70.08%, and a specificity of 85.04%, was the maximum diagnostic efficiency achieved. Conclusion. This study demonstrates PCNAP1 levels to be increased in HCC patients. As such, PCNAP1 may be a new tool useful in disease diagnosis and prognosis.

Autonomous energy systems are key to sustainably powering electronic skins. Potential autonomous energy resources include sunlight, human motion, sweat, and body heat, among which the biofuel in human sweat is a most natural and available candidate. In this perspective, we discuss the promise of wearable microbial fuel cells as autonomous power suppliers for electronic skins by using the biofuels in human sweat. In comparison to wearable enzymatic biofuel cells, wearable microbial fuel cells offer easy access, low cost and superior sustainability. We summarize the present achievements and provide our vision toward future research to make wearable microbial fuel cells reliable on-skin power suppliers.

Background Age of onset may be an important feature associated with distinct subtypes of obsessive-compulsive disorder (OCD). The amygdala joined neurocircuitry models of OCD for its role in mediating fear and regulating anxiety. The present study aims to identify the underlying pathophysiological specifics in OCD with different onset times by assessing amygdala subregional functional connectivity (FC) alterations in early-onset OCD (EO-OCD) and late-onset OCD (LO-OCD). Methods Resting-state functional magnetic resonance imaging data were acquired from 88 medication-free OCD patients (including 30 EO-OCD and 58 LO-OCD) and age- and sex-matched healthy controls (HC) for each patient group. Onset-by-diagnosis interactions were examined and comparisons between each OCD group and the corresponding HC group were performed regarding the FC of amygdala subregions including the basolateral amygdala (BLA), centromedial amygdala (CMA), superficial amygdala (SFA) and amygdalostriatal transition area (Astr). Results Significant onset-by-diagnosis interactions were found in FC between bilateral SFA, right CMA, left Astr and the cerebellum. EO-OCD patients showed abnormally increased BLA/SFA-cerebellum, BLA-precuneus and BLA/SFA-fusiform connectivity in addition to decreased BLA/SFA-orbitofrontal cortex connectivity. In contrast, LO-OCD patients exhibited increased CMA/Astr-precentral/postcentral gyrus and CMA-cuneus connectivity as well as decreased CMA/Astr-cerebellum and BLA-striatum connectivity. Limitations The exclusion of comorbidity may reduce the generalizability of our results. Conclusions These findings emphasized the different patterns of amygdala subregional connectivity alterations associated with EO-OCD and LO-OCD patients. These results provide unique insights into constructing evidence-based distinct OCD subtypes based on brain intrinsic connectivity and point to the need of specified management for EO-OCD and LO-OCD in clinical setting.

Interleukin 10 (IL-10) is a synthetic inhibitor of human cytokines with immunomodulatory and anti-inflammatory effects. This study was designed to investigate the expression variation of IL-10 in the multiple sites including cortex, hippocampus, and lung tissues of neonatal hypoxic-ischemic (HI) rats and explore the crucial role of IL-10 in alleviating HI brain damage. In this study, neonatal Sprague-Dawley rats were subjected to the right common carotid artery ligation, followed by 2 h of hypoxia. The expression of IL-10 in the cortex, hippocampus, and lung tissues was measured with immunohistochemistry, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Immunofluorescence double staining was performed to observe the localization of IL-10 in neurons and astrocytes. Moreover, not-targeting and targeting IL-10 siRNA lentivirus vectors were injected into the rats of the negative control (NC) and IL-10 group, respectively, and the mRNA levels of B-cell lymphoma 2 (Bcl-2) and endoplasmic reticulum protein 29 (ERp29) were detected by RT-qPCR following IL-10 silence. The results demonstrated that the IL-10 expression was markedly increased after HI and IL-10 were colocalized with neurons and astrocytes which were badly injured by HI insult. In addition, Bcl-2 and ERp29 were remarkably decreased following IL-10 mRNA interference compared with the NC group. Our findings revealed that IL-10 exerted its antiapoptotic and neuroprotective effects by regulating the expression of Bcl-2 and ERp29, indicating that IL-10 may be a promising molecule target for HIE treatment. Refereed/Peer-reviewed

Widespread alterations in the corpus callosum (CC) microstructure and organization have been found in children with attention-deficit/hyperactivity disorder (ADHD); however, few studies have investigated the diffusion characteristics and volume of transcallosal fiber tracts defined by specific cortical projections in ADHD, which is important for identifying distinct functional interhemispheric connection abnormalities. In the current study, an automated fiber-tract quantification (AFQ) approach based on diffusion tensor imaging identified seven CC tracts according to their cortical projections and estimated diffusion parameters and volume among 76 drug-naïve ADHD patients (53 boys and 23 girls) and 37 typically developing children (TDC) (20 boys and 17 girls) matched for age, IQ, and handedness. We found significantly lower fractional anisotropy (FA) in the occipital and superior parietal tracts and higher mean diffusivity (MD) in the posterior, superior parietal and anterior frontal tracts in children with ADHD compared with TDC. In addition, lower FA and higher radial diffusivity (RD) in the occipital callosal tract were significantly associated with higher hyperactivity and impulsivity performance in ADHD. In addition, sex-by-diagnosis interactions were observed in the occipital, posterior and superior parietal tracts. Girls with ADHD showed decreased FA and volume in the occipital tract, which were significantly associated with increased impulsivity performance and poor response control, and increased MD in the posterior and superior parietal callosal tracts, which were significantly associated with increased inattention performance, whereas boys with ADHD merely showed decreased volume in the frontal tract. Our results elucidated that sex-specific alterations in the CC tracts potentially underlie ADHD symptomatology and further suggested a differential contribution of abnormalities in different CC tracts to impulsivity and inattention among girls with ADHD.

This study aimed to determine the cause behind the outbreak of nosocomial adenoviral conjunctivitis in the Neonatal Intensive Care Unit (NICU) and the impact of infection control measures. The objectives of the present study include investigation of the hospital-borne infection associated with adenoviral conjunctivitis, analysis of the possible risk factors, setting bundle infection control measures, which were adjusted according to the control effect. The present study also aims to observe the effect of different intervention measures on controlling adenoviral conjunctivitis. During the first and second intervention periods, overall 635 and 597 NICU patients were enrolled, respectively. Ophthalmoscopy was conducted among 188 (in the first intervention) and 184 (in the second intervention) patients (P>0.05). The times of ophthalmoscopy the patients received were 417 and 457 (P

Older individuals are at higher risk of SARS-CoV-2 infection and severe outcomes, but the underlying mechanisms are incompletely understood. In addition, how age modulates SARS-CoV-2 re-infection and vaccine breakthrough infections remain largely unexplored. Here, we investigated age-associated SARS-CoV-2 pathogenesis, immune responses, and the occurrence of re-infection and vaccine breakthrough infection utilizing a wild-type C57BL/6N mouse model. We demonstrated that interferon and adaptive antibody response upon SARS-CoV-2 challenge are significantly impaired in aged mice compared to young mice, which results in more effective virus replications and severe disease manifestations in the respiratory tract. Aged mice also showed increased susceptibility to re-infection due to insufficient immune protection acquired during the primary infection. Importantly, two-dose COVID-19 mRNA vaccination conferred limited adaptive immune response among the aged mice, making them susceptible to SARS-CoV-2 infection. Collectively, our findings call for tailored and optimized treatments and prevention strategies against SARS-CoV-2 among older individuals.

The novel SARS-CoV-2 Omicron variant (B.1.1.529), first found in early November 2021, has sparked considerable global concern and it has >50 mutations, many of which are known to affect transmissibility or cause immune escape. In this study, we sought to investigate the virological characteristics of the Omicron variant and compared it with the Delta variant which has dominated the world since mid-2021. Omicron variant replicated more slowly than the Delta variant in transmembrane serine protease 2 (TMPRSS2)-overexpressing VeroE6 (VeroE6/TMPRSS2) cells. Notably, the Delta variant replicated well in Calu3 cell line which has robust TMPRSS2 expression, while the Omicron variant replicated poorly in this cell line. Competition assay showed that Delta variant outcompeted Omicron variant in VeroE6/TMPRSS2 and Calu3 cells. To confirm the difference in entry pathway between the Omicron and Delta variants, we assessed the antiviral effect of bafilomycin A1, chloroquine (inhibiting endocytic pathway), and camostat (inhibiting TMPRSS2 pathway). Camostat potently inhibited the Delta variant but not the Omicron variant, while bafilomycin A1 and chloroquine could inhibit both Omicron and Delta variants. Moreover, the Omicron variant also showed weaker cell–cell fusion activity when compared with Delta variant in VeroE6/TMPRSS2 cells. Collectively, our results suggest that Omicron variant infection is not enhanced by TMPRSS2 but is largely mediated via the endocytic pathway. The difference in entry pathway between Omicron and Delta variants may have an implication on the clinical manifestations or disease severity.

Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 μM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 μM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.

Background Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. Methods Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. Results One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. Conclusions We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC

The emergence of SARS-CoV-2 variants and potentially other highly pathogenic sarbecoviruses in the future highlights the need for pan-sarbecovirus vaccines. Here, we discovered a new STING agonist, CF501, and found that CF501-adjuvanted RBD-Fc vaccine (CF501/RBD-Fc) elicited significantly stronger neutralizing antibody (nAb) and T cell responses than Alum- and cGAMP-adjuvanted RBD-Fc in mice. Vaccination of rabbits and rhesus macaques (nonhuman primates, NHPs) with CF501/RBD-Fc elicited exceptionally potent nAb responses against SARS-CoV-2 and its nine variants and 41 S-mutants, SARS-CoV and bat SARSr-CoVs. CF501/RBD-Fc-immunized hACE2-transgenic mice were almost completely protected against SARS-CoV-2 challenge, even 6 months after the initial immunization. NHPs immunized with a single dose of CF501/RBD-Fc produced high titers of nAbs. The immunized macaques also exhibited durable humoral and cellular immune responses and showed remarkably reduced viral load in the upper and lower airways upon SARS-CoV-2 challenge even at 108 days post the final immunization. Thus, CF501/RBD-Fc can be further developed as a novel pan-sarbecovirus vaccine to combat current and future outbreaks of sarbecovirus diseases.

Chronic obstructive pulmonary disease (COPD) affects the health of more than 300 million people worldwide; at present, there is no effective drug to treat COPD. Smoking is the most important risk factor, but the molecular mechanism by which smoking causes the disease is unclear. The senescence of lung epithelial cells is related to development of COPD. Regulation of miRNAs is the main epigenetic mechanism related to aging. β-Galactose staining showed that the lung tissues of smokers have a higher degree of cellular senescence, and the expression of miR-125a-5p is high. This effect is obvious for smokers with COPD/emphysema, and there is a negative correlation between miR-125a-5p levels and values for forced expiratory volume in one second (FEV1)/forced vital capacity (FVC). After Balb/c mice were chronically exposed to various concentrations of cigarette smoke (CS), plethysmography showed that lung function was impaired, lung tissue senescence was increased, and the senescence-associated secretory phenotype (SASP) in bronchoalveolar lavage fluid was increased. For mouse lung epithelial (MLE)-12 cells treated with cigarette smoke extract (CSE), Sp1 and SIRT1 levels were low, HIF-1α acetylation levels were high, and cell senescence and secretion of SASP factors were elevated. Down-regulation of miR-125a-5p or up-regulation of Sp1 reversed these effects. In addition, compared with mice exposed to CS, knockdown of miR-125a-5p reduced lung epithelial cell senescence and COPD/emphysema. Therefore, in smoking-induced COPD, elevated miR-125a-5p participates in the senescence of lung epithelial cells through Sp1/SIRT1/HIF-1α. These findings provide evidence related to the pathogenesis of COPD/emphysema caused by chronic smoking.

Socio-economic metabolism refers to the human-driven migration and transformation of material and energy within and at the boundary of the socio-economic system. The research of socio-economic metabolism has become the core in industrial ecology. We introduced the connotation and basic steps of socio-economic metabolism research with typical cases, and summarized the main findings of socio-economic metabolism research. The research provide a method and model to track the sources, sinks, and flow path of materials in the socio-economic system, reveal how materials and their socio-economic metabolic processes supported modern production and lifestyle. Related studies have clarified the mechanism by which human activities driving the ecological and environmental problems related to material metabolism. It provides the model and database for evaluating the resource efficiency, the trend of resource supply and demand, and the potential of urban mining. We put forward the future directions of socio-economic metabolism research: to increase research objects and enhance the research precision of each object; to expand and deepen the temporal and spatial boundaries of the research system; to introduce and integrate new data sources and research methods; to connect the material flows of socio-economic metabolism with its related ecological and environmental impacts; and to establish a data platform that could be shared, expanded and accumulated.社会经济代谢是指由于人类活动导致的物质和能量在社会经济系统内部和边界上的迁移和转换。社会经济代谢研究已经成为产业生态学的核心领域。本文结合典型案例介绍了社会经济代谢研究的内涵和基本步骤,总结了社会经济代谢研究的主要发现:提供了追踪物质在社会经济系统的来源、去向和流动路径的方法与模型;揭示了物质材料及其社会经济代谢过程对现代化生产和生活方式的支撑作用;阐明了人类活动驱动与物质代谢相关的生态环境问题的机制;提供了评估资源利用效率、资源供需趋势和城市矿产开发潜力的模型与基础数据。最后指出了社会经济代谢研究的发展方向:增加研究对象并深化对每种对象的研究精度;拓展或细化研究系统的时空边界;引入并融合新的数据来源和研究方法;将社会经济代谢中的物质流对接到与其相关的生态环境影响;建立可共享、可拓展、可累积的数据平台。.

WHAT IS KNOWN AND OBJECTIVES Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. METHODS A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS AND DISCUSSION The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8 L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340 L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. WHAT IS NEW AND CONCLUSION CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.

The aim of study is to estimate the role of energy financing for energy retrofit in COVID-19, with the intervening role of green bond financing. For this, Kalman technique is applied to infer the empirical findings. It is found that energy financing is significantly dependent on green bonds, and green bonds have a significant role in energy retrofit in E-7 economies specifically. It is further found that E-7 economies gained significant rise in energy efficiency financing green bonds financing, that has supportively extended energy retrofit - before and during COVID-19 crises. It is further found significant that the E-7 nations have to put alot of money into hydro and nuclear energy for energy retrofit, with low carbon emissions. In the light of COVID-19 crises, this study offers policy recommendations for effective energy management. However, such policy recommendations are expected to finely serve the financial intermediaries and national governments of E-7 economies to better optimize energy financing through green bond financing. The novelty of the study exists in topical framework and research directions, talking about the way forwards for energy efficiency financing - which is one of the latest issue of the recent times. Hence, this research provides some empirical verifications about energy financing in COVID-19 crises for energy retrofit, and shares some suggestions for stakeholders.

Objective To evaluate the outcomes of cervical spondylotic radiculopathy secondary to bony foraminal stenosis treated with anterior cervical discectomy and fusion (ACDF) combined with anterior cervical foraminotomy (ACF) assisted by High‐Definition 3‐Dimensional Exoscope. Methods In this retrospective study, a total of 19 consecutive patients (12 males and seven females, with an average of 49.2 years, range from 40 to 59 years) with spondylotic radiculopathy caused by bony foraminal stenosis underwent ACDF combined with ACF assisted by High‐Definition 3‐Dimensional Exoscope in our hospital between January 2019 and December 2019 were included in this study. All patients signed the consent form before the surgery. The patient baseline information such as gender, age, body mass index (BMI), surgery time, blood loss, hospital stay, lesion segment, side, follow‐up time and postoperative complications were recorded. The Japanese Orthopedic Association (JOA), Neck Disability Index (NDI), and Visual Analogue Scale (VAS) were measured and compared before surgery, 1 months and final follow‐up after surgery. The radiographic outcomes were evaluated using the C2‐C7 angel, disc height, foraminal height, superior diagonal distance, inferior diagonal distance, and foraminal area. Results The involved levels included C4‐C5 (six cases), C5‐C6 (10 cases), C6‐C7 (three cases). The mean duration of the surgery, mean blood loss, mean hospital stay, and mean follow‐up were 100 ± 11.10 min, 19.4 ± 7.05 mL, 7.1 ± 0.99 days, and 12.1 ± 2.25 months, respectively. The average preoperative JOA score was 11.9 ± 1.31, then improved to 15.7 ± 0.73 (t = −13.45, P, ACDF combined with ACF assisted by High‐Definition 3‐Dimensional Exoscope is an effective and safe for the treatment of CSR caused by secondary to bony foraminal stenosis. In addition to sufficient decompression, this technique can also significantly reduce intraoperative bleeding.

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus

To observe the effect of navel acupuncture on bladder emptying function in patients with urinary retention after stroke based on the conventional treatment.A total of 106 patients with urinary retention after stroke were randomly divided into an observation group (53 cases, 3 cases dropped off) and a control group (53 cases, 3 cases dropped off). Patients in the control group were treated with drugs, catheterization and bladder function rehabilitation training. On the basis of the treatment in the control group, the observation group was treated with navel acupuncture, 30 min each time, once every other day, for 4 weeks. The bladder residual urine volume, spontaneous urination volume and catheterization times before and after treatment were compared between the two groups, and the clinical efficacy was evaluated.After treatment, in the two groups, the bladder residual urine volume and catheterization times were lower than those before treatment (On the basis of conventional treatment, navel acupuncture can effectively improve the bladder emptying function of patients with urinary retention after stroke.

Altres ajuts: Fundació La Marató de TV3/TV3-201803-10 Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in contrast, RNase 3 shows the highest bactericidal action, alas with a reduced catalytic activity. Starting from both parental proteins, we designed a first RNase 3/1-v1 chimera. The construct had a catalytic activity much higher than RNase 3, unfortunately without reaching an equivalent antimicrobial activity. Thus, two new versions were created with improved antimicrobial properties. Both of these versions (RNase 3/1-v2 and -v3) incorporated an antimicrobial loop characteristic of RNase 3, while a flexible RNase 1-specific loop was removed in the latest construct. RNase 3/1-v3 acquired both higher antimicrobial and catalytic activities than previous versions, while retaining the structural determinants for interaction with the RNase inhibitor and displaying non-significant cytotoxicity. Following, we tested the constructs' ability to eradicate macrophage intracellular infection and observed an enhanced ability in both RNase 3/1-v2 and v3. Interestingly, the inhibition of intracellular infection correlates with the variants' capacity to induce autophagy. We propose RNase 3/1-v3 chimera as a promising lead for applied therapeutics.

Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs.

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments-selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes β-coronavirus lineage B (β-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional “down” conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD “up”. Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against β-CoV-B and newly emerging SARS-CoV-2 variants of concern. Supplementary Information The online version contains supplementary material available at 10.1007/s13238-021-00871-6.

Neonatal hypoxic-ischaemic (HI) injury is a serious complication of neonatal asphyxia and the leading cause of neonatal acute death and chronic neurological injury, and the effective therapeutic method is lacking to improve patients' outcomes. We reported in this study that panax notoginseng saponin (PNS) may provide a treatment option for HI. HI model was established using neonatal Sprague-Dawley rats and then intraperitoneally injected with different dosage of PNS, once a day for 7 days. Histological staining and behavioural evaluations were performed to elucidate the pathological changes and neurobehavioural variation after PNS treatment. We found PNS administration significantly reduced the infarct volume of brain tissues and improved the autonomous activities of neonatal rats, especially with higher dosage. PNS treatment at 40 mg/kg reduced neuronal damage, suppressed neuronal apoptosis and depressed astroglial reactive response. Moreover, the long-term cognitive and motor functions were also improved after PNS treatment at 40 mg/kg. Importantly, PNS treatment elevated the levels of BDNF and TrkB but decreased the expression of p75NTR both in the cortex and hippocampus of HI rats. The therapeutic efficacy of PNS might be correlated with PNS-activated BDNF/TrkB signalling and inactivation of p75NTR expression, providing a novel potential therapy for alleviating HI injury.

The prevalence of coronary artery disease (CAD) in Tibetan Highlanders is lower than that in plain-living individuals, but the mechanism still unclear. Gut microbiota (GM) disorder is considered one of the potential factors involved in the pathogenesis of CAD, but the GM characteristics of Tibetan Highlanders suffering from CAD are unknown. We sequenced the V3-V4 region of the 16S ribosomal RNA of gut bacteria from fecal samples from Tibetan and Han CAD patients and healthy individuals inhabiting the Qinghai-Tibet Plateau, as well as from Han CAD patients and healthy individuals living at sea level, and we analyzed the GM characteristics of these subjects by bioinformatics analysis. The results showed that Tibetan Highlanders suffering from CAD had higher GM α-diversity, with differently distributed cluster compared with healthy Tibetan Highlanders and Han CAD patients living at high and low altitudes. Genera Catenibacterium, Clostridium_sensu_stricto, Holdemanella, and Ruminococcus 2 were enriched in Tibetan Highlanders suffering from CAD compared with healthy Tibetan Highlanders and Han CAD patients living at high- and low-altitudes. Prevotella was enriched in Tibetan Highlanders suffering from CAD compared with Han CAD patients living at high- and low-altitudes. Moreover, Catenibacterium was positively correlated with Prevotella. Additionally, Catenibacterium, Holdemanella, and Prevotella were positively correlated with fermented dairy product, carbohydrate and fiber intake by the subjects, while Clostridium_sensu_stricto was negatively correlated with protein intake by the subjects. In conclusion, our study indicated that Tibetan Highlanders suffering from CAD showed distinct GM, which was linked to their unique dietary characteristics and might associated with CAD.

Metabolite identification plays a critical role in the phases during drug development. Drug metabolites can contribute to efficacy, toxicity, and drug-drug interaction. Thus, the correct identification of metabolites is essential to understand the behavior of drugs in humans. Drug administration authorities (e.g., FDA, EMA, and NMPA) emphasize evaluating the safety of human metabolites with exposure higher than 10% of the total drugrelated components. Many previous reviews have summarized the various methods, tools, and strategies for the appropriate and comprehensive identification of metabolites. In this review, we focus on summarizing the importance of identifying metabolites in the preclinical and clinical phases of drug development. Summarized scenarios include the role of metabolites in pharmacokinetics/pharmacodynamics (PK/PD) analysis, disproportional exposure of metabolites that contribute to drug toxicity, changes in metabolite exposure in renal-impaired patients, covalent tyrosine kinase inhibitors (anticancer drugs), and metabolite identification of drug candidates from natural medicines. This review is aimed to provide meaningful insight into the significant role of metabolite identification in drug development.

Purpose Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. Methods RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-β signaling. Results We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-β signaling pathway due to its inhibitory role on SMAD7. Conclusion ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.

Lijuan Zhang,1,&ast; Shengan Zhang,2,&ast; Min Jiang,1 Lu Lu,3 Yue Ding,3 Ninghui Ma,1 Yuan Zhao,4 Sihan Xuchen,1 Nailian Zhang1 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Center of Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Lu; Yue DingExperiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaEmail yjll66@outlook.com; dingyue-2001@hotmail.comIntroduction: As high cholesterol level has been reported to be associated with cancer cell growth and cholesterol is vulnerable to oxidation, the conventional liposomes including cholesterol in the formulation seem to be challenged. Timosaponin AIII (TAIII), as a steroid saponin from Anemarrhena asphodeloides Bunge, possesses a similar structure with cholesterol and exhibits a wide range of antitumor activities, making it possible to develop a TAIII-based liposome where TAIII could potentially stabilize the phospholipid bilayer as a substitution of cholesterol and work as a chemotherapeutic drug as well. Meanwhile, TAIII could enhance the uptake of doxorubicin hydrochloride (DOX) in human hepatocellular carcinoma (HCC) cells and exhibit synergistic effect. Thus, we designed a novel thermally sensitive multifunctional liposomal system composed of TAIII and lipids to deliver DOX for enhanced HCC treatment.Methods: The synergistic effects of DOX and TAIII were explored on HCC cells and the tumor inhibition rate of TAIII-based liposomes carrying DOX was evaluated on both subcutaneous and orthotopic transplantation tumor models. TAIII-based multifunctional liposomes were characterized.Results: Synergistic HCC cytotoxicity was achieved at molar ratios of 1:1, 1:2 and 1:4 of DOX/TAIII. TAIII-based liposomes carrying a low DOX dose of 2 mg/kg exhibited significantly enhanced antitumor activity than 5 mg/kg of DOX without detected cardiotoxicity on both subcutaneous and orthotopic transplantation tumor models. TAIII-based liposomes were characterized with smaller size than cholesterol liposomes but exhibited favorable stability. Mild hyperthermia generated by laser irradiation accelerated the release of DOX and TAIII from liposomes at tumor site, and cell permeability of TAIII enhanced uptake of DOX in HCC cells.Conclusion: The innovative application of TAIII working as bilayer stabilizer and chemotherapeutic drug affords a stable multifunctional liposomal delivery system for synergistic therapy against HCC, which may be referred for the development of other types of saponins with similar property.Keywords: doxorubicin, timosaponin AIII, liposomes, hepatocellular carcinoma, cholesterol

LCZ696 is a novel neuroendocrine inhibitor that has been widely used in heart failure (HF). However, its advantage over other neuroendocrine inhibitors, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) has not been fully elucidated. This study aimed to provide the latest evidence regarding the efficacy and safety of LCZ696 as compared to other ACEis and ARBs with regards to the treatment of HF.We systematically searched databases, including PubMed, Embase, and the Cochrane Library, for relevant randomized controlled trials (RCTs). The outcome measures included all-cause mortality, rate of hospitalizations for HF, rate of death from cardiovascular causes, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and decline of renal function.Five RCTs involving 19,078 patients were identified. The meta-analysis indicated that LCZ696 was associated with a significant reduction in all-cause mortality (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.76-0.93; P = .0005), rate of hospitalizations for HF (HR = 0.80; 95% CI, 0.73-0.87; P .00001), reduction in NT-proBNP levels (rate ratio = 0.78; 95% CI, 0.70-0.88; P .0001), and decline in renal function (odds ratio = 0.77; 95% CI, 0.68-0.88; P .0001) compared with ACEis and ARBs. However, there was no statistical difference in the rate of death from cardiovascular causes (HR = 0.86; 95% CI, 0.72-1.03; P = .09) between LCZ696 and ACEis and ARBs.LCZ696 is superior to ACEis and ARBs in the treatment of HF. Hence, it should be more widely used clinically.

Background: School bullying is a major public health problem with a large impact on children’s health. There is an increasing number of cases of school bullying reported in China. Studies have shown that the health consequences of different ways of responding to school bullying may be quite different and that psychological resilience is also closely related to aggressive behaviors. However, there has been little research on whether individuals with different psychological resilience levels respond differently. Objective: To explore the relationship between responses to school bullying and psychological resilience, which may provide new ideas and strategies to better prevent and intervene in school bullying. Methods: A random sample of 5425 primary school students aged 7–14 years were recruited in Luzhou, China. All students completed a questionnaire anonymously. The statistical significance of differences between groups was tested using the χ2 test or t test. Binary logistic regression was conducted to explore the relationship between responses and psychological resilience. Results: Over two-thirds of primary school students in this study reported experiencing bullying in the past year. The rate of positive responses among victims was 69.10% (2596/3757, 95% CI: 67.62~70.58%). There was a positive relationship between psychological resilience and positive responses. This relationship was observed for all victims (OR = 1.605, 95% CI: 1.254~2.055), especially male victims (OR = 2.300, 95% CI: 1.624~3.259). Conclusions: There was a positive relationship between primary school bullying responses and psychological resilience among victims, with differences by sex. Therefore, increasing students’ level of psychological resilience, possibly by improving their responses, is important for preventing school bullying. Meanwhile, effective interventions for school bullying should be developed from multiple perspectives, particularly sex, bullying roles, and psychological resilience.

To compare the effectiveness of Logistic regression, BP neural network and support vector machine models in the prediction of 30-day risk of readmission in elderly patients with an exacerbation of chronic obstructive pulmonary disease (COPD) and to provide a scientific basis for the screening and prevention of high-risk patients with readmission.The COPD patient survey questionnaire was made, including the general data questionnaire, modified Medical Research Council dyspnea scale (mMRC), activities of daily living (ADL), the geriatric depression scale, the mini nutritional assessment-short form (MNA-SF) and COPD assessment test (CAT). Elderly COPD patients were selected from the department of respiratory medicine of 13 general hospitals in Ningxia from April 2019 to August 2020 by convenience sampling method, and they were followed up 30 days after discharge. To explore the risk factors of patient readmission, Logistic regression model, BP neural network model and support vector machine models were constructed based on the risk factors. According to the ratio of the training set to the testing set of 7:3, the model was divided into the training set sample and the testing set sample. The prediction efficiency of the model was compared by the precision rate, recall rate and accuracy rate, F1 index and the area under the receiver operator characteristic curve (AUC).A total of 1 120 patients were investigated, including 879 non-readmission patients and 241 readmission patients. Univariate regression analysis showed that there were statistically significant differences in age, education level, smoking status, proportion of diabetes and coronary heart disease, hospitalization times of acute exacerbation of COPD in the past 1 year, seasonal factors and long-term home oxygen therapy, regular medication, proportion of rehabilitation exercise, course of disease, ADL, depression status, mMRC, nutritional status between non-readmission patients and readmission patients. Binary Logistic regression analysis showed that education level, smoking status, coronary heart disease, hospitalization times of acute exacerbation of COPD in the past 1 year, seasonal factors, whether long-term home oxygen therapy, whether regular medication, nutritional status were the risk factors for 30-day acute exacerbation of readmission in elderly patients with COPD. The training set showed that the accuracy rate of Logistic regression model, BP neural network model and support vector machine models were 70.95%, 76.51% and 84.78%, respectively. The recall rates were 79.55%, 86.36% and 88.64%, respectively. The accuracy rates were 87.81%, 90.81% and 93.82%, respectively. F1 indexes were 0.75, 0.81 and 0.87, respectively. The AUC were 0.850, 0.893 and 0.921, respectively. The testing set showed that the precision rate of Logistic regression model, BP neural network model and support vector machine model were 78.38%, 80.65% and 88.57%, respectively. The recall rates were 70.73%, 60.98% and 75.61%, respectively. The accuracy rates were 85.82%, 84.40% and 90.07%, respectively. F1 indexes were 0.74, 0.69 and 0.82, respectively. The AUC were 0.814, 0.775 and 0.858, respectively.Comparing with Logistic regression and BP neural network, support vector machine model has better prediction effect, and can effectively predict the risk of acute exacerbation of readmission in elderly patients with COPD within 30 days.

The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.

Human use experience(HUE) is important for the research and development of Chinese medicine. For the sake of more reliable data, the Professional Committee for Clinical Evaluation of Chinese Medicine of Chinese Pharmaceutical Association drafted the Expert Consensus on Human Use Experience Research of Traditional Chinese Medicine. It highlights that the research on HUE should have clear purposes, describe the theoretical basis of traditional Chinese medicine(TCM) for the clinical indications and prescriptions and the clinical value of prescriptions, especially the advantages or characteristics in clinical orientation and target population, evaluate the dosages and number of medicinals of prescriptions, verify the accordance with the preparation process of new Chinese medicine, analyze feasibility of the process for large-scale production and the rationality of the dosage form, and assess the medicinal material resources. Moreover, such research should have reasonable protocol and the collection of clinical data on HUE must comply with medical ethics and avoid conflicts of interest. The collection method should be selected depending on the characteristics of clinical data. Quality control measures should be formulated to ensure the authenticity, accuracy, completeness, reliability, and traceability of clinical data. The definitions on the clinical data should be uniform and clear, and methods should be adopted to avoid bias. The data can be statistically analyzed after the processing. Through the study of HUE, the clinical orientation, target population, commonly used dosage, course of treatment, preliminary efficacy and safety of Chinese medicine prescriptions will be clarified. On this basis, the data on the HUE should be discussed and conclusions will be drawn. Finally, a standardized report will be formed.