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biBackground:/i/bThe microbial community in human milk is associated with many maternal and neonatal factors. This study aimed to investigate the effect of antibiotic exposure on the microbial community structure of colostrum.biMethods:/i/bTwenty women with antibiotic treatment immediately after delivery and 10 age-matched control women were enrolled at the Guangdong Women and Children Hospital. Colostrum samples were collected within postpartum 30 hours. The V4 variable region of the bacterial 16S rRNA gene was sequenced to characterize the microbial profile using Illumina MiSeq platform.biResults:/i/bPhylaiProteobacteria/iandiFirmicutes/iwere the predominant bacteria in colostrum samples. The core and abundant genera in colostrum includediStreptococcus/i,iStaphylococcus/i, andiPseudomonas/i. Compared with the control group, principal coordinate analysis based on the Bray-Curtis distance showed a significant difference in milk microbial community in women with antibiotic exposure, accompanied by a significantly lower alpha diversity and a different microbial ecological network. Furthermore, the relative abundances of generaiActinomyces/i,iAnaerobacter/i, andiClostridium_/isensui_stricto/isignificantly decreased after antibiotic treatment.biConclusions:/i/bThis study provided evidence of alterations in the colostrum microbial community with antibiotic exposure, improving our understanding of the effects of antibiotic treatment on the milk microbiome.

Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells to promote malignant tumor survival. Designing drugs that inhibit TrxR activity is a promising approach to achieve highly effective cancer chemotherapy. However, the selectivity of TrxR inhibitors continue to be a challenge for scientists. In this work, we demonstrate a new strategy to selectively inhibit TrxR through constructing electrophilic center -N-Se(δ

Graphic Abstract The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide for almost 2 years. It starts from viral adherence to host cells through an interaction between spike glycoprotein 1 (S1) containing a receptor-binding domain (RBD) and human angiotensin-converting enzyme-2 (ACE2). One of the useful strategies to prevent SARS-CoV-2 infection is to inhibit the attachment of RBD to ACE2. Therefore, the current work proposed potent peptides against SARS-CoV-2 infection by carrying out MM-PBSA calculation based on the binding of 52 antiviral peptides (AVPs) to RBD. Considering the binding free energies of AVPs to RBD, cyanovirin-N (CV-N) showed the strongest RBD binding affinity among 52 AVPs. Upon structural analysis of RBD complex with CV-N, it was observed that 12 of the 13 key residues of RBD binding to ACE2 were hijacked by CV-N. CV-N bound to RBD at a smaller affinity of 14.9 nM than that of ACE2 and inhibited the recruitment of S1 to human alveolar epithelial cells. Further analysis revealed that CV-N suppressed SARS-CoV-2 S pseudovirion infection with a half-maximal inhibitory concentration (IC50) of 18.52 μg/mL. This study demonstrated a drug screening for AVPs against SARS-CoV-2 and discovered a peptide with inspiring antiviral properties, which provided a promising strategy for the COVID-19 therapeutic approach. Supplementary Information The online version contains supplementary material available at 10.1007/s12539-021-00477-w.

The ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg−1of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19.Graphical Table of Contents

Resting‐state functional connectivity in the human brain is heritable, and previous studies have investigated the genetic basis underlying functional connectivity. However, at present, the molecular mechanisms associated with functional network centrality are still largely unknown. In this study, functional networks were constructed, and the graph‐theory method was employed to calculate network centrality in 100 healthy young adults from the Human Connectome Project. Specifically, functional connectivity strength (FCS), also known as the “degree centrality” of weighted networks, is calculated to measure functional network centrality. A multivariate technique of partial least squares regression (PLSR) was then conducted to identify genes whose spatial expression profiles best predicted the FCS distribution. We found that FCS spatial distribution was significantly positively correlated with the expression of genes defined by the first PLSR component. The FCS‐related genes we identified were significantly enriched for ion channels, axon guidance, and synaptic transmission. Moreover, FCS‐related genes were preferentially expressed in cortical neurons and young adulthood and were enriched in numerous neurodegenerative and neuropsychiatric disorders. Furthermore, a series of validation and robustness analyses demonstrated the reliability of the results. Overall, our results suggest that the spatial distribution of FCS is modulated by the expression of a set of genes associated with ion channels, axon guidance, and synaptic transmission., This transcription‐neuroimaging association study identified that the expression profiles of a set of genes, especially those involved in processes related to ion channels, the axon guidance pathway and synaptic transmission, are related to FCS. These findings provide new insight into the biological substrates underlying intrinsic functional network centrality.

Studies have shown the indicative role of handgrip strength in health. However, there is limited evidence revealing its potential effect on death events among middle-aged and older adults in China. We aimed to prospectively evaluate if lower handgrip strength is associated with the event of death. Among 17,167 middle-aged and older adults between age 45 to 96, handgrip strength was collected by a handheld dynamometer in a Chinese longitudinal study of aging trend (CHARLS) 2011–2018. Using Cox proportional hazard models with exposures, we assessed the association between handgrip strength and death events. Elevated handgrip strength values were independently associated with the decreased death risk. These results illustrate that lower handgrip strength is an independent indicator of death risks among middle-aged and older Chinese, which highlights the significance of related intercessions. The median values of five levels of handgrip strength in the entire cohort were 16.5,23,28,33,42kg at baseline. A linear association existed between the handgrip strength values and the risk of all-cause death within 34.2kg. Handgrip strength can serve as an independent indicator for death risks.

Much evidence indicates the influence of the oxytocin receptor (OXTR) gene on autism spectrum disorders (ASDs), a set of disorders characterized by a range of deficits in prosocial behaviors, which are closely related to the personality trait of reward dependence (RD). However, we do not know the effect of the OXTR polygenic risk score for ASDs (OXTR-PRSASDs) on RD and its underlying neuroanatomical substrate. Here, we aimed to investigate associations among the OXTR-PRSASDs, gray matter volume (GMV), and RD in two independent datasets of healthy young adults (n = 450 and 540). We found that the individuals with higher OXTR-PRSASDs had lower RD and significantly smaller GMV in the right posterior insula and putamen. The GMV of this region showed a positive correlation with RD and a mediation effect on the association between OXTR-PRSASDs and RD. Moreover, the correlation map between OXTR-PRSASDs and GMV showed spatial correlation with OXTR gene expression. All results were highly consistent between the two datasets. These findings highlight a possible neural pathway by which the common variants in the OXTR gene associated with ASDs may jointly impact the GMV of the right posterior insula and putamen and further affect the personality trait of RD.

Backgroud: Cell membrane-based nanocarriers are promising candidates for delivering antitumor agents. The employment of a simple and feasible method to improve the tumor-targeting abilities of these systems is appealing for further application. Herein, we prepared a platelet membrane (PM)-camouflaged antitumor nanoparticle. The effects of irradiation pretreatment on tumor targeting of the nanomaterial and on its antitumor action were evaluated. Results: The biomimetic nanomaterial constructed by indocyanine green, poly(d,l-lactide-co-glycolide), and PM is termed PINPs@PM. A 4-Gy X-ray irradiation increased the proportions of G2/M phase and Caveolin-1 content in 4T1 breast cancer cells, contributing to an endocytic enhancement of PINPs@PM. PINPs@PM produced hyperthermia and reactive oxygen species upon excitation by near-infrared irradiation, which were detrimental to the cytoplasmic lysosome and resulted in cell death. Irradiation pretreatment thus strengthened the antitumor activity of PINPs@PM in vitro. Mice experiments revealed that irradiation enhanced the tumor targeting capability of PINPs@PM in vivo. When the same dose of PINPs@PM was intravenously administered, irradiated mice had a better outcome than did mice without X-ray pretreatment. Conclusion: The study demonstrates an effective strategy combining irradiation pretreatment and PM camouflage to deliver antitumor nanoparticles, which may be instrumental for targeted tumor therapy.

Objectives: To investigate VEGF and Ang-2 level changes in the systemic circulation after laser photocoagulation in premature infants with ROP. Methods: Eleven infants (4 girls and 7 boys) had seru...

Rationale: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear. Methods: We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31hiEmcnhi tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model. Results: We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31hiEmcnhi vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure. Conclusions: Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.

Background: Relapse and metastasis of patients with Colorectal Cancer (CRC) is the major obstacle to the long-term life of patients. Its mechanisms remain defined. Methods: A total of 48 CRC patients were enrolled and 68 samples were obtained from the peripheral blood of patients before or after treatments in this study. Twenty non-cancer patients were also detected as a negative control. Circulating Tumor Cells (CTCs), including Epithelial CTCs (eCTCs), Mesenchymal (MCTCs), and epithelial/ mesenchymal mixed phenotypes (mixed CTCs), were identified by CanPatrolTM CTC enrichment and RNA in situ hybridization. The relationship between CTCs number and Progression-Free Survival (PFS) or Overall Survival (OS) was evaluated. Results: Thirty-four of 48 patients (70.8%) were found to have positive CTCs. Total CTCs and MCTCs in the post-treatment had a significant correlation PFS and OS. When total CTCs or MCTCs in 5 mL blood of patients were more than 6 CTCs or 5 MCTCs, PFS of the patients was significantly shorter (p < 0.05) than that in patients with less than 6 CTCs or 5 MCTCs. The patients with > 5 CTCs count changes were found to exhibit poor PFS and OS rates (p < 0.05). Conclusion: Total CTCs and MCTCs number detection in patients with colorectal cancer was very useful biomarker for predicting the prognosis of patients. Higher CTCs or MCTCs had poorer PFS and OS rates.

Brain death (BD), the irreversible cessation of function in the whole brain, is a well-known condition in most countries. The criteria and practical guidelines for brain death determination (BDD) in China were issued by the Brain Injury Evaluation Quality Control Center (BQCC) of the National Health and Family Planning Commission in 2013. Thereafter, we proposed a plan called the three-step quality control plan (three-step QCP) to ensure the safety and consistency of the clinical judgments regarding BD. By retrospectively reviewing this plan, we aimed to identify problems during its implementation and to provide suggestions for future work on quality control for BDD.Data were retrieved from the BQCC database. The characteristics and test results of physicians undergoing a BDD training course and the BD case records submitted by hospitals before and after receiving accreditation were analyzed.In the first step of the plan, the error rate for physicians undergoing the BDD paper test was highest for limb movement discrimination (26.29%); this error rate was correlated with age (per 10-year increase) (odds ratio = 1.262, 95% confidence interval 1.067-1.491, P = 0.007) but was nonsignificantly associated with sex, specialty category, professional level, and hospital level (P 0.05). During the second step of the plan, the highest percentage of problems was associated with apnea testing (22.75%), followed by ancillary testing of BDD (16.17%). In the last step, the highest percentage of problems in the case records was associated with apnea testing (41.73%).The three-step QCP is of significant utility for ensuring accuracy and appropriateness in BDD. Simultaneously, this study provides important evidence for advancing quality control for BDD in the next stage.

Background Faecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium difficile infections and chronic gastrointestional infections. However, the risks of FMT and the selection process of suitable donors remain insufficiently characterized. The eligibility rate for screening, underlying microbial basis, and core ethical issues of stool donors for FMT are yet to be elucidated in China. Results The potential stool donors were screened from December 2017 to December 2019 with the help of an online survey, clinical assessments, and stool and blood testing. Bioinformatics analyses were performed, and the composition and stability of gut microbiota in stool obtained from eligible donors were dynamically observed using metagenomics. Meanwhile, we build a donor microbial evaluation index (DoMEI) for stool donor screening. In the screening process, we also focused on ethical principles and requirements. Of the 2071 participants, 66 donors were selected via the screening process (3.19% success rate). Although there were significant differences in gut microbiota among donors, we found that the changes in the gut microbiota of the same donor were typically more stable than those between donors over time. Conclusions DoMEI provides a potential reference index for regular stool donor re-evaluation. In this retrospective study, we summarised the donor recruitment and screening procedure ensuring the safety and tolerability for FMT in China. Based on the latest advances in this field, we carried out rigorous recommendation and method which can assist stool bank and clinicians to screen eligible stool donor for FMT.

Previous studies have demonstrated patients with autism spectrum disorder (ASD) are accompanied by alterations of spontaneous brain activity in gray matter. However, whether the alterations of spontaneous brain activity exist in white matter remains largely unclear. In this study, 88 ASD patients and 87 typical controls (TCs) were included and regional homogeneity (ReHo) was calculated to characterize spontaneous brain activity in white matter. Voxel-wise two-sample t-tests were performed to investigate ReHo alterations, and cluster-level analyses were conducted to examine structural-functional coupling changes. Compared with TCs, the ASD group showed significantly decreased ReHo in the left superior corona radiata and left posterior limb of internal capsule, and decreased ReHo in the left anterior corona radiata with a trend level of significance. In addition, significantly weaker structural-functional coupling was observed in the left superior corona radiata and left posterior limb of internal capsule in ASD patients. Taken together, these findings highlighted abnormalities of white matter's regional spontaneous brain activity in ASD, which may provide new insights into the pathophysiological mechanisms of this disorder.

Background Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune inflammatory disease predominantly found in women of child-bearing age. Neurogenic pulmonary edema (NPE) is a recalcitrant complication that occurs after injury to the central nervous system and has an acute onset and rapid progression. Limbic encephalitis is an inflammatory encephalopathy caused by viruses, immune responses, or other factors involving the limbic system. NPE caused by SLE is rare. Case presentation Here, we report a case of a 21-year-old woman with SLE who experienced five episodes of generalized tonic–clonic seizure after headache and dyspnea. Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 2 antibody was tested positive in the serum and cerebrospinal fluid. Electrocardiography (EEG) indicated paroxysmal or sporadic medium amplitude theta activity. In addition, chest computed tomography (CT) showed multiple diffuse consolidations and ground-glass opacities. We finally considered a diagnosis of NPE and AMPAR limbic encephalitis. The patient's symptoms improved obviously after methylprednisolone pulse therapy and antiepileptic treatment. Conclusions NPE can be a complication of neuropsychiatric lupus erythematosus (NPSLE). AMPAR2 antibodies may be produced in NPSLE patients, especially in those with high polyclonal IgG antibody titers. More basic and clinical studies are required to confirm these observations and elucidate the pathogenicity of encephalitis-related autoantibodies in SLE patients.

Background The roles played by cholesterol in cancer development and progression represent a popular field in the cancer community. High cholesterol levels are positively correlated with the risk of various types of cancer. APOA-I binding protein (AIBP) promotes the reverse cholesterol transport pathway (RCT) in cooperation with Apolipoprotein A-I (APOA-I) or high-density lipoprotein cholesterol. However, the combined effect of AIBP and APOA-I on intestinal tumor cells is still unclear. Methods Immunohistochemistry, western blot and qPCR were performed to investigate the expression of AIBP and APOA-I in intestinal tumor tissues and cell lines. The anti-tumor activity of AIBP and APOA-I was evaluated by overexpression or recombinant protein treatment. Cholesterol efflux and localization of lipid raft-related proteins were analyzed by a cholesterol efflux assay and lipid raft fraction assay, respectively. Results Here, we reported that both AIBP expression and APOA-I expression were associated with the degree of malignancy in intestinal tumors. Co-overexpression of AIBP and APOA-I more potently inhibited colon cancer cell-mediated tumor growth and metastasis compared to overexpression of each protein individually. Additionally, the recombinant fusion proteins of AIBP and APOA-I exhibited a significant therapeutic effect on tumor growth in Apcmin/+ mice as an inherited intestinal tumor model. The synergistic effect of the two proteins inhibited colon cancer cell migration, invasion and tumor-induced angiogenesis by promoting cholesterol efflux, reducing the membrane raft content, and eventually disrupting the proper localization of migration- and invasion-related proteins on the membrane raft. Moreover, cyclosporine A, a cholesterol efflux inhibitor, rescued the inhibitory effect induced by the combination of AIBP and APOA-I. Conclusions These results indicate that the combination of APOA-I and AIBP has an obvious anticancer effect on colorectal cancer by promoting cholesterol efflux. Electronic supplementary material The online version of this article (10.1186/s12967-019-1910-7) contains supplementary material, which is available to authorized users.

In order to develop a sensitive immunoassay for Aflatoxin B1 (AFB1) monitoring, a hybridoma secreting anti-AFB1 monoclonal antibody with high binding affinity was screened. A new type of CdTe/CdS/ZnS quantum dot was synthesized and conjugated with an artificial antigen for use as a fluorescent probe in a simple one-step fluorescence immunoassay (FLISA). The developed FLISA allowed a sensitive determination of AFB1 in cereal samples in a wide linear range, from 0.08 to 1.97 ng mL−1, with a detection limit of 0.01 ng mL−1 in cereal samples. The corresponding immunoglobulin genes of the Fab fragment were cloned and sequenced, and expression of Fab was successfully verified in HEK293 cells, with a KD value of 1.09 × 10−7 mol L−1 for AFB1. To investigate the interactions between the antibody and AFB1, molecular docking, molecular dynamic simulation, and quantum-chemical computation were performed on AFB1 and a homology model of the Fab fragment. Our results showed that residues Ser32, Trp93, and Trp98 played the most important roles in the binding through hydrogen bonds formation, Pi-Pi stacked/Pi-alkyl interactions, and van der Waals interactions. In addition, the electrostatic potential study of AFB1 demonstrated that electrostatic interactions also played an important role in the recognition process. Results from theoretical studies provide guidance for hapten design and antibody improvement through genetic engineering.

Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor-targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)-targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron-donating or -withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet-triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro-substituted benzenesulfonamide (ER-Cy-poNO

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19

SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD blockade, LL37 inhibits SARS-CoV-2 S pseudovirion infection, with a half-maximal inhibitory concentration of 4.74 μg/mL. Interestingly, LL37 also binds to ACE2 with an affinity of 25.5 nM and cloaks the ligand-binding domain (LBD), thereby decreasing S1 adherence and protecting cells against pseudovirion infection in vitro. Intranasal administration of LL37 to C57 mice infected with adenovirus expressing human ACE2 either before or after pseudovirion invasion decreased lung infection. The study identified a versatile antimicrobial peptide in humans as an inhibitor of SARS-CoV-2 attachment using dual mechanisms, thus providing a potential candidate for coronavirus disease 2019 (COVID-19) prevention and treatment.

Acute cerebral infarction is a form of Trousseau syndrome (TS), but is relatively rare and often overlooked by clinicians. The aim of this study was to investigate the clinical, laboratory and imaging features of acute cerebral infarction in non-small cell lung cancer (NSCLC) patients with TS.Clinical data, laboratory examination and imaging data of 25 NSCLC patients with TS presented with acute cerebral infarction were collected retrospectively for analysis.Of the 25 patients, 18 males and 7 females, aged 39-78 years old, including 22 cases of adenocarcinoma, 2 cases of squamous cell carcinoma, and 1 case of large cell carcinoma; all patients had clinical symptoms and signs of acute cerebral infarction; plasma D-dimer was significantly increased, and prothrombin time and activated partial thromboplastin time were shortened to varying degrees; all patients showed acute multiple cerebral infarction foci involving multiple intracranial arterial blood supply areas on plain head magnetic resonance imaging (MRI) [diffusion-weighted imaging (DWI) sequence], the blood supply vessel lumen corresponding to the infarction foci did not show moderate to severe stenosis on the head MR angiography (MRA).NSCLC with multiple acute cerebral infarctions is a rare manifestation of TS, which is characterized by multiple acute cerebral infarctions involving multiple arterial blood supply areas with significant hypercoagulability. Improving the early understanding of this disease can provide some help for clinical diagnosis and treatment.【中文题目：非小细胞肺癌合并Trousseau综合征 以急性脑梗死为表现的临床及影像学特征】 【中文摘要：背景与目的 急性脑梗死是Trousseau综合征（Trousseau syndrome, TS）的一种表现形式，但相对少见，往往容易被临床医师忽视。本研究探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）合并TS以急性脑梗死为表现的临床、实验室检查及影像学特点。方法 回顾性收集25例以急性脑梗死为表现的NSCLC合并TS患者的临床资料、实验室检查和影像学资料，进行分析总结。结果 25例患者中男性18例，女性7例，年龄39岁-78岁，其中腺癌22例、鳞癌2例和大细胞癌1例；所有患者均有急性脑梗死的临床症状和体征；血浆D-二聚体明显升高，凝血酶原时间及活化部分凝血活酶时间均有不同程度的缩短；所有患者在头部磁共振成像（magnetic resonance imaging, MRI）［扩散加权成像（diffusion-weighted imaging, DWI）序列］平扫上均表现为累及多个颅内动脉供血区的急性多发性脑梗死灶，头磁共振血管成像（MR angiography, MRA）上梗死灶对应的供血血管管腔未见中重度狭窄。结论 NSCLC合并急性多发性脑梗死是TS的少见表现类型，其特点是累及多个动脉供血区的急性多发性脑梗死灶伴有明显高凝状态；提高对该病的早期认识可以为临床诊疗提供一定的帮助。 】 【中文关键词：Trousseau综合征；肺肿瘤；脑梗死；高凝状态；磁共振；扩散加权成像】.

Background. Helicobacter pylori eradication with therapies employing a proton pump inhibitor (PPI) and antimicrobial agents is mainly achieved via bacterial susceptibility to antimicrobial agents and the magnitude of acid secretion inhibition. However, annual eradication rates have greatly declined in Mainland China, and therefore, tailored H. pylori eradication regimens that inhibit acid secretion and employ optimal antimicrobial agents determined based on gene clip testing may improve eradication rates. This study was aimed at evaluating the efficacy of tailored H. pylori eradication therapy guided by visual gene clip testing for antibiotic resistance and PPI metabolism genotypes. Methods. This prospective study included 244 patients (141 men and 103 women aged 20–79 years) receiving initial treatment for H. pylori infection. Visual gene clip testing using gastric mucosal specimens was performed to detect antibiotic resistance to clarithromycin conferred by the A2142G and A2143G point mutations of the H. pylori 23S rRNA gene and to levofloxacin conferred by the Asn87 and Asp91 point mutations of the H. pylori gyrA gene. Patients received a 14-day bismuth quadruple therapy regimen guided by testing for antibiotic resistance and CYP2C19 polymorphisms, and primary H. pylori eradication was assessed at least 4 weeks after therapy. Results. H. pylori strains were successfully isolated from the gastric mucosa tissues of 244 patients. Antibiotic resistant isolates were identified in 63 patients, with clarithromycin resistance observed in 50 patients, levofloxacin resistance in 7 patients, and dual resistance in 6 patients. The PPI metabolic genotype of CYP2C19 was detected in 242 of 244 cases, and 97 cases were categorized as extensive metabolizers, 141 as intermediate metabolizers, and 4 as poor metabolizers. Among the 242 patients who received tailored therapy, the H. pylori eradication rate was 90.9% (95% confidence interval 87.3%~94.6%) in the intention-to-treat analysis and 96.9% (95% confidence interval 94.7%~99.2%) in the per protocol analysis. Conclusions. Tailored therapy for H. pylori infection guided by determination of antibiotic resistance and CYP2C19 polymorphism using visual gene chip technology may provide high clinical effectiveness as initial H. pylori eradication therapy.

Kinesin family member 4A (KIF4A), located in the human chromosome band Xq13.1, is aberrantly overexpressed in various cancers. Our study intended to assess the expression of KIF4A in insulinoma and to gain new insights into the molecular mechanisms of this rare disease. First, KIF4A was significantly recruited in pancreatic endocrine cells relative to other cell types. A significant correlation existed between the overexpression of KIF4A and the poor survival of pancreatic adenocarcinoma patients. As revealed by CCK-8, TUNEL assay, flow cytometry, wound healing, Matrigel-transwell, senescence-associated β-galactosidase staining, ELISA, and subcutaneous tumor formation analysis in nude mice, knocking down KIF4A significantly inhibited the growth and metastasis of insulinoma cells in vivo and in vitro. Mechanistically, we observed that KIF4A promoter sequences had reduced H3K27me3 modifications, and decline in enhancer of zeste homolog-2 (EZH2) expression promoted KIF4A expression by reducing the modification, thus leading to insulinoma. Moreover, EZH2 knockdown-induced insulinoma cell proliferation was dependent on KIF4A overexpression since KIF4A knockdown eradicated shEZH2-induced proliferation of insulinoma cells. In summary, KIF4A was identified as a possible therapeutic target for insulinoma.

Cytosolic DNA sensing is a fundamental mechanism by which organisms handle various stresses, including infection and genotoxicity. The hematopoietic system is sensitive to stresses, and hematopoietic changes are often rapid and the first response to stresses. Based on the transcriptome database, cytosolic DNA sensing pathways are widely expressed in the hematopoietic system, and components of these pathways may be expressed at even higher levels in hematopoietic stem and progenitor cells (HSPCs) than in their certain progeny immune cells. Recent studies have described a previously unrecognized role for cytosolic DNA sensing pathways in the regulation of hematopoiesis under both homeostatic and stress conditions. In particular, the recently discovered cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical modulator of hematopoiesis. Perturbation of the cGAS-STING pathway in HSPCs may be involved in the pathogenesis of hematopoietic disorders, autoimmune diseases, and inflammation-related diseases and may be candidate therapeutic targets. In this review, we focus on the recent findings of the cGAS-STING pathway in the regulation of hematopoiesis, and its physiopathological significance including its implications in diseases and therapeutic potential.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Recent studies showed that snRNPs were implicated in human cancer development. The role of SNRPA1, which is a member of U2 snRNPs, in HCC, remains undocumented. Here, we found that SNRPA1 was highly expressed in HCC tissue compared with normal adjacent liver tissues. Up-regulation of SNRPA1 was correlated with the clinical stage of HCC and the overall survival of HCC patients. In vitro and in vivo results showed that knockdown of SNPRA1 inhibited the cell proliferation, colony formation and xenografted tumorigenesis of HCC cells. Apoptosis was induced by SNPRA1 down-regulation. Mechanistically, SNPRA1 was stimulated by mTOR activation. In addition, whole-genome microarray analysis identified that 262 genes were up-regulated and 462 genes were down-regulated by SNPRA1 knockdown in HCC cells. qPCR analysis suggested that the fibroblast growth factor-2 (FGF2), Alpha-fetoprotein (AFP), β-catenin, Ki-67 and cyclin B1 were down-regulated and caspase 3, p53 as well as p21 were up-regulated after SNRPA1 knockdown. Taken together, our findings implicate that SNPRA1 functions as an oncogene in HCC.

The topics of human health and disease are always the focus of much attention. Hydrogen sulfide (H

Natural killer (NK)–cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Targeted deletion of SRC-3 altered normal NK-cell distribution and compromised NK-cell maturation. SRC-3 deficiency led to significantly impaired NK-cell functions, especially their antitumor activity. The expression of several critical T-bet target genes, including Zeb2, Prdm1, and S1pr5, but not T-bet itself, was markedly decreased in NK cells in the absence of SRC-3. There was a physiologic interaction between SRC-3 and T-bet proteins, where SRC-3 was recruited by T-bet to regulate the transcription of the aforementioned genes. Collectively, our findings unmask a previously unrecognized role of SRC-3 as a coactivator of T-bet in NK-cell biology and indicate that targeting SRC-3 may be a promising strategy to increase the tumor surveillance function of NK cells.

Fusobacterium nucleatum. nucleatum (Fn.n) is associated with colorectal carcinoma. A highly sensitive fluorescence quenching-recovery detection platform based on rolling circle amplification and hairpin molecular beacon technology for the specific analysis of Fn.n, hairpin MB being used to achieve double quenching. First, a specific recognition sequence target in the padlock probe was designed based on the nusG specific gene of Fn.n. The padlock probe then formed circular DNA using the ligase. After digestion, linear amplification was achieved by the phi29 DNA polymerase and the RCA primer, and a large amount of amplified products was obtained. Subsequently, the amplification products hybridized with the signal probe, leading to the opening of the hairpin structure in MBs. As a result, FAM at 5′ end and BHQ-1 at 3' end became separated, which allowed for the recovery of the fluorescence signal. The proposed method showed high sensitivity and specificity for the detection of Fn.n genomic DNA (LOD as low as 0.7 ng L−1) and performed well in the identification of this bacteria in real samples.

Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.

Ionizing radiation (IR) triggers the generation of reactive oxygen species (ROS), which shows potential roles in damaging the DNA and proteins at the nucleus, and eventually results in apoptosis and even cell death. Antioxidant agents can inhibit the generation of ROS after IR exposure. Tannic acid (TA), has an antioxidant activity involving in preventing cardiovascular and cerebrovascular diseases. However, little is known about the effects of TA on irradiation-induced apoptosis in megakaryocytes. Here, we evaluated the anti-radiation activity of TA in megakaryocytes. Our results showed that TA protected megakaryocytes from apoptosis induced by IR, attenuated IR-induced increases in the production of ROS, and inhibited the changes of mitochondrial membrane potential (MMP). Moreover, TA down-regulated NAPDH oxidase 1 (Nox1) expression, and decreased the phosphorylated levels of JNK and p38. Furthermore, JNK inhibitor could reduce apoptosis induced by X-irradiation in M07e cells. In vivo experiments confirmed that TA could promote the platelet recovery, reduce the percentage of apoptosis CD41+ megakaryocytes in bone marrow and raise survival during 30 days in mice by total body irradiation. In conclusion, TA can protecte the megakaryocytes from apoptosis caused by IR through inhibiting Nox1 expression to reduce ROS generation and repressing JNK/p38 MAPK pathway activation.

Atherosclerosis (AS) is the main cause of cardiovascular diseases (CADs). Lipid accumulation and inflammatory response in macrophages are two key factors in the pathogenesis of AS. In this study, we aimed to explore the regulating role of long non-coding RNA (LncRNA)-H19 in oxygenized low density lipoprotein (ox-LDL)-treated Raw264.7 cells. Compared with the healthy control, a relatively higher level of H19 was detected in the blood samples from AS patients. Obviously up-regulated expression of TG (triglycerides)/TC (total cholesterol)/LDL-C (low density lipoprotein-cholesterol) and down-regulated level of HDL-C (high density lipoprotein-cholesterol) were detected in ox-LDL-treated Raw264.7 cells. Besides that, increased expression of H19 was detected in ox-LDL-treated Raw264.7 cells. To examine the function of H19, gene knockdown was performed using short hairpin RNAs (shRNAs). The expression of TG, TC, LDL-C and HDL-C was detected by enzyme linked immunosorbent assay (Elisa) and the expression of lipolytic genes/lipogenic genes (PPARα, CPT-1/REBP-1c, ACS) was examined through western blot. In combination with the result of oil red O staining, we concluded that H19 shRNA effectively decreased lipid accumulation in ox-LDL-treated Raw264.7 cells. Besides that, H19 shRNA decreased the level of pro-inflammatory factors (TNF-α, IL-1β)/CD68+ cells and increased the level of anti-inflammatory factors (IL-4, IL-10)/CD163+ cells compared with the control group. Combined the bioinformatics analyses/luciferase assay with the promoting effect of H19 shRNA on the expression of miR-130b, we speculated that miR-130b was a target of H19 in ox-LDL-treated Raw264.7 cells. Moreover, the adding of LncRNA H19 abolished the facilitating effect of miR-130b inhibitor on adipogenesis and inflammation response by up-regulating the expression of miR-130b. Taken together, our research indicated a H19-miR130b pathway in regulating lipid metabolism and inflammation response in ox-LDL-treated Raw264.7 cells, providing new targets for AS treatment.

Background Circular RNAs (circRNAs) are implicated in modulating cancer progression, exerting a pro- or anti-cancer effect. This work is aimed to probe the biological function of circ_0084615 in colorectal cancer (CRC) and its underlying mechanism. Methods Circ_0084615 was selected from two circRNA microarray datasets (GSE138589 and GSE142837). Circ_0084615, microRNA (miR)-599 and DNA methyltransferases 3A (DNMT3A) mRNA expression in CRC tissues and cell lines were examined by qRT-PCR. The relationship between circ_0084615 expression level and clinical features were analyzed with chi-square test. Circ_0084615 knockdown model was constructed by siRNA in two CRC cell lines. The biological functions of circ_0084615 in CRC cells were evaluated by CCK-8 and Transwell experiments. The effect of circ_0084615 on CRC cell metastasis in vivo was examined with lung metastasis model of nude mice. Dual luciferase reporter gene assay was used to determine whether circ_0084615 and miR-599, and miR-599 and DNMT3A interacted with each other. Western blot was employed to examine the regulatory effects of circ_0084615 and miR-599 on DNMT3A protein expression in CRC cells. Results Circ_0084615 was up-regulated in CRC and was correlated with poor overall survival rate and advanced clinical stage of CRC patients. Functional assays validated that depletion of circ_0084615 impeded CRC cell proliferation, migration and invasion. Circ_0084615 acted as a molecular sponge for miR-599 to repress its expression. DNMT3A was a downstream target of miR-599. Functional compensation experiments showed that miR-599 inhibitors partially counteracted the the biological effects of silencing circ_0084615 on CRC cells. Conclusions Circ_0084615 is a tumor-promoting circRNA in CRC that functions as a competing endogenous RNA to regulate DNMT3A expression via sponging miR-599. Our research provides a potential therapeutic target for CRC patients.

Graphical abstract, The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global concern and necessitates efficient drug antagonists. Angiotensin-converting enzyme-2 (ACE2) is the main receptor of SARS-CoV-2 spike 1 (S1), which mediates viral invasion into host cells. Herein, we designed and prepared short peptide inhibitors containing 4–6 critical residues of ACE2 that contribute to the interaction with SARS-CoV-2 S1. Among the candidates, a peptide termed GK-7 (GKGDFRI), which was designed by extracting residues ranging from Gly353 to Ile359 in the ligand-binding domain of ACE2, exhibited the highest binding affinity (25.1 nM) with the SARS-CoV-2 spike receptor-binding domain (RBD). GK-7 bound to the RBD and decreased SARS-CoV-2 S1 attachment to A549 human alveolar epithelial cells. Owing to spike blockade, GK-7 inhibited SARS-CoV-2 spike pseudovirion infection in a dose-dependent manner, with a half-maximal inhibitory concentration of 2.96 μg/mL. Inspiringly, pulmonary delivery of GK-7 by intranasal administration did not result in toxicity in mice. This study revealed an easy-to-produce peptide inhibitor for SARS-CoV-2 spike blockade, thus providing a promising candidate for COVID-19 treatment.

Dopamine (DA), a catecholamine neurotransmitter, is known to for its diverse roles on hematopoiesis, yet its function in thrombopoiesis remains poorly understood. This study shows that DA stimulation can directly induce platelet production from megakaryocytes (MKs) in the final stages of thrombopoiesis via a reactive oxygen species (ROS)-dependent pathway. The mechanism was suggested by the results that DA treatment could significantly elevate the ROS levels in MKs, and time-dependently activate oxidative stress-mediated signaling, including p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, and caspase-3 signaling pathways, while the antioxidants N-acetylcysteine and L-glutathione could effectively inhibit the activation of these signaling pathways, as well as the ROS increase and platelet production triggered by DA. Therefore, our data revealed that the direct role and mechanism of DA in thrombopoiesis, which provides new insights into the function recognition of DA in hematopoiesis.

A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity). We used a stepwise imaging genetics approach in 328 healthy young adults to test the hypothesis that 10 SNPs in OXTR are associated with differences in DMN synchronicity and structure of some of the associated brain regions. As OXTR effects may be sex-dependent, we also tested whether our findings were modulated by sex. OXTR rs2254298 A allele carriers had significantly lower rsFC with PCC in a cluster extending from the right fronto-insular cortex to the putamen and globus pallidus, and in bilateral dorsal anterior cingulate cortex (dACC) compared to individuals with the GG genotype; all observed effects were found only in males. Moreover, compared to the male individuals with GG genotype ofrs2254298, the male A allele carriers demonstrated significantly thinner cortical gray matter in the bilateral dACC. Our findings suggest that there may be sexually dimorphic mechanisms by which a naturally occurring variation of the OXTR gene may influence brain structure and function in DMN-related regions implicated in neuropsychiatric disorders.

A growing body of evidence indicates that S100 calcium‑binding protein A8 (S100A8) is frequently overexpressed in malignant tumor tissues and regulates tumor progression; however, the role of S100A8 in cholangiocarcinoma (CCA) remains unclear. The present study demonstrated that the protein expression of S100A8 was significantly higher in pathological tissues compared with adjacent normal tissues from patients with CCA. In addition, S100A8 expression was significantly associated with differentiation, lymph node metastasis and poor prognosis in patients following surgical resection of CCA. Furthermore, both in vitro and in vivo experiments revealed that overexpression of S100A8 promoted, while S100A8 knockdown attenuated, the migration and metastasis of CCA cells. Of note, the present results indicated that S100A8 promoted the CCA tumor cell‑induced migration of vascular endothelial cells. Finally, S100A8 was demonstrated to positively regulate the expression of vascular endothelial growth factor (VEGF) in CCA cells, which was mediated by activation of the Toll‑like receptor 4 (TLR4)/NF‑κB pathway. In conclusion, the present study demonstrated that S100A8 had an important role in facilitating CCA cell migration and metastasis via upregulation of VEGF expression by activating the TLR4/NF‑κB pathway. These findings may provide a novel target for CCA treatment.[the original article was published in International Journal of Oncology 56: 101‑112, 2020; DOI: 10.3892/ijo.2019.4907].

The activation and execution of cancer invasion and metastasis involves a complex network of intracellular and extracellular molecule levels (such as reactive oxygen species (ROS), matrix metalloproteinases (MMPs)) and signaling cascades. Fluorescence sensing is a powerful detection tool for analytes. However, for imaging the intracellular signal cascades involving multiple molecules, traditional fluorescence probes are unsuitable, because most of them can only determine the change of species rather than response of multiple species simultaneously. Herein we constructed a novel probe: a H2O2-responding fluorophore donor was linked to a MMP2-sensitive peptide tagged with a FRET Cy5 acceptor. Upon addition of H2O2, the system was subjected to green fluorescence emission (555 nm), further triggering a brighter red fluorescent emission (672 nm, belonging to Cy5 acceptor), owing to FRET. In contrast, in the presence of MMP2, the FRET was turned off, due to the special cleavage of the peptide linker. The stimulation with H2O2 made the probe-loaded living cells emit multicolor fluorescence, mainly red fluorescence in normal RAW264.7 cells and poorly invasive MCF7 cells, and only green fluorescence in highly invasive MDA-MA-231 cells, owing to overexpressed MMP2. This means that after the activation with H2O2, the probe can be used to distinguish MDA-MA-231 cells from RAW264.7 macrophages and MCF7 cells. Therefore, this multicolor fluorescent probe is a powerful tool in monitoring cancer invasion and metastasis, which will provide precision information for cancer control and cure.

Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34+ and CD41+ cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation-induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3-kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1-orchestrated activation of ERK1/2 and Akt signaling.

Few studies determined the role of intracellular labile Ca

Glutenin is the main protein of flour and is a very important source of protein nutrition for humans. Methylglyoxal (MGO) is an important product of the Maillard reaction that occurs during the hot-processing of flour products, and it reacts with glutenin to facilitate changes in glutenin properties. Here, the effects of MGO on glutenin digestion during the heating process were investigated using a simulated MGO-glutenin system. MGO significantly reduced the digestibility of glutenin. The structure of MGO-glutenin and physicochemical properties were studied to understand the mechanism of the decrease of digestibility. These data suggest that changes in digestibility were caused by decreases in surface hydrophobicity and increases in disulfide bonds. MGO induces strong aggregation of glutenin after heating that led to the masking of cleavage sites for proteases. Moreover, carbonyl oxidation induced by MGO leads to intermolecular cross-linking of glutenin that increasingly masks or even destroys cleavage sites, further decreasing digestibility.

Folic acid (FA) is an essential vitamin in humans, and thus, rapid, accurate, and sensitive methods for its quantification in different biological samples are needed. This work describes a novel, simple, and effective dual-emission fluorescence nanoprobe for FA detection and quantification. The probe was covalently linked to amino-modified orange quantum dots (QDs) and carboxyl-modified blue graphene quantum dots (GQDs). The resulting material exhibited two emission peaks at 401 and 605 nm upon excitation at 310 nm. The probe had good selectivity and sensitivity toward FA with an exceptionally low detection limit (LOD = 0.09 nM). This probe was effectively used to quantify FA in animal serum samples. The method has potential utility for FA analysis in different types of biological samples. Graphical abstract.

Bismuth-containing nanoparticles (BNPs) are potential enhancers for tumor radiotherapy. Improving the bioavailability and developing synergistic therapeutic regimens benefit the drug transformation of BNPs. In the present study, we prepare a mesoporous silica-coated bismuth nanorod (BMSNR) camouflaged by a platelet membrane (PM). This biomimetic material is termed BMSNR@PM. The PM camouflage enhances the immune escape of the BMSNRs by lowering endocytosis by macrophages in the reticuloendothelial system. Additionally, the PM camouflage strengthens the material tumor-targeting capacity and leads to better radiotherapeutic efficacy compared with bare BMSNRs. Owing to the photothermal effect, BMSNR@PMs alters the cell cycle of 4T1 cancer cells post-treatment with 808 nm near-infrared irradiation (NIR). The proportions of S phase and G2/M phase cells decrease and increase, respectively, which explains the synergistic effect of NIR on BMSNR@PM-based radiotherapy. BMSNR@PMs efficiently eradicates cancer cells by the combined action of photothermal therapy (PTT) and radiotherapy in vivo and markedly improves the survival of 4T1-tumor-bearing mice. The synergistic therapeutic effect is superior to the outcomes of PTT and radiotherapy performed alone. Our study demonstrates a versatile bismuth-containing nanoplatform with tumor-targeting, immune escape, and radiosensitizing functionalities using an autologous cell membrane biomimetic concept that may promote the development of radiotherapy enhancers.

Alterations to the gut microbiota have been previously suggested to be tightly linked to chronic systemic inflammation, which is a major contributing factor to complications and disease progression in chronic kidney disease (CKD). Nevertheless, the effect of gut dysbiosis on the pathogenesis and/or production of inflammatory factors in CKD has not been extensively studied to date. In the present study, we conducted 16S ribosomal DNA pyrosequencing using fecal microbiota samples and analyzed the production of serum inflammatory factors in 50 patients with CKD and 22 healthy control (HC) subjects. The results revealed that compared to the HC subjects, patients with CKD exhibited a significant reduction in the richness and structure of their fecal microbiota. At the phylum level, compared to the HC group, patients with CKD also presented reduced abundance of Actinobacteria but increased abundance of Verrucomicrobia. Moreover, the genera Lactobacillus, Clostridium IV, Paraprevotella, Clostridium sensu stricto, Desulfovibrio, and Alloprevotella were enriched in the fecal samples of patients with CKD, while Akkermansia and Parasutterella were enriched in those of the HC subjects. The abundance of Akkermansia in the CKD group was significantly lower than that in the HC group (3.08 vs. 0.67%); this decrease in the abundance of Akkermansia, an important probiotic, in patients with CKD is a striking discovery as it has not been previously reported. Finally, we analyzed whether these changes to the fecal microbiota correlated with CKD clinical characteristics and/or the production of known inflammatory factors. Altered levels of the microbiota genera Parasutterella, Lactobacillus, Paraprevotella, Clostridium sensu stricto, and Desulfovibrio were shown to be correlated with CKD disease-severity indicators, including the estimated glomerular filtration rate. Most notably, Akkermansia was significantly negatively correlated with the production of interleukin-10. The results of the present study suggest that microbiota dysbiosis may promote chronic systemic inflammation in CKD. Furthermore, they support that modifying the gut microbiota, especially Akkermansia, may be a promising potential therapeutic strategy to attenuate the progression of, and/or systemic inflammation in, CKD.

Antimicrobial peptides (AMPs) that are able to neutralize toxins are promising antibiotics. In this study we investigated the role of structurally conserved amino acids in reduced human defensin 5 (HD5RED ), which is an endogenous peptide with antibacterial action and the ability to neutralize lipopolysaccharide (LPS). Cys residues and high Arg content, rather than Gly18 and Arg6 -Glu14 , were found to be indispensable for HD5RED binding to lipid A, for penetrating the bacterial outer and inner membranes, and for eliminating bacteria. Otherwise, all the conserved sites were requisite for HD5RED to block the interaction between LPS and LPS-binding protein and to suppress the TLR4-NF-κB signaling pathway initiated by LPS. Accordingly, we designed the acetamidomethylated Acm Cys-E21R-HD5RED , which was much more potent than HD5RED at eliminating bacteria and which can neutralize LPS. Acm Cys-E21R-HD5RED was also found to exhibit a synergistic effect with ciprofloxacin in killing multidrug-resistant Acinetobacter baumannii. The results of this study, in which multifunctional AMPs were designed based on structure-activity research, may help in the development of more peptide antibiotics.

Hematopoietic stem cells (HSCs) are characterized by a potent multilineage regenerative capability that is dependent on their quiescence property. In the past few decades, researchers have found many intrinsic and niche-derived factors that can regulate HSCs, whereas how to precisely control HSC behaviors remains elusive. Recently, mitochondrial metabolism has been shown to be involved in the regulation of HSC biology. The purpose of this review is to overview recent advances in the relationship between mitochondrial metabolism and maintenance of HSC quiescence.On the basis of fact that HSCs are heterogeneous populations that have their unique metabolic characteristics, increasing studies have demonstrated that the quiescence and function of HSCs are closely correlated with the mitochondrial mass and activity, as well as the levels of mitochondria-derived reactive oxygen species and metabolites. Apart from that, mitochondria have been reported to undergo internal protective programs, including mitochondrial unfolded protein response, autophagy and mitochondrial dynamics, which are beneficial to maintaining HSC homeostasis.The maintenance of HSC quiescence needs a metabolic balance in mitochondria, and unraveling the metabolic complexity may provide deep understanding of the functional heterogeneity of HSCs.

For the first time, a quantitative photothermal-sensing immunochromatographic sensor (PT-ICS) is described using Au nanoparticle-enhanced two-dimensional black phosphorus (BP-Au) as signal component for the photothermal-sensing antibody probe. BP-Au has good photothermal properties at 808 nm, and the photothermal conversion efficiency of the BP-Au nanosheet increased by 12.9% over the black phosphorus nanosheet alone. In addition, the antibody was more easily coupled to this nanosheet due to the good physical adsorption capacity of Au nanoparticles. We used this PT-ICS to detect veterinary antibiotics enrofloxacin (ENR), the photothermal-sensing antibody probe was competitive captured by ENR target and antigen coating on test (T) lines of the sensor. This process was exothermic under an 808 nm laser, and the thermal energy decreased as the ENR in the sample increased. This thermal energy was recorded by an infrared thermal imager or an infrared thermometer, and the concentration of the ENR residues in animal-derived foods was obtained by analyzing the temperature changes in T-lines. Under optimal conditions, the PT-ICS exhibited sensitive and specific detection of ENR from 0.03 μg/L to 10 μg/L with detection limits of 0.023 μg/L. The results agreed well with a commercial enzyme-linked-immunosorbent assay kit. This PT-ICS provided a promising strategy for the detection of ENR residues in animal-derived foods and expected to be used for the detection of other highly sensitive biomacromolecules.

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

Converging evidence from both human and animal studies has highlighted the pervasive role of the neuropeptide arginine vasopressin (AVP), which is mediated by arginine vasopressin receptor 1A (AVPR1A), in both social and nonsocial learning and memory. However, the effect of genetic variants in AVPR1A on verbal learning and memory is unknown. The hippocampus is a heterogeneous structure that consists of several anatomically and functionally distinct subfields, and it is the principal target structure for the memory-enhancing effect of AVP. We tested the hypothesis that genetic variants in the RS3 and RS1 repeat polymorphisms may influence verbal learning and memory performance evaluated by the California Verbal Learning Test-II (CVLT-II) by modulating the gray matter volume (GMV) and resting-state functional connectivity (rsFC) of whole hippocampus and its subfields in a large cohort of young healthy subjects (n = 1001). Using a short/long classification scheme for the repeat length of RS3 and RS1, we found that the individuals carrying more short alleles of RS3-RS1 haplotypes had poorer learning and memory performance compared to that of those carrying more long alleles. We also revealed that individuals carrying more short alleles exhibited a significantly smaller GMV in the left cornu ammonis (CA)2/3 and weaker rsFC of the left CA2/3-bilateral thalamic (primarily in medial prefrontal subfields) compared to those carrying more long alleles. Furthermore, multiple mediation analysis confirmed that these two hippocampal imaging measures jointly and fully mediated the relationship between the genetic variants in AVPR1A RS3-RS1 haplotypes and the individual differences in verbal learning and memory performance. Our results suggest that genetic variants in AVPR1A RS3-RS1 haplotypes may affect verbal learning and memory performance in part by modulating the left hippocampal CA2/3 structure and its rsFC with the thalamus.