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To investigate the efficacy of chemotherapy combined with antivirals in adult T-cell leukemia/lymphoma (ATLL) patients and the prognostic factors.Forty nine patients with previously treated or treatment-nave ATLL from January 2018 to January 2021 were included in our study. The patients were divied into two groups according to whether they received antiviral treatment, twenty-seven patients were treated with chemotherapy combined with antivirals, including thirteen patients treated with recombinant interferon alpha-2b and CHOP therapy, eight patients treated with zidovudine combined with CHOP therapy, and 6 patients treated with CHOP regimen combined with interferon and zidovudine. Twenty-two patients were treated with CHOP therapy. The changes of symptom, hematological parameters, lactic dehydrogenase, β2-microglobulin, and the Ki-67 positive rate were compared between the two groups before and after treatments. The clinical efficacy of chemotherapy combined with antiviral therapy for ATLL was evaluated. The antiviral effect was assessed by detecting HTLV-1 virus copy number, and prognostic factors were analyzed.The median follow-up time was 14 months. Compared with the patients treated with chemotherapy alone, the patients treated with chemotherapy combined with antivirals had lower tumor and virus loads, lower white blood cell count, lower lactate dehydrogenase level, lower β2-microglobulin lever, and lower Ki-67 positive rate (all P0.05). The total effective rate of patients treated with chemotherapy combined with antivirals was significantly higher than those of patients treated with chemotherapy alone (63.0% vs 31.8%, P=0.035). The one-year overall survival (OS) rates of chemotherapy combined with antivirals groups and chemotherapy alone group were (74.1±2.9)％ and (40.9±2.1)％ (P=0.021), respectively. The one-year progress free survival (PFS) rates were (51.9±3.3)％ and (13.6±2.8)％ (P=0.017), respectively. Multivariable Cox regression analysis showed that HTLV-1 virus load (HR=7.518, 95%CI: 2.517-36.192, P=0.013) and antiviral therapy ［HR=5.617 (95%CI 1.803-11.293), P=0.027］ were independent prognostic factors for the long-term efficacy.Addition of antivirals to chemotherapy can prolong PFS and OS in ATLL patients. HTLV-1 virus load and antiviral therapy are independent prognostic factors for ATLL patients.化疗联合抗病毒治疗成人T细胞白血病/淋巴瘤的临床研究.探讨化疗联合抗病毒治疗成人T细胞白血病/淋巴瘤的疗效及相关预后因素.将2018年1月至2021年1月收治的49例既往确诊或新诊断的成人T细胞白血病/淋巴瘤患者纳入研究。根据是否行抗病毒治疗将患者分为2组，化疗联合抗病毒治疗组27例，其中13例用重组人α-2b干扰素联合CHOP方案治疗，8例用齐多夫定联合CHOP方案化疗，6例采用CHOP方案联合干扰素加齐多夫定治疗；单纯化疗组22例，单用CHOP治疗。通过比较2组患者治疗前后症状、血常规、LDH、β2微球蛋白、Ki-67等指标变化，评估化疗联合抗病毒治疗ATLL的临床疗效，检测HTLV-1病毒拷贝数以评价抗病毒的效果，并进行相关预后因素分析.中位随访时间为14个月。与单纯化疗相比，经化疗联合抗病毒治疗患者肿瘤负荷较治疗前明显减轻，HTLV-1病毒拷贝数明显下降，白细胞数、LDH、β2-MG、Ki-67阳性率及HTLV-1病毒量等指标均明显降低（P＜0.05）；化疗联合抗病毒组总有效率(CR+PR)明显高于单纯化疗组(63.0% vs 31.8%, P=0.035)。化疗联合抗病毒组、单纯化疗组患者1年总生存率分别为(74.1±2.9)％和(40.9±2.1)％（P=0.021），1年无进展生存率分别为(51.9±3.3)％和(13.6±2.8)％（P=0.017）。多因素分析结果显示，HTLV-1病毒量及是否抗病毒治疗为影响患者远期疗效的独立危险因素（HR=7.518， 95%CI： 2.517-36.192, P=0.013; HR=5.617， 95%CI： 1.803-11.293， P=0.027）.ATLL化疗基础上加用抗病毒可提高其疗效，延长其无进展生存时间及总体生存时间，HTLV-1病毒量及是否抗病毒治疗可影响患者长期预后.

Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.

Ineffective site-specific delivery has seriously impeded the efficacy of nanoparticle-based drugs to a disease site. Here, we report the preparation of three different shapes (sphere, scroll, and oblate) to systematically evaluate the impact of the marginative delivery on the efficacy of magnetic resonance (MR) imaging-guided X-ray irradiation at a low dose of 1 Gy. In addition to the shape effect, the therapeutic efficacy is investigated for the first time to be strongly related to the structure effect that is associated with the chemical activity. The enhanced particle-vessel wall interaction of both the flat scroll and oblate following margination dynamics leads to greater accumulation in the lungs, resulting in superior performance over the sphere against lung tumor growth and suppression of lung metastasis. Furthermore, the impact of the structural discrepancy in nanoparticles on therapeutic efficacy is considered. The tetragonal oblate reveals that the feasibility of the charge-transfer process outperforms the orthorhombic scroll and cubic sphere to suppress tumors. Finally, surface area is also a crucial factor affecting the efficacy of X-ray treatments from the as-prepared particles.

Enzymes achieve high substrate and product selectivities by orientating and activating the substrate(s) appropriately inside a confined and finely optimized binding pocket. Although some basic aspects of enzymes have already been mimicked successfully with man-made catalysts, substrate activation by proton wires inside enzyme pockets has not been recreated with man-made catalysts so far. A proton wire facilitates the dual activation of a nucleophile and an electrophile via a reciprocal proton transfer, enabling highly stereoselective reactions under mild conditions. Here we present evidence for such an activation mode inside the supramolecular resorcin[4]arene capsule and demonstrate that it enables catalytic and highly β-selective glycosylation reactions—still a major challenge in glycosylation chemistry. Extensive control experiments provide very strong evidence that the reactions take place inside the molecular container. We show that this activation strategy is compatible with a broad scope of glycoside donors and nucleophiles, and is only limited by the cavity size.

The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood1–3. Here, to identify a phenotypically robust core set of genes and pathways that enable cancer cells to evade killing mediated by cytotoxic T lymphocytes (CTLs), we performed genome-wide CRISPR screens across a panel of genetically diverse mouse cancer cell lines that were cultured in the presence of CTLs. We identify a core set of 182 genes across these mouse cancer models, the individual perturbation of which increases either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated manner in which genes and pathways act in cancer cells to orchestrate their evasion of CTLs, and shows that discrete functional modules that control the interferon response and tumour necrosis factor (TNF)-induced cytotoxicity are dominant sub-phenotypes. Our data establish a central role for genes that were previously identified as negative regulators of the type-II interferon response (for example, Ptpn2, Socs1 and Adar1) in mediating CTL evasion, and show that the lipid-droplet-related gene Fitm2 is required for maintaining cell fitness after exposure to interferon-γ (IFNγ). In addition, we identify the autophagy pathway as a conserved mediator of the evasion of CTLs by cancer cells, and show that this pathway is required to resist cytotoxicity induced by the cytokines IFNγ and TNF. Through the mapping of cytokine- and CTL-based genetic interactions, together with in vivo CRISPR screens, we show how the pleiotropic effects of autophagy control cancer-cell-intrinsic evasion of killing by CTLs and we highlight the importance of these effects within the tumour microenvironment. Collectively, these data expand our knowledge of the genetic circuits that are involved in the evasion of the immune system by cancer cells, and highlight genetic interactions that contribute to phenotypes associated with escape from killing by CTLs. Genome-wide CRISPR screens in mouse cancer cell lines are used to identify a core, conserved set of genes and pathways that govern how cancer cells evade killing by cytotoxic T lymphocytes.

Background Hypersplenism is a serious complication of portal hypertension (PH) and can affect the prognosis of liver disease. Liver stem cells (LSCs) are involved in liver regeneration and hepatocarcinogenesis after liver cirrhosis. Aim To explore the effects and mechanism of the spleen on the proliferation and differentiation of LSCs in PH due to liver cirrhosis. Methods Fetal liver stem cells (FLSCs) were treated with splenic serum from liver cirrhosis patients with hypersplenism and control serum from healthy volunteers, and the proliferation, self-renewal, and IGF-II/ERK signaling pathway of FLSCs were then evaluated. Results We found that splenic serum from PH patients promoted FLSC proliferation, colony formation, and Ki-67 expression in vitro. Splenic serum from PH also enhanced FLSC spheroid formation in vitro. Mechanistically, we determined that insulin-like growth factor (IGF)-II concentration was elevated in splenic serum from PH patients and could promote FLSC proliferation and self-renewal. Furthermore, both IGF-II and splenic serum from PH patients enhanced ERK signaling activation through IGF-I receptor (IGF-I R) in FLSCs. Consistently, blocking IGF-I R or ERK signaling could attenuate the effects of splenic serum from PH patients on FLSCs. Conclusions The spleen in PH patients promotes FLSC proliferation and self-renewal through the IGF-II/ERK signaling pathway.

Hybridomas are a commonly used, or even the only option, for laboratory study and pilot production of monoclonal antibodies (mAbs), which are crucial for both targeted therapy and biomedical study. A long-term culture of hybridomas will inevitably induce a heterogenization of the whole hybridoma population, resulting in a continuous growth of non-producing hybridomas. To overcome the limits of existing methods of screening heterogeneous hybridomas, in which the whole multi-round screening process is performed in multi-well plates or other discrete modules, this study presents a novel method in which all processing steps of a multi-round hybridoma screening are finished in a single microfluidic chip. This microfluidic chip comprehensively performs hybridoma trapping/proliferating/transferring and fluorescent identification of protein-antibody binding at single cell level. By performing a two-round screening of anti-CD45 mAb secreting hybridomas, the novel microfluidic chip was proved capable of screening several single high-producing hybridomas with minimum cell loss/human labor/time cost, and more importantly, enhanced accuracy and definite monoclonality, which is one of the most important properties of mAb production.

Scopariusicides D-M (1-10), ten new ent-clerodane-based meroditerpenoids with a cyclobutane-fused γ/δ-lactone core, were isolated from Isodon scoparius. Their structures were determined by comprehensive analysis of spectroscopic data, single-crystal X-ray diffraction, chemical transformation, and TDDFT ECD calculation. A plausible biosynthetic pathway of 1-10 was proposed in which the asymmetrical cyclobutane ring was formed via a crossed "head-to-tail" intermolecular [2 + 2] cycloaddition in anti/syn facial approaches between an ent-clerodane lactone and a cis-4-hydroxycinnamic acid. Bioactivity evaluation manifested that 5 exhibited significant neuroprotective effect against corticosterone-induced injury in PC12 cells, while 6 and 7 exhibited moderate immunosuppressive activity against human T cell proliferation stimulated by anti-CD3/anti-CD28 mAb.

Background Patients with locally advanced sigmoid colon cancer (LASCC) have limited treatment options and a dismal prognosis with poor quality of life. This retrospective study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery as treatment for select patients with unresectable LASCC. Methods We studied patients with unresectable LASCC who received NACRT between November 2010 and April 2019. The NACRT regimen consisted of intensity modulated radiotherapy (IMRT) of 50 Gy to the gross tumor and positive lymphoma node and 45 Gy to the clinical target volume. Capecitabine‑based chemotherapy was administered every 2 (mFOLFOX6) or 3 weeks (CAPEOX). Surgery was scheduled 6–8 weeks after radiotherapy. Results Seventy‑two patients were enrolled in this study. Patients had a regular follow-up (median, 41.1 months; range, 8.3–116.5 months). Seventy‑one patients completed NACRT, and sixty-five completed surgery. Resection with microscopically negative margins (R0 resection) was achieved in 64 patients (88.9%). Pathologic complete response was observed in 15 patients (23.1%), and multivisceral resection was necessary in 38 patients (58.3%). The cumulative probability of 3-year overall survival (OS) and progression-free survival (PFS) were 75.8 and 70.7%, respectively. Conclusions For patients with unresectable LASCC, neoadjuvant chemoradiotherapy is feasible, surgery can be performed safely and may result in increased survival and organ preservation rates.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

Whole-genome sequencing on circulating tumor cells (CTCs) at the single cell level has recently been found helpful for precision medicine, as the oncogenic profiles of single CTCs are useful for discovering oncogenic mutation heterogeneities and guiding/adjusting cancer treatment. To overcome the limits of existing methods of single CTC sequencing, in which CTC enrichment, identification and gene amplification are performed by discrete modules, this study presents a novel method in which all processing steps from blood sample collection to preparation of gene amplification products for sequencers are finished in a single microfluidic chip. This microfluidic chip comprehensively performs blood filtering, CTC enrichment, CTC identification/isolation, CTC lysis and whole genome amplification (WGA) at the single cell level. By sequencing single CTCs from clinical blood samples with pointing key driver and drug-resistance mutations, the novel microfluidic chip was validated to be capable of genetically profiling single CTCs with minimum cell loss/human labor, and more importantly, high accuracy and repeatability, which are crucial factors for promoting clinical application of single CTC sequencing.

Acute influenza infection has been reported to be associated with neurological symptoms such as influenza-associated encephalopathy (IAE). Although the pathophysiology of this condition remain unclear, neuroinflammation and associated alterations in the central nervous system (CNS) are usually induced. Microglia (MGs), CNS-resident macrophages, are generally the first cells to be activated in response to brain infection or damage. We performed reverse transcriptase droplet digital PCR (RT-ddPCR) and luminex assays to investigate virus proliferation and immune reactions in BV2 MGs infected with influenza A(H1N1)pdm09 virus. Furthermore, isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics methods were used to investigate the dynamic change in the protein expression profile in BV2 MGs to gain insight into the CNS response to influenza A (H1N1) pdm09 infection. Our results showed that the influenza A(H1N1)pdm09 virus was replicative and productive in BV2 MG cells, which produced cytokines such as interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. The expression of osteopontin (OPN) in the influenza A (H1N1) pdm09-infected BV2 MGs was upregulated at 16 and 32 h post-infection (hpi) compared to that in the control group, resulting in aggravated brain damage and inflammation. Our study indicates that OPN signalling might provide new insights into the treatment of CNS injury and neurodegenerative diseases in IAE.

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.

Background: Gouty arthritis (GA) is a chronic disease caused by monosodium urate crystal deposition. Repeated attacks of arthritis may lead to the deposition of urate to form gout stone, resulting in joint deformity and joint damage. Although GA is not fatal, it causes low work productivity and low quality of life. Western drug, such as febuxostat, colchicine, allopurinol, often cannot get satisfying curative effect, and may even lead to serious side effects, such as exfoliative dermatitis or uremia. However, the therapeutic effect of Traditional Chinese medicine is very satisfactory. The treatment effect of simiao powder, a Chinese patent medicine, combined with acupuncture was widely used on treatment of GA. Although it has been widely used in clinical practice, its relative effectiveness and safety have not been confirmed. Therefore, this study will use meta-analysis to verify the efficacy and safety of simiao powder combined with acupuncture in the treatment of GA. Methods: All randomized controlled trial of simiao powder combined with acupuncture for the treatment of RA from their inception 29 October, 2020 will be searched form the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biomedical Literature Database, Pubmed, Embase, Web of Science, and the Cochrane library. Two authors will independently select studies, extract data based on pre-designed inclusion and exclusion criteria. Methodological quality assessment and risk of bias will be assessed using Cochrane bias risk tool. All data analysis will be conducted using Revman5.3, WinBUGS 1.4.3, and Stata14.2 software. Results: We will compare the different outcome indicators of various studies to provide a synthesis of the efficacy and safety of Simiao powder combined with acupuncture for GA patients. The main outcome measures included efficacy, remission rate (no drug symptoms), recurrence rate, clinical absolute score and relative score. Secondary outcome measures included related adverse reactions and uric acid concentration. Conclusion: The findings of the study will provide helpful evidence for the efficacy and safety of simiao powder combined with acupuncture in the treatment of GA. Registration number: This study protocol have been funded through a protocol registry. The registry number is INPLASY2020110028

Background Dai, Hani, and Yao people, in the trans-boundary region between China, Laos, and Vietnam, have gathered plentiful traditional knowledge about wild edible plants during their long history of understanding and using natural resources. The ecologically rich environment and the multi-ethnic integration provide a valuable foundation and driving force for high biodiversity and cultural diversity in this region. However, little study has uncovered this unique and attractive culture to the world. Methods We conducted ethnobotanical survey in 20 villages of Jiangcheng County from 2016 to 2020. Altogether 109 local Dai, Hani, and Yao people were interviewed, and their traditional knowledge about wild edible plants was recorded. Voucher specimens were identified by the authors and deposited in the herbarium of Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences (HITBC). The use value was used as a quantitative index to evaluate the consumption frequency and relative importance of the wild edible plants. The Jaccard index was calculated to assess the usage similarity of different areas. The relationship of age and recognized wild edible plants by different ethnic people was performed by R. Results A total of 211 wild edible plants, belonging to 71 families and 151 genera, were recorded. These plants were consumed as wild edible vegetables, seasonal fruits, salads, spices, sour condiments, tonic soups, tea substitutes, liquor brewing, or dyeing materials. The use value (UV), current cultivation, market availability, and the quantitative traditional knowledge inheritance situation of these wild edible plants among different generations, were analyzed. Based on the data from the threatened species list of China’s higher plants and the IUCN Red List, the food plant list for Asia Elephant, the Subject Database of China Plant, and the calculated UV score, the top 30 most important wild edible plants were selected for further cultivation in some local villages. Conclusion Traditional knowledge of wild edible plants, owned by Dai, Hani, and Yao people in Jiangcheng County, is rich but at risk of being lost among the young generation. Diversified cultivation of wild edible plants by the local communities could be a solution for the sustainable use of natural resources and to conserve the endangered species in this trans-boundary region.

Hyperthyroid heart disease (HHD) is one of the most severe complications of overt hyperthyroidism and increases the risk of mortality in affected patients. Early identification of patients at a higher risk of developing HHD can improve clinical outcomes through active surveillance and management. Connective tissue growth factor (CTGF), a secreted extracellular protein, plays a significant role in cardiac remodeling and dysfunction. We aimed to investigate the association between plasma CTGF level and the risk of HHD in this study. A total of 142 overt hyperthyroid patients without HHD and 99 patients with HHD were included. The plasma CTGF levels were measured using ELISA kits. Routine clinical medical data and echocardiography parameters were recorded for analysis. The plasma CTGF level was significantly higher in patients with HHD than in those without HHD (P=0.002). The plasma CTGF level was positively correlated with free triiodothyronin, tryrotropin receptor antibody, troponin I and lactate dehydrogenase levels and the left atrium diameters, right atrium diameters, and right ventricular end-diastolic diameters (all P

The ongoing COVID-19 pandemic, caused by the highly contagious SARS-CoV-2 virus, has overwhelmed healthcare systems worldwide, putting medical professionals at a high risk of getting infected themselves due to a global shortage of personal protective equipment. This has in-turn led to understaffed hospitals unable to handle new patient influx. To help alleviate these problems, we design and develop a contactless patient positioning system that can enable scanning patients in a completely remote and contactless fashion. Our key design objective is to reduce the physical contact time with a patient as much as possible, which we achieve with our contactless workflow. Our system comprises automated calibration, positioning, and multi-view synthesis components that enable patient scan without physical proximity. Our calibration routine ensures system calibration at all times and can be executed without any manual intervention. Our patient positioning routine comprises a novel robust dynamic fusion (RDF) algorithm for accurate 3D patient body modeling. With its multi-modal inference capability, RDF can be trained once and used across different applications (without re-training) having various sensor choices, a key feature to enable system deployment at scale. Our multi-view synthesizer ensures multi-view positioning visualization for the technician to verify positioning accuracy prior to initiating the patient scan. We conduct extensive experiments with publicly available and proprietary datasets to demonstrate efficacy. Our system has already been used, and had a positive impact on, hospitals and technicians on the front lines of the COVID-19 pandemic, and we expect to see its use increase substantially globally.

COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild, and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

The outbreak of corona virus disease 2019 (COVID-19) has developed rapidly and the situation of prevention and control is severe. During the epidemic period of COVID-19, due to the particularity of diagnosis and treatment of oral diseases, there is great challenges for how to deal with various types of dental emergency. In order to prevent and control the epidemic situation strictly, and to perform a scientific and orderly clinical diagnosis and treatment of dental emergency, this article provided suggestions on personnel management training, procedures and treatment, protection and disinfection of dental emergency during COVID-19 epidemic, and reference for dental institutions and medical staff.

Knowledge about the special characteristics of HIV-1 envelope (env) glycoproteins in rare individuals developing >90% neutralization breadth in Chinese subtype B' slow progressors may provide insights for vaccine design against local viruses. We performed a cross-sectional analysis on 7 samples. We tested the neutralization breadth and geometric mean ID50 titers (GMTs) of these samples, and divided them into hBCN+ and hBCN- group according to whether their neutralization breadth >90%. We obtained env sequences in these samples through single genome amplification (SGA) assay. By comparing with hBCN-, subtype B chronically infected group (B-SP), and Chinese subtype B group (B-Database), we analyzed the characteristics of the env sequences of hBCN+ group. Longer V1 and V4 regions with more glycosylation sites were found in hBCN+ samples compared to hBCN- samples. Further analysis compared to B-SP and B-Database showed that hBCN+ group exhibited unique extra-long V1 region containing higher proportion of N-glycan sites and additional cysteines.

Intrauterine adhesion (IUA) is one of the most common reproductive system diseases in women worldwide. The role of lncRNAs in multiple diseases has been confirmed, but the role and mechanism of lncRNA taurine upregulated gene 1 (TUG1) in the progression of IUA need to be elucidated further. Here, we found that lncRNA TUG1 was upregulated in the endometrial tissues of IUA and TGF-β1-treated human embryonic stem cells (hESCs). Moreover, lncRNA TUG1-silenced alleviated TGF-β1-induced the proliferation and migration abilities of hESCs and enhanced inflammatory cytokines secretion in vitro. In vivo experiments showed that inhibition of lncRNA TUG1 promoted endometrium regeneration in IUA rats through downregulating inflammatory response and epithelial-to-mesenchymal transition (EMT) process. Mechanistically, lncRNA TUG1 suppression attenuated EMT process and inflammation through competitively binding miR-590-5p to downregulate Fasl expression. Collectively, our findings provide vital theoretical evidence for explaining the mechanisms of the lncRNA TUG1/miR-590-5p/Fasl axis in the progression of IUA, and may provide a new biomarker for the treatment of IUA patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). To date, no prophylactic vaccines or approved therapeutic agents are available for preventing and treating this highly transmittable disease. Here we report two monoclonal antibodies (mAbs) cloned from memory B cells of patients recently recovered from COVID-19, and both mAbs specifically bind to the spike (S) protein of SARS-CoV-2, block the binding of receptor binding domain (RBD) of SARS-CoV-2 to human angiotensin converting enzyme 2 (hACE2), and effectively neutralize S protein-pseudotyped virus infection. These human mAbs hold the promise for the prevention and treatment of the ongoing pandemic of COVID-19.

We aimed to evaluate the feasibility of interventional treatment of atrial septal defect (ASD) in low weight infants under 2-year-old. Seven hundred and ninety-three secundum ASD patients were divided into 2 groups: 665 were above 2-year-old and 128 were under 2-year-old. The basic conditions before the operation, postoperative complications within 24 hours, and adverse outcomes during a three-year follow-up were compared between the 2 groups using multivariate analysis. There were significant differences in age, weight, and the diameter of the ASD between the 2 groups (p0.001). The immediate success rate of the procedure was 96.7%. There were no significant differences in the success rate of the procedure, the incidence of residual shunt, arrhythmia, procedure-related arrhythmia, and occluder shedding between 2 groups (p0.05). Similarly, we found no association between age ≤2-year-old and any adverse outcomes postprocedure within 24 hours, including procedure failure (OR = 0.35; 95%CI: 0.04 to 2.93), residual shunt (OR = 1.07; 95%CI: 0.54 to 2.14), arrhythmia (OR = 0.68; 95%CI: 0.32 to 1.43), or procedure-related arrhythmia (OR = 0.34; 95%CI: 0.04 to 2.87). In the follow-up data, we found no association between age ≤2-year-old and arrhythmia (HR = 0.95; 95%CI: 0.50 to 1.80) and procedure-related arrhythmia (HR = 0.96;95%CI:0.25 to 3.64). Kaplan-Meier survival curves indicated no significant difference in the occurrence of arrhythmia between the 2 groups (log-rank test: p = 0.776). In conclusion, percutaneous ASD closure in young and low weight infants has a high success and low complication rate, along with reliable effects.

As a new oral anticoagulant, rivaroxaban is equivalent to warfarin in preventing and treating thromboembolism, but it can significantly reduce the occurrence of severe bleeding and fatal organ bleeding. This article analyzes the clinical efficacy and drug safety of rivaroxaban in the prevention and treatment of senile thromboembolic disease. The results showed that after treatment, acute thrombosis disappeared in patients with acute venous thrombosis, and no new or recurrent venous thrombosis, pulmonary embolism and death occurred. In the rivaroxaban group, 3 cases of fecal occult blood were positive at 6 months and the incidence rate was 7%. During the follow-up period, there were no significant changes in laboratory blood tests for coagulation, hemoglobin, platelet and liver and kidney function during the follow-up observation of the rivaroxaban group and between the rivaroxaban group and the warfarin group (P0.05). Therefore, oral rivaroxaban is an effective method for the prevention and treatment of elderly patients with thromboembolic disease. Daily 10mg rivaroxaban is a safe and effective dose for the prevention and treatment of elderly patients with thrombotic diseases. The efficacy of rivaroxaban is equivalent to that of warfarin. However, the treatment is easier with better compliance and safety.

Since December 2019, the infection of the new coronavirus (COVID-19) caused an outbreak of new coronavirus pneumonia in Wuhan, China, and caused great public concern. Both COVID-19 and SARS-CoV belong to the coronavirus family and both invade target cells through ACE2. An in-depth understanding of ACE2 and a series of physiological and physiological changes caused by the virus invading the human body may help to discover and explain the corresponding clinical phenomena and then deal with them timely. In addition, ACE2 is a potential therapeutic target. This article will summarize the role of ACE2 in multiple organ damage caused by COVID-19 and SARS-CoV, targeted blocking drugs against ACE2, and drugs that inhibit inflammation in order to provide the basis for subsequent related research, diagnosis and treatment, and drug development.

Spondias pinnata (Linn. f.) Kurz (Anacardiaceae) is widely distributed in tropical Asia, where it is commonly used as a vegetable and fruit, and is attracting increasing research attention. In this study, we investigated the chemical composition and the cytotoxic, antimicrobial, and anti-inflammatory activities of the fruit peel essential oil of S. pinnata (EOSP), which has been consumed as a medicine and condiment in Xishuangbanna, southwest China. A total of 40 components were identified by Gas Chromatography/Mass spectrometry (GC-MS), representing 95.19% of the EOSP, with furfural (17.14%), α-terpineol (13.09%), and ethyl benzoate (9.05%) as the main constituents. EOSP has moderate cytotoxic activity against five cancer cells and obvious antimicrobial activity against five pathogenic strains. In particular, EOSP (Minimal Inhibitory and Fungicidal Concentration, MIC and MFC, 16‒32 µg/mL) showed a 32-times higher inhibition effect against Aspergillus fumigatus than the positive control Tigecycline (MIC and MBC 512‒1024 µg/mL). EOSP also showed strong anti-inflammatory activity by significantly inhibiting nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 cell lines at 0.08‰, with no effect on cell viability. These bioactivities of S. pinnata fruit peel validate its traditional uses and suggest that it could be a new source of natural antimicrobial and anti-inflammatory agents for food or medical industries.

Five new schinortriterpenoids, propinqtrilactones A and B (1 and 2) with rare lancischiartane scaffold, and propindilactones V-X (3-5), were isolated from the stems and leaves of Schisandra propinqua var. propinqua. Their structures were elucidated on the basis of comprehensive spectroscopic and mass spectrometric analysis. The absolute configurations of 1-5 were determined by CD methods, X-ray diffraction analysis and theoretical calculations. 4 was tested for its cytotoxic activities against five human tumor cell lines.

A phytochemical investigation of an ethyl acetate extract of the aerial parts of Isodon pharicus led to the isolation of 21 new 7α,20-epoxy-ent-kaurane diterpenoids, pharicins C-W (1-21), and 29 known (22-50) analogues. The structural characterization of 1-21 and assignment of their relative configurations were accomplished by spectroscopic data interpretation, while the structures of 1 and 16 were confirmed by X-ray crystallography. The absolute stereostructure of 1 was confirmed by electronic circular dichroism data analysis. Twenty-five of the diterpenoids were screened for their cytotoxic activities against a panel of tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW-480. Compounds 11, 16, 38, and 48 exhibited inhibitory activities against these tumor cell lines with IC50 values ranging from 1.01 to 9.62 μM, while 2, 15, 29, and 47 exhibited moderate cytotoxic potency.

The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative chemotherapy, which consist of portal vein chemotherapy, intraluminal chemotherapy and intraperitoneal chemotherapy, plus surgery group, whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2 vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group. Intraoperative chemotherapy did not decrease the rate of patients who received postoperative chemotherapy between the intraoperative group and control group (29.3 vs. 30.2%, P = 0.795). Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. ClinicalTrial.gov Register Number: NCT01465451.

Enumerating circulating tumor cells (CTCs) has been demonstrably useful in cancer treatment. Although there are several approaches that have proved effective in isolating CTC-like cells, the crucial identification of CTCs continues to rely on the manual interpretation of immunofluorescence images of all cells that have been isolated. This procedure is time consuming and more importantly, CTC identification relies on subjective criteria that may differ between examiners. In this study, we describe the design, testing, and verification of a microfluidic platform that provides accurate and automated CTC enumeration using a common objective criterion. Methods: The platform consists of a multi-functional microfluidic chip and a unique image processing algorithm. The microfluidic chip integrates blood filtering, cell isolation, and single cell positioning to ensure minimal cell loss, efficient cell isolation, and fixed arraying of single cells to facilitate downstream image processing. By taking advantage of the microfluidic chip design to reduce calculation loads and eliminate measurement errors, our specially designed algorithm has the capability of rapidly interpreting hundreds of images to provide accurate CTC counts. Results: Following intensive optimization of the microfluidic chip, the image processing algorithm, and their collaboration, we verified the complete platform by enumerating CTCs from six clinical blood samples of patients with breast cancer. Compared to tube-based CTC isolation and manual CTC identification, our platform had better accuracy and reduced the time needed from sample loading to result review by 50%. Conclusion: This automated CTC enumeration platform demonstrates not only a sound strategy in integrating a specially designed multi-functional microfluidic chip with a unique image processing algorithm for robust, accurate, and “hands-free” CTC enumeration, but may also lead to its use as a novel in vitro diagnostic device used in clinics and laboratories as readily as a routine blood test.

To evaluate the clinical efficacy of low dose combined chemotherapy（LDCC） for patients with relapsed and refractory aplastic anemia-paroxysmal nocturnal hemoglobinuria（AA-PNH） syndrome, and to analyze the advantages of LDCC in the treatment of AA-PNH syndrome.The clinical characteristics and the curative effect of LDCC in 9 patients with relapsed and refractory AA-PNH syndrome were retrospectively analyzed. Five patients were treated with MP therapy［melphalan 2 mg/(mSeven out of 9 patients responded well, the dosage of corticosteroid and the bilirubin concentration decreased significantly and anemia was relieved in 7 patients (P0.05). One patient relapsed in one year. PNH clone of 3 patients turned negative. Five patients did not rely on blood transfusion in 1 year. There was no bone marrow failure to be found in all patients.The LDCC has better efficacy and safety in the treatment of patients with AA-PNH syndrome, moreover, the patients is more tolerant to LDCC, thus the LDCC may be a selection for treatment of patients with relapsed and refractory AA-PNH syndrome.低剂量联合化疗治疗复发难治的再生障碍性贫血-阵发性睡眠性血红蛋白尿综合征的疗效.评价低剂量MP方案与HA方案治疗复发难治的再生障碍性贫血-阵发性睡眠性血红蛋白尿（AA-PNH）综合征患者的治疗效果，探讨低剂量联合化疗在治疗AA-PNH综合征方面的优势.回顾分析9例复发难治的AA-PNH综合征患者临床特征及采用低剂量联合化疗的疗效，其中5例予MP方案（马法兰2 mg/(m9例患者中7例患者治疗有效，其激素用量较化疗前明显减少，胆红素水平显著低于化疗前,化疗后贫血有所缓解（P0.05）。7例有效患者中1年内复发1例，且有效者中3例PNH克隆负荷转阴，5例患者1年内均未再输血，所有病人均未发生严重骨髓抑制.低剂量联合化疗方案对AA-PNH患者具有较好的疗效和安全性，且患者对其耐受性较好，可作为复发难治的AA-PNH综合征的治疗选择.

To investigate the clinical characteristics of patients with advanced hepatic alveolar echinococcosis, so as to provide more evidence for the diagnosis and treatment of advanced hepatic alveolar echinococcosis.The clinical records of 175 cases with hepatic alveolar echinococcosis admitted to the Affiliated Hospital of Qinghai University from 2012 to 2017 were retrospectively reviewed.Among the 175 cases with hepatic alveolar echinococcosis, the male to female ratio was 1∶1.6, and the mean age was (38.6 ± 12.9) years (range, 11 to 69 years). 93.7% of the patients (164 cases) were Tibetan, and 79.4% (139 cases) were from Guoluo Prefecture. 73.7% (129 cases) were herdsmen, and 58.3% (102 cases) were illiterate. The major clinical symptoms included upper abdominal pain, yellowing of skin and mucosa, and scleral icterus. 69.1% of the lesions were located in bilateral livers, and 63.4% of the cases have 2 and more lesions. 53.7% of the cases have their inferior vena cava involved by the lesions. In addition, the most affected neighboring organ was diaphragmatic muscle (21.7%), and lung was the most affected distant metastatic site (40.6%).Advanced hepatic alveolar echinococcosis is highly prevalent in Guoluo Prefecture, Qinghai Province. Screening of this disease is required in this region and rational treatment scheme should be developed.[

How do you navigate the norms of your new culture when living abroad? Taking an interactionist perspective, we examined how contextual factors and personality traits jointly affect sojourners’ adaptation to the host-country culture. We hypothesized that tightness (strong, rigidly imposed norms) of the host culture would be associated with lower levels of adaptation and that tightness of the home culture would be associated with higher levels of adaptation. Further, we proposed that the impact of tightness should be dependent on personality traits associated with navigating social norms (agreeableness, conscientiousness, and honesty-humility). We analyzed longitudinal data from intercultural exchange students ( N = 889) traveling from and to 23 different countries. Multilevel modeling showed that sojourners living in a tighter culture had poorer adaptation than those in a looser culture. In contrast, sojourners originating from a tighter culture showed better adaptation. The negative effect of cultural tightness was moderated by agreeableness and honesty-humility but not conscientiousness.

Plasma membrane integrity is essential for the viability of eukaryotic cells. In response to bacterial pore-forming toxins, disrupted regions of the membrane are rapidly repaired. However, the pathways that mediate plasma membrane repair are unclear. Here we show that autophagy-related (ATG) protein ATG16L1 and its binding partners ATG5 and ATG12 are required for plasma membrane repair through a pathway independent of macroautophagy. ATG16L1 is required for lysosome fusion with the plasma membrane and blebbing responses that promote membrane repair. ATG16L1 deficiency causes accumulation of cholesterol in lysosomes that contributes to defective membrane repair. Cell-to-cell spread by Listeria monocytogenes requires membrane damage by the bacterial toxin listeriolysin O, which is restricted by ATG16L1-dependent membrane repair. Cells harbouring the ATG16L1 T300A allele associated with inflammatory bowel disease were also found to accumulate cholesterol and be defective in repair, linking a common inflammatory disease to plasma membrane integrity. Thus, plasma membrane repair could be an important therapeutic target for the treatment of bacterial infections and inflammatory disorders.

Objective Temporomandibular joint osteoarthritis (TMJOA) is a common degenerative disease in jaw joint, accompanied by articular cartilage destruction. Differentiation of stem cells to cartilage has important therapeutic implications in TMJ cartilage repair. Previous studies revealed that lncRNA XIST participated in various biological processes. However, the effect of XIST on chondrogenic differentiation of synovium-derived mesenchymal stem cells (SMSCs) remains unclear. Our study aimed to investigate the function of XIST in chondrogenic differentiation of human SMSCs from TMJ. Methods Alcian blue staining was performed to determine proteoglycan in SMSCs. qPCR, western blotting and immunofluorescence assays were allowed to assess sex determining region Y-box 9 (SOX9), Collagen type II alpha 1 chain (COL2A1) and Aggrecan (ACAN) expression. The direct interaction between miR-27b-3p and XIST or ADAMTS-5 was confirmed by dual luciferase reporter assay or RNA immunoprecipitation (RIP) assay. Results XIST was remarkably down-regulated in chondrogenic differentiation of SMSCs. Functional analysis demonstrated that XIST silencing promoted chondrogenic differentiation of SMSCs. Dual luciferase reporter and RIP assays identified that XIST acted as a sponge for miR-27b-3p. Moreover, XIST regulated ADAMTS-5 expression by directly binding miR-27b-3p. More importantly, miR-27b-3p/ADAMTS-5 rescued the effects of XIST on chondrogenic differentiation of SMSCs. Conclusion The results suggest that XIST modulates SMSCs chondrogenic differentiation via the miR-27b-3p/ADAMTS-5 axis, which provides new targets for TMJOA treatment.

Theranostic nanoagents which integrate diagnostic and therapeutic moieties into a single platform have attracted broad attention in cancer therapy, however the development of more effective and less toxic diagnostic and therapeutic interventions is still of great urgency. Herein, novel core-shell PB@MIL-100(Fe) dual metal-organic-frameworks (d-MOFs) nanoparticles are fabricated and their combined theranostic effects in vitro and in vivo are investigated. The d-MOFs nanoparticles can serve as a T1-T2 dual-modal magnetic resonance imaging (MRI) contrast and fluorescence optical imaging (FOI) agent due to the existence of inner PB MOFs and outer MIL-100(Fe) MOFs. The artemisinin (a traditional Chinese anticancer medicine) with a high loading content of 848.4 mg/g is released from the d-MOFs upon tumor cellular endocytosis due to the pH-responsive degradation of outer MOFs in low pH lysosomes of tumor cells. Furthermore, the inner PB MOFs can be utilized for photothermal therapy due to its strong absorbance in NIR region. Under the guidance by such dual-modal imaging, in vivo photothermal and chemotherapy is finally carried out, achieving effective tumor ablation in an animal tumor model. Furthermore, histological analysis revealed that the drug delivery system had no obvious effect on the major organs of mice due to the low toxicity of both d-MOFs and artemisinin. The distinctive multimodal imaging capability, excellent synergistic therapy effect through the combined chemo-photothermal therapy together with the low toxicity of both d-MOFs and artemisinin endow the theranostic nanoagent a promising next generation of nanomedicine for efficient and safe cancer therapy.

Two new quinones, 1-hydroxy-5-pentyl-anthraquinone (1) and 4-(5-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-butyric acid methyl ester (2), together with two known quinones, 5-hydroxy-2-(2-hydroxy-ethylamino)-(1,4) naphthoquinone (3) and juglone (4) were isolated from the roots of Juglans mandshurica (Juglandaceae). Their structures were elucidated on the basis of spectral data. Compound 3 was isolated from the Juglans genus for the first time. Compounds 1-4 exhibited significant cytotoxicity towards cultured MDA-MB231, HepG2 and SNU638 cells with IC50 values ranging from 4.46 to 88.47 μM.

Objective: The aim of this work was to evaluate the feasibility and safety of transcatheter closure procedures for the treatment of atrial septal defects (ASDs) with insufficient rims. Methods: A total of 507 secondary ASDs were divided into two groups based on whether they had deficient rims or not (152 vs. 355 cases, respectively). Any complications, including residual shunt, heart arrhythmia, occluder translocation, etc., were followed up for 1-3 years. Results: There were no differences in gender, weight, exposure time, ECG states, pulmonary pressure, the intervention success rate, occurrence of residual shunt, the operation time and occurrence of residual shunt during follow-up between the two groups (p > 0.05). However, the occurrence of rhythm disorders was significantly different between the two groups; ASDs with deficient rims were at an elevated risk (p < 0.05). Specifically, there was a significantly higher incidence in the occurrence of arrhythmia in the deficient rims group at 24 h postoperation, but no differences in arrhythmia incidence at any of the other follow-up time points (1, 3, 6, 12 and 36 months; p > 0.05). Conclusions: Patients with deficient rims experience a high success rate of ASD intervention and low rate of complications when the procedures are performed by experienced operators.

Oxidative stress is widely considered as a central event in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying the oxidative damage-mediated loss of dopaminergic neurons in PD are not yet fully understood. Accumulating evidence has indicated that oxidative DNA damage plays a crucial role in programmed neuronal cell death, and is considered to be at least partly responsible for the degeneration of dopaminergic neurons in PD. This process involves a number of signaling cascades and molecular proteins. Proliferating cell nuclear antigen (PCNA) is a pleiotropic protein affecting a wide range of vital cellular processes, including chromatin remodelling, DNA repair and cell cycle control, by interacting with a number of enzymes and regulatory proteins. In the present study, the exposure of PC12 cells to 1-methyl-4-phenylpyridinium (MPP+) led to the loss of cell viability and decreased the expression levels of PCNA in a dose- and time-dependent manner, indicating that this protein may be involved in the neurotoxic actions of MPP+ in dopaminergic neuronal cells. In addition, a significant upregulation in p53 expression was also observed in this cellular model of PD. p53 is an upstream inducer of PCNA and it has been recognized as a key contributor responsible for dopaminergic neuronal cell death in mouse models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. This indicates that MPP+-induced oxidative damage is mediated by the downregulation of PCNA through the p53 pathway in a cellular model of PD. Thus, our results may provide some novel insight into the molecular mechanisms responsible for the development of PD and provide new possible therapeutic targets for the treatment of PD.

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.

Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.

To investigate drug knowledge of middle school students in HIV prone areas in Liangshan of Sichuan Province.Students were randomly selected from the middle schools located in the HIV prone areas in Liangshan. A questionnaire survey was conducted. Drug knowledge of the respondents and associated factors were analyzed.Of the 10 749 respondents,10.1% had wrong knowledge about drugs. The respondents of male gender and minority ethnicity in the region and those who were in a lower grade,had poor academic records,more sisters,and a schoolmate taking drugs,and lived in a family with HIV infected member were more likely to had poor drug knowledge. By contrast,the respondents who had a peasant father,lived with both parents,resided in a city or township,self-rated in the middle and low 1/3 of wealth,lived in a community with50% school attendance,and had a family member taking drugs were less likely to have wrong drug knowledge.Middle school students in the HIV prone areas in Liangshan have poor drug knowledge. Socioeconomic factors influence the drug knowledge of students,which require systematic interventions.

Background: PGE1 has been studied for prevention of CI-AKI in several RCTs and significant heterogeneous results exist. Methods: We searched PubMed, EMBase, and Cochrane Central Register of Controlled Trials up to December 26, 2017 for RCTs comparing PGE1 with placebo or other active medications for the prevention of CI-AKI in patients. Odds ratio and 95% confidence interval (CI) were used for pooling dichotomous data, while mean difference and 95% confidence interval for pooling continuous data. Results: Seven RCTs involving 1760 patients were included in this meta-analysis. All these 7 trials reported the incidence of CI-AKI and compared with placebo or other treatment options, PGE1 was associated with a reduced risk of CI-AKI (OR: 0.38, 95% CI: 0.28–0.53; P

Two new

Nuclear factor-κB (NF-κB) has an important role in immune response and inflammation. Phellinus igniarius (known as Sang huang in traditional Chinese medicine) has various pharmacologic effects. In this study, 19 chemical constituents (1-19) were isolated from the fruiting bodies of Ph. igniarius. Their structures were elucidated based on data from nuclear magnetic resonance spectroscopy and comparison with the literature. Overall, 3 compounds (2, 7, and 11) from this species were reported, to our knowledge for the first time. Two compounds (4 and 15) from the genus Phellinus and 9 compounds (1, 3, 5, 8-10, and 12-14) from the Hymenochaetaceae family were also reported for the first time. An NF-κB luciferase reporter assay of these compounds was carried out in tumor necrosis factor-α-induced HeLa cells-again, to our knowledge for the first time. Among them, compounds 5 and 7 showed moderate inhibition of NF-κB, with fold values of 0.48 ± 0.02 and 0.55 ± 0.09, respectively, in HeLa cells at 100 μmol/L. These results suggest that some of the ingredients from Ph. igniarius could be developed into antiinflammatory agents for use in clinical applications.

To determine the prevalence and determinants of smoking in middle school students in priority areas for HIV control in Liangshan of Sichuan Province.Students were randomly selected in all of the schools located in the priority areas for HIV control in Liangshan. A questionnaire survey was conducted,collecting data in relation to socio-demographic characteristics of the participants,their smoking behavior,drug abuse in family members,and HIV infections in family members. Risk factors associated with smoking were identified using univariate and multivariate statistical analyses.About 21.3% of respondents were smoking at the time of survey; 33.4% attempted smoking; 5% were heavy smokers; and 16.8% started smoking before 13 years old. The Logistic regression analysis identified male gender,senior high school students,poor academic records,low household income,rural residency,family drug abuse and HIV infections as predictors of attempted smoking. Male gender,minority ethnicity,average academic records,broken family,medium and high household income,family drug abuse and HIV infections were identified as predictors of smoking. Male gender,senior high school students,low or medium academic records,rural residency,and family drug abuse were identified as predictors of heavy smoking. Male gender,broken family,average academic records,medium or high household income,family drug abuse and HIV infections were associated with smoking before thirteen.Smoking rate in middle school students in the priority areas for HIV control in Liangshan is high. They start smoking at a young age. School smoking control programs should place priorities on those who are in the groups of boys,minority ethnicity,senior high school students,rural residency,poor academic records,and those with family drug abuse and HIV infections.

The oncogenic mutation heterogeneity of the cancer cell population has been proven to be essential for predicting both drug-response and drug-resistance of targeted therapies, such as tyrosine kinase inhibitors. It is necessary to accurately evaluate the mutation heterogeneity, oncogenic mutation and resistant mutation profiling at a single cell level. However, there are two major hurdles in the process. First, majority of the cells in tumor tissue are non-cancer cells, which cause background noise. Second, the work load and cost of next generation sequencing on dozens of single cells are prohibitive. To address both these issues, we developed a microfluidic chip for profiling of dozens of selected cells. With the help of a novel tri-states valve structure, which performs precise controlling of the cell/reagent movement, as well as active mixing of different reagents, trapping/identification/lysis and in situ MDA amplification was achieved at a single cell level on the same chip. Using a proof-of-concept assay mimicking EGFR targeting drug Gefitinib treatment of lung cancer cells, the new method was validated as capable of not only detecting the existence of multiple mutations, but also providing complete information of the mutation scenario at the single cell level by using cost-effective Sanger's sequencing.

Oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of Parkinson's disease (PD). Although reactive oxygen species (ROS) production is implicated as a causative factor in PD, the cellular and molecular mechanisms linking oxidative stress with dopaminergic neuron death are complex and not well characterized. The primary insults cause the greatest production of ROS, which contributes to oxidative damage by attacking all macromolecules, including lipids, proteins and nucleic acids, leading to defects in their physiological function. Consequently, the defects in these macromolecules result in mitochondrial dysfunction and neuroinflammation, which subsequently enhance the production of ROS and ultimately neuronal damage. The interaction between these various mechanisms forms a positive feedback loop that drives the progressive loss of dopaminergic neurons in PD, and oxidative stress‑mediated neuron damage appears to serve a central role in the neurodegenerative process. Thus, understanding the cellular and molecular mechanisms by which oxidative stress contributes to the loss of dopaminergic neurons may provide a promising therapeutic approach in PD treatment.

Multiple methods for investigating cell invasion behavior in vitro have proven useful in exploring the mechanisms behind the epithelial-mesenchymal transition (EMT) and EMT-related tumor cell invasion, for example, by revealing that cell heterogeneity existed in EMT. However, several hypotheses and predictions regarding EMT heterogeneity have remained unproven because of the inability to quantitatively profile cell invasion at the single cell level. Here, we present a microfluidic chip that provides the capability of simultaneously investigating single cell invasion behavior, phenotypic diversity, and responsiveness to anti-invasion drugs. By assessing single cell invasion behavior in separate wells, cell-cell contacts and their corresponding interference in the invasion process could be excluded. The chip allowed for both precise quantitation of cell invasion and in situ phenotyping, such that any single cell heterogeneity could be detected and accurately quantified. This study has proven that the proposed hybrid epithelial/mesenchymal cell phenotype exists and is important in the EMT process. The invasion abilities of two cell lines were also assessed, either with or without EMT-promoting or EMT-inhibiting agents, proving that the chip can also be used to assess the effectiveness of antimetastatic agents. This study has demonstrated that the strategy of isolating single cells before studying their invasive properties is correct and that it provides an in vitro method for understanding cell heterogeneity during EMT. This approach also provides a mean of screening for anti-invasion agents that are focused on single cell invasion, a process known to be important for blood-borne metastasis to occur.