Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes ...an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model.
A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively.
The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect EC50 of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment (6.48 ± 0.02 × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication (6.18 ± 0.95 × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05).
Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
The COVID-19 pandemic is one of those global challenges that transcends territorial, political, ideological, religious, cultural, and certainly academic boundaries. Public health and healthcare ...workers are at the frontline, working to contain and to mitigate the spread of this disease. Although intervening biological and immunological responses against viral infection may seem far from the physical sciences and engineering that typically work with inanimate objects, there actually is much that canand shouldbe done to help in this global crisis. In this Perspective, we convert the basics of infectious respiratory diseases and viruses into physical sciences and engineering intuitions, and through this exercise, we present examples of questions, hypotheses, and research needs identified based on clinicians’ experiences. We hope researchers in the physical sciences and engineering will proactively study these challenges, develop new hypotheses, define new research areas, and work with biological researchers, healthcare, and public health professionals to create user-centered solutions and to inform the general public, so that we can better address the many challenges associated with the transmission and spread of infectious respiratory diseases.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that ...CD73-expressing tumor cell is implicated in development of several types of cancer. However, the role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive.
CD73 expression in HCC cell was determined by RT-PCR, Western blot, and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110β and its catalytic activity. NOD/SCID/γc(null) (NOG) mice model was used to investigate the in vivo functions of CD73.
In the present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time to recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110β to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, a combination of anti-CD73 and anti-A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone.
CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.
Enormous research interest is devoted to fabricating three-dimensional graphene-based gels (3D GBGs) toward improved conversion of solar energy by virtue of the intrinsic properties of single ...graphene and 3D porous structure characteristics. Here, this concise minireview is primarily focused on the recent progress on applications of 3D GBGs, including aerogels and hydrogels, in photocatalytic degradation of pollutants from water and air, such as organic pollutants, heavy metal ions, bacteria and gaseous pollutants. In particular, the preponderances of 3D GBG photocatalysts for environmental pollutants degradation have been elaborated. Furthermore, in addition to discussing opportunities offered by 3D GBG composite photocatalysts, we also describe the existing problems and the future direction of 3D GBG materials in this burgeoning research area. It is hoped that this review could spur multidisciplinary research interest for advancing the rational utilization of 3D GBGs for practical applications in environmental remediation.
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•3D graphene-based gels (3D GBGs) possess more active sites.•Porous structure of 3D GBGs promotes the photogenerated electrons transfer.•3D framework provides an ideal support for the active components.•Applications of 3D GBGs in photocatalytic environmental remediation are overviewed.
The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic ...characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy.
We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions.
IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038).
Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC.
Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
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•Immunogenomic discrepancies among multifocal HCC vary within patients and shape tumor evolutionary trajectories.•Immune escape involves HLA alterations, M2 macrophage infiltration, inhibitory ligands and immunoediting.•Immune context imprinted by genetics can exert selective pressures.•Immune evasion correlates with tumor regression and can predict postoperative recurrence.•Personalized immunotherapy strategies should be adopted for multifocal HCC to maximize efficacy.
Sodium‐ion batteries (SIBs) are considered as a promising large‐scale energy storage system owing to the abundant and low‐cost sodium resources. However, their practical application still needs to ...overcome some problems like slow redox kinetics and poor capacity retention rate. Here, a high‐performance ZnSe/carbon fibers (ZnSe‐CFs) anode is demonstrated with high electrons/Na+ transport efficiency for sodium‐ion half/full batteries by engineering ZnSe/C heterostructure. The electrochemical behavior of the ZnSe‐CFs heterostructure anode is deeply studied via in situ characterizations and theoretical calculations. Phase conversion is revealed to accelerate the “Zn‐escape” effect for the formation of robust solid electrolyte interphase (SEI). This leads to the ZnSe‐CFs delivering a superior rate performance of 206 mAh g−1 at 1500 mA g−1 for half battery and an initial discharge capacity of 197.4 mAh g−1 at a current density of 1 A g−1 for full battery. The work here heralds a promising strategy to synthesize advanced heterostructured anodes for SIBs, and provides the guidance for a better understanding of phase conversion anodes.
A ZnSe/carbon fibers (ZnSe‐CFs) anode with high electrons/Na+ transport efficiency by engineering ZnSe/C heterostructure is designed for high performance sodium‐ion half/full batteries. Phase conversion is found to accelerate the “Zn‐escape” effect for the formation of robust solid electrolyte interphase, providing the guidance for a better understanding of phase conversion anodes for high‐performance sodium‐ion batteries.
Yunnan Province is located in southwestern China and neighbors the Southeast Asian countries, all of which are dengue-endemic areas. In 2000-2013, sporadic imported cases of dengue fever (DF) were ...reported almost annually in Yunnan Province. During 2013-2015, we confirmed that a large-scale indigenous DF outbreak emerged in cities of Yunnan Province near the China-Myanmar-Laos border.
Epidemiological characteristics of DF in Yunnan Province during 2013-2015 were evaluated by retrospective analysis. A total of 232 dengue virus (DENV)-positive sera were randomly collected for sequence analysis of the capsid/premembrane region of DENV from patients with DF in Yunnan Province. The envelope gene of DENV isolates was also amplified and sequenced. Phylogenetic analyses were performed using the neighbor-joining method with the Tajima-Nei model.
Phylogenetically, all DENV-positive samples could be classified into DENV-1 genotype I and DENV-2 Asian I genotype during 2013-2015 and DENV-4 genotype I in 2015 from Ruili City; and DENV-3 genotype II in 2013 and DENV-2 Cosmopolitan genotype in 2015 from Xishuangbanna Prefecture.
Our results indicated that imported DF from patients from Laos and Myanmar was the primary cause of the DF epidemic in Yunnan Province. Additionally, DENV strains of all four serotypes were identified in indigenous cases in Yunnan Province during the same time period, while the dengue epidemic pattern observed in southwestern Yunnan showed characteristics of a hypoendemic nature: circulation of DENV-1 and DENV-2 over consecutive years.
Abstract
The formation of protostellar disks is still a mystery, largely due to the difficulties in observations that can constrain theories. For example, the 3D alignment between the rotation of the ...disk and the magnetic fields (B-fields) in the formation environment is critical in some models, but so far it is impossible to observe. Here we study the possibility of probing the alignment between B-field and disk rotation using “polarization holes” (PHs). PHs are widely observed and are caused by unresolved B-field structures. With ideal magnetohydrodynamic simulations, we demonstrate that different initial alignments between B-field and angular momentum (AM) can result in B-field structures that are distinct enough to produce distinguishable PHs. Thus, PHs can potentially serve as probes for alignments between B-field and AM in disk formation.
In China, medical staff of children's hospitals are commonly exposed to violence. However, few studies on medical violence are conducted in the settings of children's hospitals. The aim of this study ...is to assess the incidence, magnitude, consequences, and potential risk factors of workplace violence (WPV) against medical staff of children's hospitals.
A retrospective cross-sectional design was used. A self-administered questionnaire was utilized to collect data on 12 children's hospitals. The questionnaires were distributed to a stratified proportional random sample of 2,400 medical staff; 1,932 valid questionnaires were collected. A chi-square test and multiple logistic regression analysis were conducted.
A total of 68.6% of respondents had experienced at least one WPV incident involving non-physical and/or physical violence in the past year. The perpetrators were mainly family members of patients (94.9%). Most of the WPV occurred during the day shift (70.7%) and in wards (41.8%). Males were 1.979 times (95% CI, 1.378 to 2.841) more likely than females to experience physical violence. Emergency departments were more exposed to physical violence than other departments. Oncology was 2.733 times (95% CI, 1.126 to 6.633) more exposed to non-physical violence than the emergency department. As a result of WPV, victims felt aggrieved and angry, work enthusiasm declined, and work efficiency was reduced. However, only 5.6% of the victims received psychological counseling.
Medical staff are at high risk of violence in China's children's hospitals. Hospital administrators and related departments should pay attention to the consequences of these incidents. There is a need for preventive measures to protect medical staff and provide a safer workplace environment. Our results can provide reference information for intervention strategies and safety measures.
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