NEDD9 promotes cancer stemness by recruiting myeloid-derived suppressor cells via CXCL8 in esophageal squamous cell carcinoma

Objective:Esophageal squamous cell carcinoma(ESCC)has high morbidity and mortality rates worldwide.Cancer stem cells(CSCs)may cause tumor initiation,metastasis,and recurrence and are also responsible for chemotherapy and radiotherapy failures.Myeloid-derived suppressor cells(MDSCs),in contrast,are known to be involved in mediating immunosuppression.Here,we aimed to investigate the mechanisms of interaction of CSCs and MDSCs in the tumor microenvironment.Methods:ESCC tissues and cell lines were evaluated.Neural precursor cell expressed,developmentally downregulated 9(NEDD9)was knocked down and overexpressed by lentiviral transfection.Quantitative PCR,Western blot,immunohistochemistry,cell invasion,flow cytometry,cell sorting,multiplex chemokine profiling,and tumor growth analyses were performed.Results:Microarray analysis revealed 10 upregulated genes in esophageal CSCs.Only NEDD9 was upregulated in CSCs using the sphere-forming method.NEDD9 expression was correlated with tumor invasion(P=0.0218),differentiation(P=0.0153),and poor prognosis(P=0.0373).Additionally,NEDD9 was required to maintain the stem-like phenotype.Screening of chemokine expression in ESCC cells with NEDD9 overexpression and knockdown showed that NEDD9 regulated C-X-C motif chemokine ligand 8(CXCL8)expression via the ERK pathway.CXCL8 mediated the recruitment of MDSCs induced by NEDD9 in vitro and in vivo.MDSCs promoted the stemness of ESCC cells through NEDD9 via the Notch pathway.Conclusions:As a marker of ESCC,NEDD9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit MDSCs into the tumor,suggesting NEDD9 as a therapeutic target and novel prognostic marker for ESCC.

Progress of Jinping Underground laboratory for Nuclear Astrophysics(JUNA)

Jinping Underground laboratory for Nuclear Astrophysics(JUNA) will take the advantage of the ultra-low background of CJPL lab and high current accelerator based on an ECR source and a highly sensitive detector to directly study for the first time a number of crucial reactions occurring at their relevant stellar energies during the evolution of hydrostatic stars. In its first phase, JUNA aims at the direct measurements of^(25)Mg(p,γ)^(26)Al,^(19)F(p,α)^(16)O,^(13)C(α,n)^(16)O and ^(12)C(α,γ)^(16)O reactions. The experimental setup,which includes an accelerator system with high stability and high intensity, a detector system, and a shielding material with low background, will be established during the above research. The current progress of JUNA will be given.

Engineering of triterpene metabolism and overexpression of the lignin biosynthesis gene PAL promotes ginsenoside Rg3 accumulation in ginseng plant chassis

The ginsenoside Rgfound in Panax species has extensive pharmacological properties,in particular anti-cancer effects.However,its natural yield in Panax plants is limited.Here,we report a multimodular strategy to improve yields of Rgin a Panax ginseng chassis,combining engineering of triterpene metabolism and overexpression of a lignin biosynthesis gene,phenylalanine ammonia lyase(PAL).We first performed semi-rational design and site mutagenesis to improve the enzymatic efficiency of Pq3-O-UGT2,a glycosyltransferase that directly catalyzes the biosynthesis of Rgfrom Rh.Next,we used clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)gene editing to knock down the branch pathway of protopanaxatriol-type ginsenoside biosynthesis to enhance the metabolic flux of the protopanaxadiol-type ginsenoside Rg.Overexpression of PAL accelerated the formation of the xylem structure,significantly improving ginsenoside Rgaccumulation(to 6.19-fold higher than in thecontrol).Wecombinedoverexpression of the ginsenoside aglycon synthetic genes squalene epoxidase,Pq3-O-UGT2,and PAL with CRISPR/Cas9-based knockdown of CYP716A53v2 to improve ginsenoside Rgaccumulation.Finally,we produced ginsenoside Rgat a yield of 83.6 mg/L in a shake flask(7.0 mg/g dry weight,21.12-fold higher than with wild-type cultures).The highproduction system established in this study could be a potential platform to produce the ginsenoside Rgcommercially for pharmaceutical use.

Li−Garnet Solid-State Batteries with LLZO Scaffolds

Li−garnet solid-state batteries(SSBs)have attracted a great deal of attention due to their nonflammability,nontoxicity,and potential to achieve significantly higher energy and power densities compared to those of conventional Li-ion batteries.1−5 Research that began in 20076 and focused primarily on improving the Li-ion conductivity of Li7La3Zr2O12(LLZO)has since evolved into the development of Li−garnet SSBs,encompassing aspects of the LLZO/Li interface,7,8 the electrochemical voltage window of LLZO,9−11 and compatibility with current cathode chemistries.12−15 Nevertheless,an analysis of the literature shows that there is still no clear opinion in the research community on the configuration of future Li−garnet SSBs.In particular,opinions differ on the design of the LLZO-based anode layer that accounts for(i)the dynamic expansion and shrinkage of the Li metal(from up to 5−25μm for the area capacity of 1−5 mAh cm^(−2))and(ii)the probability of void formation at the Li/LLZO interface.

HearNPV Pseudotyped with PIF1,2,and 3 from MabrNPV：Infectivity and Complex Stability

Effective oral infection is set off by interaction of a group of conserved per os infectivity factors(PIFs) with larval midgut columnar epithelial cells. We constructed pseudotyped viruses by substituting pif1, pif2 or pif3 genes of Helicoverpa armigera nucleopolyhedrovirus(Hear NPV) with their homologs from Mamestra bracissae multiple nucleopolyhedrovirus and tested their infectivity to tissue culture cells and to larvae. Transfection and infection assays revealed that all recombinant viruses generated infectious budded virus in both cell culture and in larvae. Electron microscopy showed synthesized occlusion body and occlusion derived virus(ODV) were morphologically indistinguishable from those of the parental virus. By contrast, feeding assays revealed that pseudotyped viruses could not rescue oral infectivity except for pif3 pseudotyped virus that only partially rescued oral infectivity but at a mortality rate much lower than that of the parental Hear NPV. Consistent with the bioassay result, PIF complex was detected in ODVs of pif3 pseudotyped virus only but not in pif1 or pif2 pseudotyped viruses. Our results suggest that PIF complex is essential for oral infectivity, and in the formation of the PIF complex, PIF1, 2 are virus-specific while PIF3 does not appear to be as specific and can function in heterologous environment, albeit to a much more limited extent.

P33 of Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus is a functional homolog of AcP33

Dear Editor,Baculoviruses are insect-specific viruses with a circular double-stranded DNA genome ranging in size from80–180 kb(Lu et al.,2012).Two distinct types of virions have been identified during the infectious cycle of baculoviruses,namely budded virions(BVs)and occlusion-derived virions(ODVs).BVs mediate infection from cell to cell,while ODVs initiate oral infection in the insect midgut(Braunagel and Summers,2007).

Direct visualization of percolating metal-insulator transition in V_(2)O_(3) using scanning microwave impedance microscopy

Using the extensively studied V_(2)O_(3) as a prototype system, we investigate the role of percolation in metal-insulator transition(MIT). We apply scanning microwave impedance microscopy to directly determine the metallic phase fraction p and relate it to the macroscopic conductance G, which shows a sudden jump when p reaches the percolation threshold. Interestingly, the conductance G exhibits a hysteretic behavior against p, suggesting two different percolating processes upon cooling and warming. Based on our image analysis and model simulation, we ascribe such hysteretic behavior to different domain nucleation and growth processes between cooling and warming, which is likely caused by the decoupled structural and electronic transitions in V_(2)O_(3) during MIT. Our work provides a microscopic view of how the interplay of structural and electronic degrees of freedom affects MIT in strongly correlated systems.

Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro

The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients.Virusencoded proteases are considered potential drug targets.The human immunodeficiency virus protease inhibitors(lopinavir/ritonavir)has been recommended in the global Solidarity Trial in March launched by World Health Organization.However,there is currently no experimental evidence to support or against its clinical use.We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro,and discussed the possible inhibitory mechanism in silico.The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical.Among the four tested compounds,lopinavir showed the best inhibitory effect against the novel coronavirus infection.However,further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen[marketed as Kaletraò,contained lopinavir/ritonavir(200 mg/50 mg)tablets,recommended dosage is 400 mg/10 mg(2 tablets)twice daily].This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration.Nevertheless,the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.

Polypharmacy Among People Living with Dementia — Israel and 24 Countries in European Union, 2015–2019

What is already known about this topic?With a growing number of people living with dementia(PLWD),the practice of taking multiple medications to manage symptoms or comorbidities,i.e.,polypharmacy,among PLWD has become a global health challenge.What is added by this report?In 2015–2019,polypharmacy for PLWD varied substantially among 25 studied countries,with approximately 1 in 5 Estonian PLWD and 4 in 5 Cypriot PLWD having polypharmacy.In addition,Switzerland,Poland,Austria,and the Czech Republic have experienced a significantly increasing trend in polypharmacy for PLWD.What are the implications for public health practice?Countries should pay special attention to polypharmacy and make efforts to control polypharmacy among PLWD,especially in countries where the trend of polypharmacy among PLWD has been increasing.