A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer.However,the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations.Furthermore,monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors.In this study,based on our discovery that spore shell(SS)of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity,we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy,chemodynamic therapy and antitumor immunity for synergistic cancer treatment.In detail,SS is separated from probiotic spores and then attached to the surface of liposome(Lipo)that was loaded with hemoglobin(Hb),glucose oxidase(GOx)and JQ1to construct SS@Lipo/Hb/GOx/JQ1.In tumor tissue,highly toxic hydroxyl radicals(·OH)are generated via sequential catalytic reactions:GOx catalyzing glucose into H_(2)O_(2)and Fe^(2+)in Hb decomposing H_(2)O_(2)into·OH.The combination of·OH and SS adjuvant can improve tumor immunogenicity and activate immune system.Meanwhile,JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response.In this manner,SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis.To summarize,the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

Protein phosphatase PP4 is overexpressed in human breast and lung tumors

Dear Editor, Reversible protein phosphorylation by kinases and phosphatases is one of the most common mechanisms in controlling most, if not all, cellular processes [ 1 ]. Dephos- phorylation of serine/threonine residues is regulated by two distinct groups of functionally diverse serine/threonine protein phosphatases, the PPM family （which includes PP2C） and the PPP family, which includes the type 1 （PP1） and the type 2A （PP2A, PP2B, PP3, PP4, PP5, PP6, and PP7） protein phosphatases. Members of the type 2A group ofphosphatases （PP2A, PP4, and PP6） are the most closely related in sequence. They are sensitive to inhibition by low doses of okadaic acid （OA） or fostriecin, which distinguishes them from PP 1 [ 1 ]. The regulation and function of PP2A have been thoroughly investigated. PP2A is composed of a core complex containing the catalytic subunit （C） and the scaffold subunit （A）, which interacts with a wide variety of regulatory subunits and interacting proteins that target the AC core dimer to specific substrates and subcellular locations [ 1 ]. The assembly of many different types of heterotrimeric holoenzymes accounts for the ability of PP2A, and, possibly, PP4 and PP6, to regulate a wide range of biological orocesses.

Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets

Solid dispersion(SD)systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs.To circumvent the limitations of polyvinylpyrrolidone(PVP)dispersions,HPMC E5 was applied in the formulation process and scaling-up techniques,simultaneously.In this study,SD of nimodipine(NMP)and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique,respectively.Discriminatory dissolution media were used to obtain reliable dissolution results.Meanwhile,the stability study of SDs was investigated with storage under high temperature and humidity conditions.Moreover,the solubility of SDs was measured to explore the effect of carriers.The preparations were characterized by DSC,PXRD,and FTIR.Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers.Binary NMP/PVP/HPMC-SDs released steadily,while the dissolution of single NMP/PVP-SDs decreased rapidly in water.The fluid-bed tablets(FB-T)possessed a similar dissolution behavior to the commercial Nimotop TM tablets.The characterization patterns implied that NMP existed in an amorphous state in our SDs.Furthermore,the results of stability tests suggested a better stability of the binary SDs.A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets,which could be extended to other drugs henceforth.Finally,the bioavailability of FB-T was evaluated in beagle dogs with Nimotop TM as the reference,and the results showed a higher AUC 0–12h value for FB-T.

Global Analysis of Beddington-DeAngelis Type Chemostat Model with Nutrient Recycling and Impulsive Input

In this paper, a Beddington-DeAngelis type chemostat model with nutrient recycling and impulsive input is considered. Except using Floquet theorem, introducing a new method combining with comparison theorem of impulse differential equation and by using the Liapunov function method, the sufficient and necessary conditions on the permanence and extinction of the microorganism are obtained. Two examples are given in the last section to verify our mathematical results. The numerical analysis shows that if only the system is permanent, then it also is globally attractive.

Integrated multi-omics reveals the relationship between growth performance,rumen microbes and metabolic status of Hu sheep with different residual feed intakes

Residual feed intake(RFI)is a metric that provides a more accurate measure of feed efficiency.The lower the RFI,the higher the feed efficiency.The changes in the host microbiome and metabolome contribute to the greater feed efficiency of low RFI(LRFI)animals.The aim of this study was to explore the differences in rumen microorganisms,rumen metabolites and plasma metabolites of Hu sheep with differing RFI through the microbiome and metabolome.A total of 80 Hu sheep were used.The experiment consisted of a 15-d pretrial period and a 128-d experimental period.The RFI in the experimental period was calculated for all sheep,and the sheep were screened into high RFI(HRFI,n=8)and LRFI(n=8)groups.The HRFI and LRFI sheep did not differ in their initial and final body weights,average daily gain and body measurements,but the dry matter intake of LRFI sheep was significantly decreased(28.4%,P<0.001).The sheep with LRFI had higher digestibility of crude protein(P=0.010)and ether extract(P=0.010)compared to HRFI group.The concentrations of acetate(P=0.036),propionate(P=0.010),valerate(P=0.027)and total volatile fatty acids(P=0.048)in rumen of LRFI group were higher compared to HRFI group.The results of 16S rDNA sequencing indicated that the sheep with LRFI had higher proportions of Prevotella genus in rumen liquid(P=0.031).The rumen metabolome and plasma metabolome results showed that the citrate cycle,pyruvate metabolism and alanine,aspartate and glutamate metabolism processes were more active for sheep in LRFI group,which provided more energy substrate such as malic acid,oxoglutaric acid and citric acid.In conclusion,sheep with LRFI can utilize feed more efficiently,and the more active energy metabolism pathway and the production of energy substances may account for the higher feed efficiency.

In situ biosynthesis of bacterial cellulose hydrogel spheroids with tunable dimensions

Bacterial cellulose(BC)hydrogel spheroid plays a significant role in diverse fields due to its spatial 3D structure and properties.In the present work,a series of BC spheroids with controllable size and shape was obtained via an in situ biosynthesis.Crucial factors for fabricating BC spheroid in-cluding inoculum concentration of 1.35×10^(3)CFU/mL,shaking speeds at 100 r/min,and 48-96 h incubation time during the biosynthetic process,were comprehensively established.An operable mechanism model for tuning the size of BC spheroids from 0.4 to 5.0 mm was proposed with a fresh feeding medium strategy of dynamic culture.The resulting BC spheroids exhibit an inter-active 3D network of nanofibers,a crystallinity index of 72.3%,a specific surface area of 91.2 m^(2)/g,and good cytocompatibility.This study reinforces the understanding of BC spheroid forma-tion and explores new horizons for the design of BC spheroids-derived functional matrix materials for medical care.

An antibody cocktail with broadened mutational resistance and effective protection against SARS-CoV-2

Neutralizing antibodies have been proven to be highly effective in treating mild and moderate COVID-19 patients,but continuous emergence of SARS-CoV-2 variants poses significant challenges.Antibody cocktail treatments reduce the risk of escape mutants and resistance.In this study,a new cocktail composed of two highly potent neutralizing antibodies(HB27 and H89Y)was developed,whose binding epitope is different from those cocktails that received emergency use authorization.This cocktail showed more potent and balanced neutralizing activities(IC_(50)0.9–11.3 ng mL^(-1))against a broad spectrum of SARS-CoV-2 variants over individual HB27 or H89Y antibodies.Furthermore,the cocktail conferred more effective protection against the SARS-CoV-2 Beta variant in an aged murine model than monotherapy.It was shown to prevent SARS-CoV-2 mutational escape in vitro and effectively neutralize 61 types of pseudoviruses harbouring single amino acid mutation originated from variants and escape strains of Bamlanivimab,Casirivimab and Imdevimab with IC_(50)of 0.6–65 ng mL^(-1).Despite its breadth of variant neutralization,the HB27+H89Y combo and EUA cocktails lost their potencies against Omicron variant.Our results provide important insights that new antibody cocktails covering different epitopes are valuable tools to counter virus mutation and escape,highlighting the need to search for more conserved epitopes to combat Omicron.

Mutation N856K in spike reduces fusogenicity and infectivity of Omicron BA.1

Dear Editor,COVID-19 lung pathology is characterized by interstitial pneumonia with cell-cell fusion-induced syncytia and extensive tissue damage.1 The correlation between viral fusogenicity and pathogenicity has been reported in SARS-CoV-2 variants.2 Compared with the previous Delta or D614G variants,Omicron BA.1 has been proven to be less fusogenic and pathogenic.

Analytical and experimental study of a valveless piezoelectric micropump with high flowrate and pressure load

Miniaturized gas pumps based on electromagnetic effect have been intensively studied and widely applied in industries.However,the electromagnetic effect-based gas pumps normally have large sizes,high levels of noises and high power consumption,thus they are not suitable for wearable/portable applications.Herein,we propose a high-flowrate and high-pressure load valveless piezoelectric micropump with dimensions of 16 mm*16 mm*5 mm.The working frequency,vibration mode and displacement of the piezoelectric actuator,the velocity of gas flow,and the volume flowrate of the micropump are analyzed using the finite element analysis method.The maximum vibration amplitude of the piezoelectric actuator reaches~29.4μm.The output gas flowrate of the pump is approximately 135 mL/min,and the maximum output pressure exceeds 40 kPa.Then,a prototype of the piezoelectric micropump is fabricated.Results show that performance of the micropump is highly consistent with the numerical analysis with a high flowrate and pressure load,demonstrated its great potential for wearable/portable applications,especially for blood pressure monitoring.

NIR light-induced tumor phototherapy using ICG delivery system based on platelet-membrane-camouflaged hollow bismuth selenide nanoparticles

Near-infrared(NIR)light-triggered photothermal therapy(PTT)is a promising treatment strategy for treating cancer.The combination of nanotechnology and NIR has been widely applied.However,the therapeutic efficacy of the drug-delivery system depends on their ability to avoid phagocytosis of endothelial system,cross the biological barriers,prolong circulation life,localize and rapidly release the therapeutic at target sites.In this work,we designed a platelet membrane(PM)-camouflaged hollow mesoporous bismuth selenide nanoparticles(BS NPs)loading with indocyanine green(ICG)(PM@BS-ICG NPs)to achieve the above advantages.PM-coating has active tumor-targe ting ability which could preve nt drug leakage and provide drug long circulation,causing drug delivery systems to accumulate in tumor sites effectively.Moreover,as a type of the photothermal sensitizers,BS NPs are used as the inner cores to improve ICG stability and are served as scaffolds to enhance the hardness of this drug delivery system.For one hand,the thermal vibration of BS NPs under NIR laser irradiation causes tumor inhibition through hyperthermia.For another hand,this hyperthermia process could damage PM and let ICG rapid release from PM@BS-ICG NPs.The in vitro and in vivo results showed that this biomimetic nano-drug delivery system exhibits obvious antitumor activity which has good application prospect.

Milk selenium content and speciation in response to supranutritional selenium yeast supplementation in cows

The effects of selenium(Se)yeast supplementation on performance,blood biochemical and antioxidant parameters,and milk Se content and speciation were evaluated.Thirty-six mid-lactation Holstein dairy cows were randomly assigned to 1 of 3 treatments:1)control(basal diet containing Se at 0.11 mg/kg DM),2)basal diet+0.5 mg supplemental Se/kg DM(SY-0.5),and 3)basal diet+5 mg supplemental Se/kg DM(SY-5).Selenium was supplemented as Se yeast.The trial consisted of a 1-week pretrial period and an 8-week experimental period.Milk somatic cell score decreased with SY-5 supplementation(P<0.05),but other performance parameters were not affected(P>0.05).The serum Se concentration increased with the increasing levels of Se yeast supplementation(P<0.05),however,blood biochemical parameters showed few treatment effects.The antioxidant capacity of dairy cows was improved with Se yeast supplementation reflected in increased serum glutathione peroxidase activity(P<0.05)and total antioxidant capacity(P=0.08),and decreased malondialdehyde concentration(P<0.05).Milk total Se concentration increased with Se dose(P<0.05).Also,the selenomethionine concentration increased with Se dose from 13.0±0.7 pg/kg in control to 33.1±2.1 pg/kg in SY-0.5 and 530.4±17.5 pg/kg in SY-5 cows(P<0.05).Similarly,selenocystine concentration increased from 15.6±0.9μg/kg in control and 18.9±1.1 pg/kg in SY-0.5 to 22.2±1.5 pg/kg in SY-5 cows(P<0.05).In conclusion,Se yeast is a good organic Se source to produce Se-enriched cow milk with increased Se species including selenomethionine and selenocystine.The results can provide useful information on milk Se species when a high dose Se yeast was supplemented in the cow diet.

Association of single nucleotide polymorphism rs2065955 of the filaggrin gene with susceptibility to Epstein-Barr virus-associated gastric carcinoma and EBV-negative gastric carcinoma

The relationship between the Filaggrin gene(FLG) rs2065955 polymorphism and susceptibility to Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVa GC) and EBV-negative gastric carcinoma(EBVn GC) was investigated in Shandong Province,China.We detected the FLG rs2065955 genotype and allele distribution by using PCR and restriction fragment length polymorphism(RFLP) in 64 EBVa GC,82 EBVn GC,and 111 normal control samples.Immunohistochemistry was used to detect the level of FLG protein in 35 EBVa GC and 51 EBVn GC tumor tissues.Compared with normal controls,the genotype CC and allele C of FLG rs2065955 showed higher frequency in EBVa GC and EBVn GC.There was no significant difference between EBVa GC and EBVn GC in allele distribution of FLG rs2065955,but the genotype CC was found more frequently in EBVa GC than in EBVn GC.The risk of developing either EBVa GC or EBVn GC in genotype CC was higher than in other genotypes.Furthermore,genotype CC of FLG rs2065955 may contribute more to the risk of developing EBVa GC than EBVn GC.There was no significant difference in the expression level of FLG protein between EBVa GC and EBVn GC.In conclusion,the FLG rs2065955 polymorphism was significantly related to gastric carcinoma.Allele C of FLG rs2065955 could be a risk factor for EBVa GC or EBVn GC,while genotype CC of FLG rs2065955 was especially associated with EBVa GC.

Peptide stapling with the retention of double native side-chains

All-hydrocarbon stapling strategy has been widely applied for enhancing the proteolytic stability of peptides. However, two major technical hurdles to some extent limit the development of stapled peptides for therapeutic usage: rational selection of the stapling sites and the corresponding deletion of the native side chains. Previously we described the development of the olefin-terminated amino acids with the retention of native side chains and successfully applied them in the synthesis of hydrocarbon stapled peptides with single side-chain retention. Here, we explored the feasibility and effectiveness of hydrocarbon stapling strategy characterized as double side-chains retention. Modeled after a lengthy human immunodeficiency virus-1(HIV-1) fusion inhibitor SC34 EK, Leu^(i), Ser^(i+4)and Lys^(i), Leu^(i+4)stapled peptides with the retention of double side-chains were effectively obtained. Our complementary study provided a convenient alternative to address where to install the staple in sequence for conventional all-hydrocarbon peptide stapling. Furthermore, this method not only conferred conformational reinforcement for SC34 EK with high α-helicity and protease resistance, but also preserved the structural characteristic(key peripheral residues, charge and solubility) of the linear peptide to the maximum, which are crucial for anti-HIV-1 activity.

Photoluminescent properties of Sb^(3+)-doped and(Sb^(3+),Eu^(3+))co-doped YBO3 phosphors prepared via hydrothermal method and solid-state process

Sb^(3+)-doped YBO3 crystals were prepared through a low-temperature hydrothermal method and a high-temperature solid-state technique,respectively.The effects of preparation methods on the morphologies and luminescent properties of YBO_(3) phosphors were investi-gated.The YBO3 crystals from the hydrothermal system look likeflowers,whereas those from the solid-state process look like some agglomerates of little spheres.The Sb^(3+)-doped YBO3 powders prepared via both methods showed the blue emission with the peak at around 452 nm,which corresponds to the 3P1→1S0 transition of Sb^(3+)ions.However,the emission intensity of the Sb^(3+)-doped YBO3 from the hydrothermal system is about 3.5 times as much as that from the solid-state process.The(Sb^(3+),Eu^(3+))co-doped YBO3 crystals were also prepared through the two methods.The results showed that the emission intensity of Sb^(3+)ions in(Sb^(3+),Eu^(3+))co-doped YBO3 synthesized by the hydrothermal method is stronger than that by the solid-state process.

Corrigendum to“Peptide stapling with the retention of double native side-chains”[Chinese Chemical Letters 32(2021)4045-4048]

The authors regret having incorrectly labelled the molar concentration of 1^(st)Grubbs'catalyst in Fig.3B.The original manuscript illustrates molar concentration of 1^(st)Grubbs'catalyst at 6 mol/L.This should have been 10 mmol/L;consistent with the molar concentration described in Supporting Information.