Simulation Analysis of Flow Characteristics in the Vortex Diode with Double Tangential Tube

The paper analyzed flow characteristics in vortex diode with double tangential tube by numerical simulation. Compared to traditional vortex diode with one tangential tube, the structure of double tangential tube can reduce the forward resistance and improve overall performance. The symmetrical design adopted in vortex diode with double tangential tube;the internal flow field in chamber showed symmetrical distribution in the reverse flow, which can improve the flow stability and accelerate the convergence speed in simulation.

Identification and molecular characterization of two novel mutations in COL1A2 in two Chinese families with osteogenesis imperfecta

Osteogenesis imperfecta（OI,also known as brittle bone disease）is caused mostly by mutations in two type I collagen genes,COL1A1 and COLIA2 encoding the pro-α1（I）and pro-α2（I）chains of type I collagen,respectively.Two Chinese families with autosomal dominant OI were identified and characterized.Linkage analysis revealed linkage of both families to COL1A2 on chromosome 7q21.3-q22.1.Mutational analysis was carried out using direct DNA sequence analysis.Two novel missense mutations,c.3350AG and c.3305GC,were identified in exon 49 of COL1A2 in the two families,respectively.The c.3305GC mutation resulted in substitution of a glycine residue（G）by an alanine residue（A）at codon 1102（p.G1102A）,which was found to be mutated into serine（S）,argine（R）,aspartic acid（D）,or valine（V）in other families.The c.3350AG variant may be a de novo mutation resulting in p.Y1117C.Both mutations co-segregated with OI in respective families,and were not found in 100 normal controls.The G1102 and Y1117 residues were evolutionarily highly conserved from zebrafish to humans.Mutational analysis did not identify any mutation in the COX-2 gene（a modifier gene of OI）.This study identifies two novel mutations p.G1102A and p.Y1117C that cause OI,significantly expands the spectrum of COL1A2 mutations causing OI,and has a significant implication in prenatal diagnosis of OI.

Use of a Removable Backbone Modification Strategy to Prevent Aspartimide Formation in the Synthesis of Asp Lactam Cyclic Peptides

The synthesis of an Asp lactam derivative of A-183,a selective inhibitor of Factor 7a with good anticoagulant and antithrombotic activity,is described.Our synthesis depends on the use of a removable backbone modification(RBM)strategy to prevent aspartimide formation,which thwarted all attempts to synthesize this target using direct solid-phase peptide synthesis.Validation of the RBM strategy in the synthesis of a second Asp lactam derivative was also accomplished.The RBM strategy is therefore proposed as a general method for the synthesis of Asp lactam cyclic peptides.

Total synthesis of TRADD death domain with arginine N-GlcNAcylation by hydrazide-based native chemical ligation

TNFR1-associated death domain protein(TRADD)with arginine N-GlcNAcylation is a novel and structurally unique posttranslational modification(PTM)glycoprotein that blocks the formation of death-inducing signaling complex(DISC),orchestrating host nuclear factorκB(NF-κB)signaling in entero-pathogenic Escherichia coli(EPEC)-infected cells.This particular glycosylated modification plays an extremely vital role for the effective colonization and pathogenesis of pathogens in the gut.Herein we describe the total synthesis of TRADD death domain(residues 195-312)with arginine235 NGlcNAcylation(Arg-GIcNAc TRADD(195-312)).Two longish peptidyl fragments of the wild-type primary sequence were obtained by robust,microwave-assisted,highly efficient,solid-phase peptide synthesis(SPPS),the N-GlcNAcylated sector was built by total synthesis and attached specifically to resinbound peptide with an unprotected ornithine residue via silver-promoted on-resin guanidinylation,ArgGlcNAc TRADD(195-312)was constructed by hydrazide-based native chemical ligation(NCL).The facile synthetic strategy is expected to be generally applicable for the rapid synthesis of other proteins with Arg-GIcNAc modification and to pave the way for the related chemically biological study.

Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells.The all-hydrocarbon peptide stapling technique has already widely adopted with great success,yielding numerous potent peptide-based molecules.Based on our prior efforts,we conceived and prepared a double-stapled peptide in this study,termed FRNC-1,which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3β.The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form.Additionally,FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized(OVX)mice after intravenous injection and importantly,after oral(intragastric)administration.The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis(PMOP).

Protective efficacy of a universal influenza mRNA vaccine against the challenge of H1 and H5 influenza A viruses in mice

Current influenza vaccines need to be updated annually owing to constant antigenic drift in the globular head of the viral surface hemagglutinin(HA)glycoprotein.The immunogenic subdominant stem domain of HA is highly conserved and can be recognized by antibodies capable of binding multiple HA subtypes.Therefore,the HA stem antigen is a promising target for the design of universal influenza vaccines.On the basis of an established lipid nanoparticle-encapsulated mRNA vaccine platform,we designed and developed a novel universal influenza mRNA vaccine(mHAs)encoding the HA stem antigen of the influenza A(H1N1)virus.We tested the efficacy of the mHAs vaccine using a mouse model.The vaccine induced robust humoral and specific cellular immune responses against the stem region of HA.Importantly,two doses of the mHAs vaccine fully protected mice from lethal challenges of the heterologous H1N1 and heterosubtypic H5N8 influenza viruses.Vacci-nated mice had less pathological lung damage and lower viral titers than control mice.These results suggest that an mRNA vaccine using the conserved stem region of HA may provide effective protection against seasonal and other possible influenza variants.

Structural modification and antitumor activity of antimicrobial peptide HYL

HYL derived from the venom of the solitary bee Hylaeus signatus(Hymenoptera:Colletidae)is anα-helical antimicrobial peptide with 16 residues.To explore whether HYL can be applied in anti-tumor therapy,we synthesized HYL and further modified its structure by using a solid-phase synthesis method,and then evaluated their antitumor activities.Firstly,we identified the key residues of HYL by alanine scanning strategy,and then a series of stapled peptides were synthesized by hydrocarbon stapling strategy without destroying the key residues.All the stapled peptides of HYL showed significant improvement not only inα-helicity,but also in antitumor activity and protease resistance when compared to the parent peptide HYL.The results showed that hydrophobicity and amphiphilicity are important factors affecting the antitumor activity of HYL,and the stapling strategy can significantly affect the proteolytic stability and helicity of HYL.What’s more,we find that the stapled peptides HYL-14,HYL-16 and HYL-18 show a promising prospect for novel anti-tumor drug development.

Chemical Synthesis of Structurally Defined Phosphorylated Ubiquitins Suggests Impaired Parkin Activation by Phosphorylated Ubiquitins with a Non-Phosphorylated Distal Unit

Mutations in genes encoding PINK1(PTEN-induced kinase 1)and Parkin(E3 ubiquitin ligase)are identified in familial Parkinson’s disease.However,it remains unclear whether the phosphorylated Ub chains activate wild-type Parkin(w-Parkin)or phosphorylated Parkin(p-Parkin),with the consequent expulsion of the damaged mitochondria.