A subspace expanding technique for global zero finding of multi-degree-of-freedom nonlinear systems

A subspace expanding technique(SET) is proposed to efficiently discover and find all zeros of nonlinear functions in multi-degree-of-freedom(MDOF) engineering systems by discretizing the space into smaller subdomains, which are called cells. The covering set of the cells is identified by parallel calculations with the root bracketing method. The covering set can be found first in a low-dimensional subspace, and then gradually extended to higher dimensional spaces with the introduction of more equations and variables into the calculations. The results show that the proposed SET is highlyefficient for finding zeros in high-dimensional spaces. The subdivision technique of the cell mapping method is further used to refine the covering set, and the obtained numerical results of zeros are accurate. Three examples are further carried out to verify the applicability of the proposed method, and very good results are achieved. It is believed that the proposed method will significantly enhance the ability to study the stability, bifurcation,and optimization problems in complex MDOF nonlinear dynamic systems.

Recent advances in chemical protein synthesis:method developments and biological applications

The central dogma of modern biology underscores the pivotal roles proteins play in diverse biological processes,the study of which necessitates advanced methods to produce proteins with precision and versatility.Chemical protein synthesis,a powerful approach utilizing chemical reactions for the de novo construction of structurally accurate proteins,has emerged as a transformative tool for studying proteins and generating protein derivatives/mimics inaccessible by natural biological machinery,including post-translationally modified proteins,proteins comprised of unnatural amino acids,as well as mirror-image proteins.This review summarizes recent strides in synthetic method developments for chemical protein synthesis,including innovative techniques in solid-phase peptide synthesis,the challenges presented by difficult sequences in either synthesis or folding and the exploration of novel ligation reactions using both chemical and enzymatic methods.Furthermore,the review also delves into newly developed protocols for site-selective protein modifications and the generation of stapled or macrocyclized peptides/miniproteins,highlighting the power of chemical methods to make structurally diverse proteins.Recent applications of synthetic proteins in investigating post-translational modifications(phosphorylation,lipidation,glycosylation,ubiquitination,etc.),mirror-image biological processes and drug development are further discussed.Together,these topics provide a comprehensive overview of the current landscape of chemical protein synthesis.

Change of Phosphate Fraction during Composting of Fresh Waste Leaves of Tobacco

Environmental issue has concerned the public with the build-up of soil phosphorus(P) following application of organic manure.This demands a fully understanding of the change of phosphorus during composting of fresh waste leaves of tobacco and finding out the status of P fertilizer in leaf-made manure.This study had shown that water-soluble and HCl-soluble phosphon were the dominant fractions of P in the compost of fresh waste leaves,in the ranges of 19%-41% and 17%-43%,respectively.However,the former declined progressively upon composting time,but the latter increased,indicating transformation of the more vulnerable water soluble P to the more recalcitrant HCl-extractable P.

Targeting UBE2C for degradation by bioPROTACs based on bacterial E3 ligase

UBE2C(Ubiquitin conjugating enzyme E2 C), a key regulator of cell cycle progression, is a promising target for discovery of antitumor agents. However, it is challenging to develop inhibitors of UBE2C owing to its lack of “druggable” pockets. Bio PROTACs(biological proteolysis targeting chimeras) are a kind of protein-based degraders by fusing an adaptor to a subunit of E3 ligase for ubiquitination and subsequent proteasome-dependent degradation of target protein. We report herein the design and biological evaluation of a UBE2C-targeting bio PROTAC based on the NEL(novel E3 ligase) domain of bacterial E3 ligase Ipa H9.8 and the UBE2C-binding WHB(winged-helix B) domain of APC_(2)(anaphase promoting complex subunit 2). The in vitro ubiquitination test and Mass Spectrometry analysis showed that the bio PROTAC could transfer ubiquitin to surface exposed lysines on UBE2C and catalyzed the formation of polyubiquitin chains. In addition, the transient co-expression experiment showed that the bio PROTAC could promote proteasomal degradation of heterologous UBE2C and rescue its downstream substrates in mammalian cells.

N-cap helix nucleation： methods and their applications

Recapitulation of well-defined α-helices could result in constrained peptide mimetics with preferable secondary structures and enhanced therapeutic properties for various purposes. Among the helix-stabilizing strategies, the nucleation strategies are able to maximize recognition specificity of the original sequence without compromising the molecular recognition surface. In this review,current methodologies of helix nucleation are introduced including their constructing strategies, structure features and proof of concept biological applications.

Self-Assembly of Constrained Cyclic Peptides Controlled by Ring Size

The de novo design of new peptide assemblies that expands the repertoire of biomaterial nanostructures has been of a tremendous challenge.Hence,it is evident that a successful research achievement in this area would increase the understanding of molecular interactions in supramolecules and create novel scaffolds exploitable in biotechnology and synthetic biology.The manipulation of cyclic peptide self-assembly is particularly intriguing for this purpose.Herein,we report that a novel type of cyclic peptides,referred to as chiral tether constrained cyclic peptides(CCP),shows promising self-assembly properties.CCPs are the first example of a controllable assembly of all-L-α-cyclic peptides with different ring sizes.A noteworthy feature of the CCP system is good tolerance of different secondary structures,ring size,and peptide sequence.Based on this system,a variety of nanostructures could be constructed,which display different physical properties,rendering it an excellent platform for molecular interaction studies.Further,demonstrate potential applications of these peptide assemblies in bioimaging and energy storage.

Reversibly switching the conformation of short peptide through in-tether chiral sulfonium auxiliary

A chirality induced helicity method has been developed to modulate the peptide＇s biophysical and biochemical properties. We report herein a novel approach for reversibly switching the conformation of short constraint a-helical peptides through alkylation of the in-tether thioether and dealkylation of the chiral sulfonium. This traceless redox sensitive tagging strategy broadened our scope of CIH （chirality induced helicity） strategy and provided a valuable approach to functionalize the peptide tether.

A Proximity-Triggered Strategy toward Transferable Proteolysis Targeting Chimeras

Over the past 20 years,great efforts have been invested in developing site-specific approaches to protein modification to dissect protein functions directly and accurately.Here,we report a proximitytriggered group transfer strategy from a sulfonium warhead to a Cysteine(Cys)residue of the target protein.With a guiding ligand,cargoes could be transferred selectively from a sulfonium center onto the Cys residue in the vicinity of their binding interface.The successful thalidomide transfer of sulfonium 1-X could be applied intracellularly for epidermal growth factor receptor degradation,highlighting the potential of group transfer strategy as a suite of chemical biology studies,including cell imaging,protein profiling,and protein degradation by simply employing different transferrable groups.

A novel inhibitor of N^(6)-methyladenosine demethylase FTO induces m RNA methylation and shows anti-cancer activities

N^(6)-methyladenosine(m^(6)A)modification is critical for m RNA splicing,nuclear export,stability and translation.Fat mass and obesity-associated protein(FTO),the first identified m^(6)A demethylase,is critical for cancer progression.Herein,we developed small-molecule inhibitors of FTO by virtual screening,structural optimization,and bioassay.As a result,two FTO inhibitors namely 18077 and 18097 were identified,which can selectively inhibit demethylase activity of FTO.Specifically,18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells.In addition,18097 reprogrammed the epi-transcriptome of breast cancer cells,particularly for genes related to P53 pathway.18097 increased the abundance of m^(6)A modification of suppressor of cytokine signaling1(SOCS1)m RNA,which recruited IGF2 BP1 to increase m RNA stability of SOCS1 and subsequently activated the P53 signaling pathway.Further,18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma(PPARγ),CCAAT/enhancer-binding protein alpha(C/EBPa),and C/EBPβ.Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells.Collectively,we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Whole-body PET tracking of a D-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors

Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.

A bifunctional vinyl-sulfonium tethered peptide induced by thio-Michael-type addition reaction

The modification and functionalization of peptides is of great significance in modern biotechnology and drug development. Here we report a highly reactive Michael-type warhead for the covalently modification of cysteine on peptide and protein. By installing a vinyl group onto a methionine residue of peptide,the produced vinyl sulfonium can be efficiently nucleophilic added by appropriate cysteine residue of this peptide, and thus yield a cyclized peptide. This peptide cyclization strategy was proven to exhibit improved cell penetration and good stability. Moreover, a peptide ligand bearing vinyl sulfonium could covalently bind to the cysteine in the target protein, indicating the potential of vinyl sulfonium as a novel warhead for developing covalent peptide inhibitor.

Proximity-induced amino-yne reaction for selective MDM4 conjugation via propargylated sulfonium

Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues,proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues.We report one example here that the propargylated-sulfonium center undergoes a nucleophilic reaction with lysine residue via proximity-induced conjugation.This propargylated-sulfonium tethered peptide resulting from a facile propargylation of thiolethers,enables amino-yne reaction at the selected lysine on MDM4 protein.This strategy represents a viable approach of lysine-targeted covalent inhibition in proximity.

Development of a potent peptide inhibitor of estrogen receptor α

We have developed a facile N-terminus helix-nucleating strategy using an unnaturally tethered aspartic acid(TD strategy). Relatively weak nuclear translocation efficiency of TD PERM limits its further biological applications. A potent peptide inhibitor of estrogen receptor α(ER-α) with significantly increased cellular uptake and cellular distribution was developed by cell penetrating peptide attachment.The resulted peptide conjugate showed selective toxicity towards estrogen receptor positive cell lines and induced decreased transcription of estrogen receptor a downstream genes.

Nucleic acids induced peptide-based AIE nanoparticles for fast cell imaging

Herein,we utilized nucleic acids induced peptide co-assembly strategy to develop novel nucleic acids induced peptide-based AIE(NIP-AIE)nanoparticles.Strong fluorescent of AIE could be observed when a little amount of nucleic acids was added into the peptide solution,and the intensity could be regulated by the concentration of nucleic acids.This AIE nanoparticle with good biocompatibility could achieve fast cell imaging.It is also proved that the fluorescence intensity of AIE decreased with time,which indicates that the reducible cross-linkers of Wpc peptide by GSH and nanoparticles gradually disintegrate in cell.Based on the different of AIE fluorescence signals which regulated by the formation and disintegration of nanoparticles,this AIE system is expected to be used for real-time monitoring of drug release from peptide-based nano carriers in vivo or in vitro,and may provide a new platform for the construction of other organic AIE nanoparticles.

A simple and novel method for the quantitative detection of 5-hydroxymethylcytosine using carbon nanotube field- effect transistors

5-hydroxymethylcytosine （5-hmC） is an important epigenetic derivative of cytosine and quantitative detection of 5-hmC could be used as a reliable biomarker for a variety of human diseases. Current technologies used in 5-hmC detection are complicated and time/cost inefficient. In this work, we report the first application of antibody-functionalized carbon nanotube field-effect transistors （CNT-FETs） in quantitative detection of 5-hmC from mouse tissues. This method achieves facile and ultra-sensitive 5-hmC detection based on electrical performance device and avoids complicated processing for DNA samples. The 5-hmC content percentages of normal mouse cerebrum, cerebellum, spleen, lung, liver, and heart samples presented in the genomic DNA were measured as 0.653, 0.573, 0.002, 0.020, 0.076, and 0.009, respectively, which is consistent with previous reports. This technology could be developed into fadle routine 5-hmC monitoring devices for clinic human disease diagnoses.