Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its function.However,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive.In this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent y-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in mice.Finaly,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout mice.This data demonstrates that the a-secretase is essential for CNTNAP2 processing and its function.Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

Biomass valorization via electrocatalytic carbon–carbon bond cleavage

Renewable electrocatalytic upgrading of biomass feedstocks into valuable chemicals is one of the promising strategies to relieve the pressure of traditional energy-based systems.Through electrocatalytic carbon–carbon bond cleavage of high selectivity,various functionalized molecules,such as organic acids,amides,esters,and nitriles,have great potential to be accessed from biomass.However,it has merely received finite concerns and interests in the biorefinery.This review first showcases the research progress on the electrocatalytic conversion of lipid/sugar-and lignin-derived molecules(e.g.,glycerol,mesoerythritol,xylose,glucose,1-phenylethanol,and cyclohexanol)into organic acids via specific carbon–carbon bond scission processes,with focus on disclosing reaction mechanisms,recognizing actual active species,and collecting feasible modification strategies.For the guidance of further extensive studies on biomass valorization,organic transformations via a variety of reactions,including decarboxylation,ring-opening,rearrangement,reductive hydrogenation,and carboxylation,are also disclosed for the construction of similar carbon skeletons/scaffolds.The remaining challenges,prospective applications,and future objectives in terms of biomass conversion are also proposed.This review is expected to provide references to develop renewed electrocatalytic carbon–carbon bond cleavage transformation paths/strategies for biomass upgrading.

Roles of host proteases in the entry of SARS-CoV-2

The spike protein(S)of SARS-CoV-2 is responsible for viral attachment and entry,thus a major factor for host suscep-tibility,tissue tropism,virulence and pathogenicity.The S is divided with S1 and S2 region,and the S1 contains the receptor-binding domain(RBD),while the S2 contains the hydrophobic fusion domain for the entry into the host cell.Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various c leavage sites.In this article,we review host proteases including furin,trypsin,transmembrane protease serine 2(TMPRSS2)and cathepsins in the activation of SARS-CoV-2 S.Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin.The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2,and the binding triggers further conformational changes and exposure of the S2'site to proteases such as type Il transmembrane serine proteases(TTPRs)including TMPRSS2.In the presence of TMPRSS2 on the target cells,SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane.In the absence of TMPRSS2,SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry.Additional host proteases involved in the cleavage of the S were discussed.This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2,and discussed the dual roles of such inhibitors in virus replication.

CLEAVAGES OF TRANSCRIPTS OF TOBACCO MOSAIC VIRUS BY SYNTHETIC RIBOZYMES in vitro

Based upon computer-assisted predictions on the secondary structures of tobacco mosaicvirus (TMV) genomic RNA (both polarities), hammerhead type ribozymes were synthesizedin vitro, which all shared a conserved domain adapted from satellite tobacco ringspot virus(sTobRV)RNA. Ribozymes RZ1, RZ2 and RZ3 were designed to cleave the phosphodiester bondsimmediate to the 3’--end of GUC between the residues 5384-5385 and 6312--6313 on the plusstrand and 1214-1215 on the minus strand, respectively. The in vitro data indicated that RZ1 wasable to cleave completely its substrates BT1(+ ) and BT2(+ ), representing partial sequencesof the plus strand of the TMV MP region at 50, 37 and 30℃ with a molar ratio of ribozymeto the target as low as 1:1. Its two iso-ribozymes RZ1A and RZ1B which were respectivelymodified to contain a CUUCGG sequence in the conserved region and in an additional 3’-ter-minal stem-loop of UUUUUCUUCGGAAAAA were able to cleave BT1(+) and BT2(+) asefficiently as RZ1. Ribozyme RZ3 cleaved, with

Discriminating non-ylidic carbon-sulfur bond cleavages of sulfonium ylides for alkylation and arylation reactions

A sulfonium ylide participated alkylation and arylation under transition-metal free conditions is described.The disparate reaction pattern allowed the separate activation of non-ylidic S-alkyl and S-aryl bond.Under acidic conditions,sulfonium ylides serve as alkyl cation precursors which facilitate the alkylations.While under alkaline conditions,cleavage of non-ylidic S-aryl bond produces O-arylated compounds efficiently.The robustness of the protocols were established by the excellent compatibility of wide variety of substrates including carbohydrates.

Research perspectives for catalytic valorization of biomass

Efficient utilization of biomass for the supply of energy and synthetic materials would mitigate the heavy reliance on fossil resources and the growing CO_(2) emission, thus contributing to establishing sustainable and carbon–neutral societies. Much effort has been devoted to catalytic transformations of lignocellulosic biomass, the most abundant and nonedible form of biomass.

Promoter and coding sequence diversity of CsCCD1 may contribute to the differential accumulation of floralβ-ionone in fresh tea leaves

The carotenoid-derived volatileβ-ionone makes an important contribution to tea fragrance.Here,we qualitatively and quantitatively analysed 15 carotenoids in tea leaves of 13 cultivars by UHPLC-APCI-MS/MS.The 13 cultivars were divided into two groups by PCA(Principal Component Analysis)clustering analysis of their carotenoid content,and OPLS-DA(Orthogonal projections to latent structures)indicated that the levels ofβ-carotene(VIP=2.89)and lutein(VIP=2.30)were responsible for much of the variation between the two groups.Interestingly,theβ-carotene toβ-ionone conversion rates in Group 1 were higher than in Group 2,while theβ-carotene content was significantly lower in Group 1 than in Group 2.Theβ-ionone content was significantly higher in Group 1.Pearson Correlation Coefficient calculation between the transcription level of candidate genes(CsCCD1 and CsCCD4)and the accumulation ofβ-ionone indicated that CsCCD1 may involve in the formation ofβ-ionone in 13 cultivars.Prokaryotic expression and in vitro enzyme activity assays showed that‘Chuanhuang 1’had an amino acid mutation in carotenoid cleavage dioxygenases 1(CsCCD1)compared with‘Shuchazao’,resulting in a significantly higherβ-ionone content in‘Chuanhuang 1’.Sequence analysis showed that‘Chuanhuang 1’and‘Huangdan’had different CsCCD1 promoter sequences,leading to significantly higher CsCCD1 expression andβ-ionone accumulation in‘Chuanhuang 1’.These results indicated that the promoter and coding sequence diversity of CsCCD1 might contribute to the differential accumulation ofβ-ionone in different tea cultivars.

Inducing prion protein shedding as a neuroprotective and regenerative approach in pathological conditions of the brain:from theory to facts

In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.

Ni-catalyzed carbon–carbon bonds cleavage of mixed polyolefin plastics waste

The inert carbon–carbon(C–C) bonds cleavage is a main bottleneck in the chemical upcycling of recalcitrant polyolefin plastics waste. Here we develop an efficient strategy to catalyze the complete cleavage of C–C bonds in mixed polyolefin plastics over non-noble metal catalysts under mild conditions. The nickelbased catalyst involving Ni_(2)Al_(3) phase enables the direct transformation of mixed polyolefin plastics into natural gas, and the gas carbon yield reaches up to 89.6%. Reaction pathway investigation reveals that natural gas comes from the stepwise catalytic cleavage of C–C bonds in polypropylene, and the catalyst prefers catalytic cleavage of terminal C–C bond in the side-chain with the low energy barrier.Additionally, our developed approach is evaluated by the technical economic analysis for an economically competitive production process.

Cooperative catalysis of Co single atoms and nanoparticles enables selective CAr-OCH_(3) cleavage for sustainable production of lignin-based cyclohexanols

In this work,a dual-size MOF-derived Co catalyst(0.2Co_(1-NPs)@NC)composed of single atoms(Co_(1))and highly dispersed nanoparticles(Co NPs)was prepared by in-situ Zn evaporation for the highperformance conversion of lignin-derived o-methoxyphenols(lignin oil)to cyclohexanols(up to 97%yield)via cascade demethoxylation and dearomatization.Theoretical calculations elaborated that the dual-size Co catalyst exhibited a cooperative effect in the selective demethoxylation process,in which the Co NPs could initially dissociate hydrogen at lower energies while Co1remarkably facilitated the cleavage of the C_(Ar)-OCH_(3)bond.Moreover,the intramolecular hydrogen bonds formed in the omethoxy-containing phenols were found to result in a decrease in the bond energy of the C_(Ar)-OCH_(3)bond,which was more prone to be activated by the dual-size Co sites.Notably,the pre-hydrogenated intermediate(e.g.,2-methoxycyclohexanol from guaiacol)is difficult to undergo demethoxylation,indicating that the selective C_(Ar)-OCH_(3)bond cleavage is a prerequisite for the synthesis of cyclohexanols.The 0.2Co_(1-NPs)@NC catalyst was highly recyclable with a neglect decline in activity during five consecutive cycles.This cooperative catalytic strategy based on the metal size effect opens new avenues for biomass upgrading via enhanced C-O bond cleavage of high selectivity.

Selective photocatalytic aerobic oxidative cleavage of lignin C–O bonds over sodium lignosulfonate modified Fe_(3)O_(4)/TiO_(2)

Lignocellulose shows significantly potential in sustainable conversion to high-quality fuel and valueadded chemicals with the demands for realizing the rapid cycle of carbon resources and helping to reach carbon neutrality in nature.Selective tailoring of α-O-4,β-O-4,etc.linkages in lignin has always been viewed as "death blow" for its depolymerization.Herein,novel sodium lignosulfonate(SL) modified Fe_(3)O_(4)/TiO_(2)(SL-Fe_(3)O_(4)/TiO_(2)) spherical particles have been developed and used as catalysts for selectively photocatalytic oxidative cleavage of organosolv lignin.As expected,80% selective conversion of lignin in C2-C4 esters has been achieved,while C-O bonds in lignin model compounds can be effectively cleaved.Other than normal hydroxyl radical-mediated photocatalytic depolymerization of lignin over TiO_(2)-based materials,in this contribution,mechanism studies indicate that photogenerated holes and superoxide anion radicals are main active species,which trigger the cleavage of α/β-O-4 bond,and the isotopelabeling study confirms the crucial factor of C_β-H dehydrogenation in cleavage of β-O-4 bonds.

Pregnancy outcomes following supplementation of single dose GnRH agonist to sustain the luteal phase in antagonist fresh embryo transfer cycles:A multicentric prospective cohort study

Objective:To determine whether a single dose of gonadotropin-releasing hormone(GnRH)agonist administered subcutaneously in addition to the regular progesterone supplementation could provide a better luteal support in antagonist protocol fresh embryo transfer cycles.Methods:This prospective,multicentric,cohort study included total 140 women,70 in each group.Controlled ovarian stimulation was carried out as per fixed GnRH antagonist protocol.The trigger was given with hCG.In vitro fertilization/intracytoplasmic sperm injection(IVF/ICSI)was performed and day-3 embryos were transferred.Patients were divided into groups 1 and 2 based on computer generated randomization sheet.Six days following oocyte retrieval,group 1 received 0.2 mg decapeptyl subcutaneously in addition to regular progesterone support while group 2 received progesterone only.Luteal support was given for 14 days to both groups;if pregnancy was confirmed luteal support was continued till 12 weeks of gestation.The clinical pregnancy rate was the primary outcome.The implantation rate,miscarriage rate,live birth delivery rate,and multiple pregnancy rates were the secondary outcomes.Results:A total of 140 patients were analysed,70 in each group.Clinical pregnancy rates(47.1%vs.35.7%;P=0.17),implantation rates(23.4%vs.18.1%,P=0.24),live birth delivery rates(41.4%vs.27.1%,P=0.08),and multiple pregnancy rates(21.2%vs.16.0%,P=0.74)were higher in group 1 than in group 2.Group 1 had a lower miscarriage rate than group 2(5.7%vs.8.6%;P=0.75).However,these differences were not statistically significant between the two groups.Conclusions:Administration of a single dose of GnRH agonist in addition to regular natural micronized vaginal progesterone as luteal support in GnRH antagonist protocol cycles marginally improves implantation rates,clinical pregnancy rates,and live birth delivery rates.However,more studies with higher sample sizes are needed before any conclusive statements about GnRH agonist as luteal phase support can be made.

RNA-binding protein CPSF6 regulates IBSP to affect pyroptosis in gastric cancer

BACKGROUND Extensive evidence has illustrated the promotive role of integrin binding sialoprotein(IBSP)in the progression of multiple cancers.However,little is known about the functions of IBSP in gastric cancer(GC)progression.AIM To investigate the mechanism underlying the regulatory effects of IBSP in GC progression,and the relationship between IBSP and cleavage and polyadenylation factor 6(CPSF6)in this process.METHODS The mRNA and protein expression of relevant genes were assessed through realtime quantitative polymerase chain reaction and Western blot,respectively.Cell viability was evaluated by Cell Counting Kit-8 assay.Cell invasion and migration were evaluated by Transwell assay.Pyroptosis was measured by flow cytometry.The binding between CPSF6 and IBSP was confirmed by luciferase reporter and RNA immunoprecipitation(RIP)assays.RESULTS IBSP exhibited higher expression in GC tissues and cell lines than in normal tissues and cell lines.IBSP knockdown suppressed cell proliferation,migration,and invasion but facilitated pyroptosis.In the exploration of the regulatory mechanism of IBSP,potential RNA binding proteins for IBSP were screened with catRAPID omics v2.0.The RNA-binding protein CPSF6 was selected due to its higher expression in stomach adenocarcinoma.Luciferase reporter and RIP assays revealed that CPSF6 binds to the 3’-untranslated region of IBSP and regulates its expression.Knockdown of CPSF6 inhibited cell proliferation,migration,and invasion but boosted pyroptosis.Through rescue assays,it was uncovered that the retarded GC progression mediated by CPSF6 knockdown was reversed by IBSP overexpression.CONCLUSION Our study highlighted the vital role of the CPSF6/IBSP axis in GC,suggesting that IBSP might be an effective biotarget for GC treatment.

Copper-Catalyzed C-C(O)C Bond Cleavage of Monoalkylated β-Diketone: Synthesis of α,β-Unsaturated Ketones

A new and simple route for the synthesis of α,β-unsaturated ketones via cleavage of the C-C(O)C single bond of monoalkylated β-diketone has been described. The reaction was catalyzed by copper, a cheap transition metal in a weakly basic medium (K3PO4) at room temperature. To carry out this study, we first had to synthesize the monoalkylated β-diketones 1. Afterwards, α,β-unsaturated ketones 2 were obtained with high yields around 80%. Finally, all the products were characterized by 1H NMR, 13C NMR, and HRMS spectra. .

CNBr裂解结合ESIMS/MS测定重组人TNFR和纽兰格林的C端序列

C-terminal sequence is important for the function of a protein.C-terminal sequencing is necessary for structure identification of recombinant drugs.In this paper,a new method based on CNBr cleavage coupled with ESI MS/MS was established and successfully applied to C-terminal sequence analysis of recombinant human TNFR and neuregulin.Results showed,C-terminal sequences with 19 and 11 amino acids were identified respectively.This new method was sensitive,reproducible and useful for C-terminal sequence analysis of recombinant proteins.

Structural and electronic effects boosting Ni-doped Mo_(2)C catalyst toward high-efficiency C-O/C-C bonds cleavage

The selective cleavage of C-O and C-C is facing a challenge in the field of catalysis.In the present work,we studied the influence of doped Ni on the structure and electronic properties,as well as the selective C-O/C-C bond cleavages in the hydrodeoxygenation of palmitic acid over Ni-Mo_(2)C catalyst.The catalytic activity on Ni doped Mo_(2)C with TOF of 6.9×10^(3)h^(-1)is much superior to intrinsic Mo_(2)C catalyst,which is also higher than most noble metal catalysts.Structurally,the doped Ni raises the active particle dispersion and the coordination numbers of Mo species(Mo-C and Mo-O),improves the graphitization degree to promote the electron transfer,and increases the amount of Lewis and Br?nsted acid,which are responsible for the excellent hydrodeoxygenation performance.The Ni promotes simultaneously C-O and C-C bonds cleavage to produce pentadecane and hexadecane owing to the increase of electron-rich Mo sites after Ni doping.These findings contribute to the understanding of the nature of Ni-doped Mo_(2)C on the roles as catalytic active sites for C-O and C-C bonds cleavage.

Efficient and Convenient Procedures forthe Formation and cleavage of steroid acetals catalysed by montmorillonite aite K 10

Acetalization of steroid ketones and cleavage of the acetals have ben carried out inexcellent yield under catalysis of montmorillonite K 10.

Effect of Microstructure Refinement on the Strength and Toughness of Low Alloy Martensitic Steel

Martensitic microstructure in quenched and tempered 17CrNiMo6 steel with the prior austenite grain size ranging from 6 μm to 199 μm has been characterized by optical metallography （OM）, scanning electron microscopy （SEM） and transmission electron microscopy （TEM）. The yield strength and the toughness of the steel with various prior austenite grain sizes were tested and correlated with microstructure characteristics. Results show that both the prior austenite grain size and the martensitic packet size in the 17CrNiMo6 steel follow a HalI-Petch relation with the yield strength. When the prior austenite grain size was refined from 199 μm to 6 μm , the yield strength increased by 235 MPa, while the Charpy U-notch impact energy at 77 K improved more than 8 times, indicating that microstructure refinement is more effective in improving the resistance to cleavage fracture than in increasing the strength. The fracture surfaces implied that the unit crack path for cleavage fracture is identified as being the packet.

ROS-responsive drug delivery systems for biomedical applications

In the field of biomedicine, stimuli-responsive drug delivery systems(DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species(ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes,whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore,ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.

The Maximum Effective Moment Criterion (MEMC) and Its Implications in Structural Geology

The MohroCoulomb criterion has been widely used to explain formation of fractures. However, it fails to explain large strain deformation that widely occurs in nature. There is presently a new theory, the MEMC, which is mathematically expressed as Meff = （（σ1-σ3） L.sin 2α sin α）/2, where σ1-σ3 represents the yield strength of the related rock, L is a unit length and a is the angle between σ1 and deformation bands. This criterion demonstrates that the maximum value appears at angles of ±54.7° to σ1 and there is a slight difference in the moment in the range of 55°±10°. The range covers the whole observations available from nature and experiments. Its major implications include： （1） it can be used to determine the stress state when the related deformation features formed; （2） it provides a new approach to determine the Wk of the related ductile shear zone if only the ratio of the vorticity and strain rate remains fixed; （3） It can be used to explain （a） the obtuse angle in the contraction direction of conjugate kink-bands and extensional crenulation cleavages, （b） formation of low-angle normal faults and high-angle reverse faults, （c） lozenge ductile shear zones in basement terranes, （d） some crocodile structures in seismic profiles and （e） detachment folds in foreland basins.