Multiple effects of polydopamine nanoparticles on Cu^(2+)-mediated Alzheimer's β-amyloid aggregation

Deposition of β-amyloid protein(Aβ) is the main hallmark of Alzheimer's disease(AD), and it has been well recognized that Cu^(2+)-mediated Aβ aggregation plays a crucial role in AD pathological processes.Cu^(2+)binding to Aβ can promote the production of reactive oxygen species(ROS) through Fenton-like reactions and produce more toxic Aβ-Cu^(2+)species under Cu^(2+)stimulation. Thus, the development of nanomaterials that can inhibit Cu^(2+)-mediated Aβ aggregation and degrade Aβ-Cu^(2+)complexes is considered an effective strategy for the prevention and treatment of AD. In this study, polydopamine nanoparticles(PDA NPs) were prepared and the results reveal that PDA NPs potently inhibit Cu^(2+)-mediated Aβaggregation and effectively reduce the formation of Aβ-Cu^(2+)complexes. In vitro experiments show that PDA NPs efficiently eliminate ROS generation catalyzed by Cu^(2+)or Aβ-Cu^(2+)complexes, thus rescuing cultured cells by reducing intracellular ROS levels. More importantly, PDA NPs can depolymerize Aβ-Cu^(2+)complexes, and the degradation of Aβ-Cu^(2+)complexes is promoted by near-infrared light irradiation due to their high photothermal conversion ability. In vivo studies reveal that PDA NPs significantly reduce the deposition of Aβ plaques in the presence of Cu^(2+)and extend the lifespan of AD nematodes from 11 to 14 d. Thus, the PDA NPs developed herein are multifunctional against Cu^(2+)-mediated Aβ aggregation for the potential prevention and treatment of AD.

Facile purification and immobilization of organophosphorus hydrolase on protein-inorganic hybrid phosphate nanosheets

Oriented immobilization of enzymes helps to maintain their native structure and proper orientation for high-performance engineering to meet extensive biocatalysis demands.However,the supporting materials used for orientated immobilization are usually costly or complicated in preparation,affecting their practical applications.In this work,a facile purification and immobilization method was proposed for enzyme immobilization based on organic-inorganic hybrid calcium phosphate nanocrystal(Ca Ps)induced by Cu^(2+) modified bovine serum albumin(BSA-Cu).Then,the as-prepared hybrid calcium phosphate nanosheet,BSA-Cu@Ca Ps,was utilized for one-pot purification and immobilization of His-tagged organophosphorus hydrolase(OPH)by metal-affinity binding to the incorporated BSA.BSA-Cu@Ca PsOPH exhibited enhanced p H stability and thermal stability compared to the free enzyme.Moreover,BSA-Cu@Ca Ps-OPH could retain more than 75%and 56%of initial activity after reuse 5 and 10 times,respectively.The results demonstrated that this facile strategy was promising for the effective biodegradation of organophosphorus pesticides with the immobilized enzyme.

Evaluation of miR-122-regulated suicide gene therapy for hepatocellular carcinoma in an orthotopic mouse model

Objective： Intratumoral administration of adenoviral vector encoding herpes simplex virus （HSV） thymidine kinase （TK） gene （Ad-TK） followed by systemic ganciclovir （GCV） is an effective approach in treating experimental hepatocellular carcinoma （HCC）. However, hepatotoxicity due to unwanted vector spread and suicide gene expression limited the application of this therapy, miR-122 is an abundant, liver-specific microRNA whose expression is decreased in human primary HCC and HCC-derived cell lines. These different expression profiles provide an opportunity to induce tumor-specific gene expression by miR-122 regulation. Methods： By inserting miR-122 target sequences （miR-122T） in the 3＇ untranslated region （UTR） ofTK gene, we constructed adenovirus （Ad） vectors expressing miR-122-regulated TK （Ad-TK-122T） and report genes. After intratumoral administration of Ad vectors into an orthotopic miR-122-deficient HCC mouse model, we observed the miR-122-regulated transgene expression and assessed the antitumor activity and safety of Ad-TK-122T. Results： Insertion of miR-122T specifically down-regulated transgene expression in vitro and selectively protected the miR-122-positive cells from killing by TK/GCV treatment. Insertion of miR-122T led to significant reduction of tansgene expression in the liver without inhibition of its expression in tumors in vivo, resulting in an 11-fold improvement of tumor-specific transgene expression. Intratumoral injection of Ad vectors mediated TK/GCV system led to a vector dosage-dependent regression of tumor. The insertion of miR-122T does not influence the antitumor effects of suicide gene therapy. Whereas mice administrated with Ad-TK showed severe lethal hepatotoxicity at the effective therapeutic dose, no liver damage was found in Ad-TK-122T group. Conclusions： miR-122-regulated TK expression achieved effective anti-tumor effects and increased the safety of intratumoral delivery of adenovirus-mediated TK/GCV gene therapy for miR-122-deficient HCC.

Fabrication and characterization of epoxylated zwitterionic copolymergrafted silica nanoparticle as a new support for lipase immobilization

Our previous work proved that the thermal stability of Candida rugosa lipase(CRL)immobilized on zwitterionic polymer(poly(carboxybetaine methacrylate))grafted silica nanoparticle(SNP)was much higher than that on poly(glycidyl methecrylate)(pGMA)grafted SNP,while the latter showed significantly increased activity.Inspired by the research,we have herein proposed to synthesize copolymers of zwitterionic sulfobetaine methacrylate(SBMA)and GMA for CRL immobilization.The copolymers were grafted onto SNP surface at three GMA/SBMA(G/S)molar ratios(G100/S0,G50/S50,G10/S90),followed by the covalent coupling of CRL to the surface copolymers.The immobilized CRLs on the corresponding supports were denoted as p(G100-S0)-CRL,p(G50-S50)-CRL and p(G10-S90)-CRL.The enzyme loading increased with the increase of GMA content in the copolymer,while the activity varied with the grafted copolymer composition.Kinetic study proved the improvement of enzyme-substrate affinity after immobilization.In comparison to p(G100-S0)-CRL,p(G50-S50)-CRL and p(G10-S90)-CRL presented remarkably enhanced thermal stability and pH tolerance,and p(G10-S90)-CRL showed the highest stability.These results suggest that the copolymer design is promising for development as a versatile platform for enzyme immobilization.

Lysozyme adsorption to cation exchanger derivatized by sequential modification of poly(ethylenimine)-Sepharose with succinic anhydride and ethanolamine: Effect of p H and ionic strength

In our previous work, a series of polyethylenimine(PEI)-derived cation exchangers were synthesized using PEIgrafted resin FF-PEI-L740(ionic capacity, 740 mmol·L^-1) as the basic resin to study lysozyme adsorption and chromatographic behavior. It was found that the resin with an ionic capacity of 630 mmol·L^-1(FF-PEI-CR630)possessed high adsorption performance towards lysozyme at 0–100 mmol·L^-1 Na Cl. Therefore, in this work,FF-PEI-CR630 was selected to study the influences of pH and ionic strength(IS) on protein adsorption and chromatographic behavior towards lysozyme. The increase of lysozyme adsorption capacity in the pH range of 6 to 10 was observed. However, the uptake rate decreased in the pH range of 6 to 8 and then remained essentially unchanged from pH 8 to pH 10. Increasing IS led to decreased protein adsorption capacity and increased uptake rate in different pH ranges. Besides, FF-PEI-CR630 maintained dynamic binding capacity as high as over150 mg·ml^-1 at pH 8–10 without NaCl. The research has thus provided insight into the selection of proper pH and IS conditions for protein purification by using FF-PEI-CR630.

Insights into the cross-amyloid aggregation of Aβ_(40) and its N-terminal truncated peptide Aβ_(11-40) affected by epigallocatechin gallate

Inhibition of protein misfolding and aggregation is a great challenge in the field of biochemical and biopharmaceutical engineering.Alzheimer’s disease(AD)is a protein-misfolding disease,and the interactions between 40-amino-acid-residueβ-amyloid peptide(Aβ_(40)) and its N-terminal truncated peptide Aβ_(11-40) demonstrate that Aβ_(11-40) may play an important role in the pathological process of AD.However,the effect of inhibitors on Aβ_(11-40) aggregation and on the cross-amyloid aggregation(coassembly)between Aβ_(40) and Aβ_(11-40) has never been studied.Herein,coaggregation and seeding interactions between Aβ_(40) and Aβ_(11-40) as well as the effect of epigallocatechin gallate(EGCG),a small molecule inhibitor,on the cross-amyloid aggregation have been investigated by extensive analyses.It is found that Aβ_(11-40) participates in the aggregation of Aβ_(40) and leads to the formation of coaggregates that contain lessβ-sheet structures than pure Aβ_(40) aggregates.The aggregation kinetics along with morphologies and secondary structures of the coaggregates are also significantly affected by the Aβ_(40)/Aβ_(11-40) ratio.EGCG accelerates the nucleation of Aβ_(40) but retards that of Aβ_(11-40) by affecting their elongation and secondary nucleation processes in solution and on solid surfaces.Meanwhile,EGCG makes the conformations of the seeding-induced Aβaggregates more compact,especially for the homologous seedings.Isothermal titration calorimetry measurement indicates that hydrophobic interactions mainly contribute to the inhibition of the two Aβisoforms by EGCG.The findings of this research have provided new insights into Aβaggregation and the effect of an important inhibitor and the results would benefit in the development of potent inhibitors against co-assembly of different amyloid proteins.

Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

The modulation of protein aggregation is involved not only in biochemical engineering processes,but also in in vivo biological events such as Alzheimer's disease(AD)that features amyloid-βprotein(Aβ)deposits.Inspired by the different pharmacological efficacy of enantiomers,taking heptapeptide LVFFARK(LK7)as an example,herein the chiral influence of peptide inhibitors on Aβfibrillogenesis and cytotoxicity was investigated by extensive biophysical and biological analyses.It was intriguing to find that although both LLK7 and D-LK7 could inhibit Aβaggregation in a concentration-dependent manner,it was the D-enan-tiomer that exhibited chirality preference and selectivity for modulation of Aβself-assembly.As com-pared with L-LK7 at the same conditions,D-LK7 showed significantly enhanced potency on suppressing cross-βsheet formation,fibrillar Aβaggregates deposition,Aβconformational transition,and Aβ-triggered neurotoxicity on cultured cells.For instance,L.LK7 and D-LK7 rescued cells by increasing cell via-bility from 60%to 62%and 84%at 100μmolL^(-1),respectively.The chiral discrimination of L-LK7 and D-LK7 was further validated by the different elimination efficiency on amyloid accumulation in AD model nematodes.It is considered that the higher binding affinity of D-LK7 to Aβmonomers than that of L LK7 resulted in the stronger inhibition effect.This work provided new insights into understanding chiral-ity in the interaction with Aβand the consequent inhibitory effect,and would contribute to the design of anti-amyloid agents.

Conjugation of a zwitterionic polymer with dimethyl chains to lipase significantly increases the enzyme activity and stability

Enzyme-polymer conjugates are complex molecules with great practical significance.This work was designed to develop a novel enzyme-polymer conjugate by covalently coupling a zwitterionic polymer with side dimethyl chains(pID)to Candida rugosa lipase(CRL)via the reaction between the anhydrides of polymer chains with the amino groups of the enzyme.The resulting two CRL-pID conjugates with different pID grafting densities were investigated in term of the catalytic activity,stability and structural changes.In comparison with native CRL,both the CRL conjugates displayed 2.2 times higher activity than the native enzyme,and showed an increase in the maximum reaction rate(V_(max))and a decrease in the Michaelis constant(K_(m)),thus resulting in about three-fold increases in the catalytic efficiency(k_(cat)/K_(m)).These are mainly attributed to the activation of lipase by the hydrophobic alky side chains.Moreover,the thermostability and pH tolerance of the lipase conjugates were significantly enhanced due to the stabilizing effect of the zwitterion moieties.For instance,a five-fold increase of the enzyme half-life at 50℃ for the high-pID conjugated CRL was observed.Spectroscopic studies reveal that the pID conjugation protected the enzyme in the changes in its microenvironment and conformation,well correlating with enhanced activity and stability of lipase conjugates.The findings indicate that enzyme conjugation to the zwitterionic polymer is promising for improving enzyme performance and deserves further development.

Implications from γ-globulin adsorption onto cation exchangers fabricated by sequential alginate grafting and sulfonation

Our previous work proved that high adsorption capacity and uptake rate of lysozyme were achieved on alginate(Alg)-grafted re sin with an ionic capacity(IC) of 240 mmol·L^(-1)(Alg-FF-240).Moreover,the salt-tolerant feature of Alg-FF-230 was improved by using sequential alginate grafting and sulfonation strategy.Inspired by the enhanced adsorption performance of lysozyme,we have herein proposed to investigate the static and dynamic adsorption behaviors of γ-globulin on a series of Alg-grafted resins with different grafting densities and sulfonation degrees.The adsorption ca pacity of γ-globulin decreased with increa sing alginate-grafting density(IC) from 160 to 230 mmol·L^(-1) at 0 mmol·L^(-1) NaCl because of the steric hindrance caused by the alginate-grafting layer.Effects of ionic strength(IS) indicated that the adsorption capacities of the resins with the IC value of 230-370 mmol·L^(-1) were much higher than CM Sepharose FF at 50-100 mmol·L^(-1) NaCl,and the uptake rate of Alg-FF-230 was about twice as much as that of CM Sepharose FF.This work demonstrated the important effects of alginate-grafting layer and IS in γ-globulin adsorption behavior,which would be helpful in the design of Alggrafted resins and the selection of proper IS condition for protein purification.

Construction and Detection of a Novel Type of Recombinant Human rAAV2/2-ND4

Purpose:To construct a novel AAV-mediated gene delivery of the human ND4 complex I subunit and to detect its expression level in mitochondria for potential application in gene therapy for Leber's hereditary optic neuropathy (LHON). Methods:A novel type of normal human ND4 gene was synthesized artificially to contain a mitochondrial targeting sequence that induces the translocation of this gene into mitochondria.This recombinant adeno-associated virus type 2/serotype 2 (rAAV2/2)-mediated NADH dehydrogenase subunit 4 (ND4) gene was constructed, purified, condensed, and amplified by PCR.The physical titer of rAAV2/2-ND4 was determined by slot-blot hybridization using a digoxigeninlabeled H1 probe.Expression of ND4 in mitochondria was evaluated by immunofluorescence. Results: The constructed rAAV2/2-ND4 specifically amplified the target gene band of ND4 and the physical titer of ND4 gene was 1.0×1011 vg/mL,confirming that the recombinant adenovirus vector contained the ND4 target gene. Expression of the ND4 gene was detected in mitochondria by immunofluorescence. Conclusion:A new type of rAAV2/2-ND4 was successfully constructed and may have potential in gene therapy for LHON.

Treatment of SMA type 1 infants using a single-dose AAV9-mediated gene therapy via intrathecal injection of GC101:An open-label,single-arm study

Spinal muscular atrophy(SMA),a neurodegenerative disorder caused by mutations in survival motor neuron 1(SMN1)resulting in reduced expression of the survival motor neuron(SMN)protein,is inherited in an autosomal recessive manner.SMA type 1 is the most frequent subtype of SMA characterized by onset before 6 months of life,inability to achieve independent sitting,and rapidly progressive respiratory and bulbar deterioration,causing a mortality of>90%before 2 years of age.[1]Currently,there have been two lifelong splice-modifying therapies(nusinersen and risdiplam),and a single-dose gene replacement therapy via intravenous onasemnogene abeparvovec for SMA type 1 patients.

A novel lead-free relaxor with endotaxial nanostructures for capacitive energy storage

Dielectric capacitors with a fast charging/discharging rate,high power density,and long-term stability are essential components in modern electrical devices.However,miniaturizing and integrating capacitors face a persistent challenge in improving their energy density(W_(rec))to satisfy the specifications of advanced electronic systems and applications.In this work,leveraging phase-field simulations,we judiciously designed a novel lead-free relaxor ferroelectric material for enhanced energy storage performance,featuring flexible distributed weakly polar endotaxial nanostructures(ENs)embedded within a strongly polar fluctuation matrix.The matrix contributes to substantially enhanced polarization under an external electric field,and the randomly dispersed ENs effectively optimize breakdown phase proportion and provide a strong restoring force,which are advantageous in bolstering breakdown strength and minimizing hysteresis.Remarkably,this relaxor ferroelectric system incorporating ENs achieves an exceptionally high W_(rec)value of 10.3 J/cm^(3),accompanied by a large energy storage efficiency(η)of 85.4%.This work introduces a promising avenue for designing new relaxor materials capable of capacitive energy storage with exceptional performance characteristics.

Ensifer alkalisoli YIC4027趋化受体基因的比较及相关蛋白序列分析

【目的】田菁共生根瘤菌Ensifer alkalisoli YIC4027是从宿主植物田菁的根瘤中分离出来的一株新型高效的固氮菌。本研究对E.alkalisoli的趋化受体基因与其他研究透彻的物种进行比较以及相关蛋白分析。【方法】利用NCBI的BLAST对E.alkalisoli趋化受体基因进行序列相似性搜索。以Pfam数据库为基础,用HMMR3对甲基化趋化受体蛋白(MCP)进行比较分析。【结果】E.alkalisoli有2个趋化基因簇,共有13个MCP,含有不同的信号传感结构。此外,这些MCPs的胞质结构域除了一个是由40个七肽重复序列组成,其余都是由36个七肽重复序列组成。【结论】尽管E.alkalisoli的趋化受体与已被广泛研究的物种的趋化受体具有较高的相似性,但仍显示出其特性。通过基因的比对以及相关蛋白的分析,我们能够更好地理解E.alkalisoli是如何通过趋化系统来响应外界变化的。

Realizing enhanced energy storage and hardness performances in 0.90NaNbO_(3)-0.10Bi(Zn_(0.5)Sn_(0.5))O_(3)ceramics

Ceramic dielectric capacitors have a broad scope of application in pulsed power supply devices.Relaxor behavior has manifested decent energy storage capabilities in dielectric materials due to its fast polarization response.In addition,an ultrahigh energy storage density can also be achieved in NaNbO_(3)(NN)-based ceramics by combining antiferroelectric and relaxor characteristics.Most of the existing reports about lead-free dielectric ceramics,nevertheless,still lack the relevant research about domain evolution and relaxor behavior.Therefore,a novel lead-free solid solution,(1-x)NaNbO_(3)-xBi(Zn_(0.5)Sn_(0.5))O_(3)(abbreviated as xBZS,x=0.05,0.10,0.15,and 0.20)was designed to analyze the domain evolution and relaxor behavior.Domain evolutions in xBZS ceramics confirmed the contribution of the relaxor behavior to their decent energy storage characteristics caused by the fast polarization rotation according to the low energy barrier of polar nanoregions(PNRs).Consequently,a high energy storage density of 3.14 J/cm^(3)and energy efficiency of 83.30%are simultaneously available with 0.10 BZS ceramics,together with stable energy storage properties over a large temperature range(20-100℃)and a wide frequency range(1-200 Hz).Additionally,for practical applications,the 0.10 BZS ceramics display a high discharge energy storage density(W_(dis)≈1.05 J/cm^(3)),fast discharge rate(t_(0.9)≈60.60 ns),and high hardness(H≈5.49 GPa).This study offers significant insights on the mechanisms of high performance lead-free ceramic energy storage materials.

Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein

Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. How- ever, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area （MM/PBSA） analysis, we examined the effect of three peptide inhibitors （KLVFF, VVIA, and LPFFD） on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modifica- tion and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.

High energy storage density and power density achieved simultaneously in NaNbO_(3)-based lead-free ceramics via antiferroelectricity enhancement

High-performance lead-free dielectric ceramics with simultaneously high energy storage density and power density are in high demanded for pulse power systems.To realize excellent energy-storage characteristics,a strategy to enhance antiferroelectricity and construct a local random field simultaneously was proposed in this study.Based on the above strategy,a series of(1-x)NaNbO_(3)-xBi(Ni_(1/2)Sn_(1/2))O3[xBNS,x=0.05,0.10,0.15,0.20,and 0.22]solid solutions were designed and fabricated.An ultrahigh energy storage density(Utotal)of 7.35 J/cm^(3),and recoverable energy density(Urec)of 5.00 J/cm^(3) were achieved in the 0.10BNS ceramics.In addition,an adequate stability of energy storage properties at a range of temperatures(20e140℃),frequencies(1e100 Hz),and fatigue test durations(1e1-10^(4) cycles)were realized in 0.10BNS ceramics.0.10BNS ceramics displayed a high current density of 1005 A/cm2,an ultrahigh power density of 100.5 MW/cm^(3,)and an ultrashort discharge time of 46.5 ns?This remarkable performance not only justified our strategy but also confirmed 0.10BNS ceramics as a promising candidate for energy storage.

Enhanced thermal and frequency stability and decent fatigue endurance in lead-free NaNbO_(3) -based ceramics with high energy storage density and efficiency

Lead-free ceramic capacitors have the application prospect in the dielectric pulse power system due to the advantages of large dielectric constant,lower dielectric loss and good temperature stability.Never-theless,most reported dielectric ceramics have limitation of realizing large energy storage density(W_(rec))and high energy storage efficiency(h)simultaneously due to the low breakdown electric field(E_(b)),low maximum polarization and large remanent polarization(P_(r)).These issues above can be settled by raising the bulk resistivity of dielectric ceramics and optimizing domain structure.Therefore,we designed a new system by doping(Bi_(0.5)Na_(0.5))_(0.7)Sr_(0.3)TiO_(3) into 0.9NaNbO_(3)-0.1Bi(Ni_(0.5)Zr_(0.5))O_(3) ceramics,which simulta-neously obtained a higher bulk resistivity by decreasing the grain size and achieved a smaller P_(r) by optimizing domain structure,thus the better E_(b) of 530 kV/cm and W_(rec) of 6.43 J/cm^(3) were achieved,h was improved from 34%to 82%.Besides,the 0.4BNST ceramics show excellent temperature,frequency and fatigue stability under the conditions of 20-180℃,1-100 Hz and 104 cycles,respectively.Mean-while,superior power density(P_(D)=107 MW/cm^(3)),large current density(C_(D)=1070 A/cm^(2))and discharge speed(1.025 m s)were achieved in 0.4BNST ceramic.Finally,the charge-discharge performance displayed good temperature stability in the temperature range of 30℃-180℃.The above results indicated that the ceramics have potential practical value in the field of energy storage capacitor.

Head-to-tail cyclization of a heptapeptide eliminates its cytotoxicity and significantly increases its inhibition effect on amyloid β-protein fibrillation and cytotoxicity

Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK （LK7）. LK7 shows a promising inhibitory capability on Aft fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 （cLK7）. cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to Aβ40 by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for Afl40 （KD = 4.96 μmol/L） is six times higher than that of LK7 （KD = 32.2 μmol/L）. The strong binding enables cLK7 to stabilize the secondary structure of Aβ40 and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit Aβ40 fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.

PM_(2.5) exposure associated with microbiota gut-brain axis:Multi-omics mechanistic implications from the BAPE study

Recent studies have shown that PM_(2.5) may activate the hypothalamus-pituitary-adrenal(HPA)axis by inducing hormonal changes,potentially explaining the increase in neurological and cardiovascular risks.In addition,an association between PM_(2.5) and gut microbiota and metabolites was established.The above evidence represents crucial parts of the gut-brain axis(GBA).In view of this evidence.

Relevance of placental type I interferon beta regulation for pregnancy success

Pregnancy is a unique immunologic and microbial condition that requires an adequate level of awareness to provide a fast and protective response against pathogens as well as to maintain a state of tolerance to paternal antigens.Dysregulation of inflammatory pathways in the placenta triggered by pathogens is one of the main factors responsible for pregnancy complications.Type I IFNs are key molecules modulating immune responses at the level of the placenta and are crucial for protection of the pregnancy via their antiviral and immune modulatory properties.In this study,we elucidate the mechanisms controlling the basal expression of IFNβand its negative feedback.Using in vitro and in vivo animal models,we found that TLR signaling maintains basal IFNβlevels through the TLR4-MyD88-independent TBK/IRF3 signaling pathway.We describe the role of the TAM receptor Axl in the regulation of IFNβfunction in human and mouse trophoblast cells.The absence of TAM receptors in vivo is associated with fetal demise due to dysregulation of IFNβexpression and its pro-apoptotic downstream effectors.Collectively,our data describe a feedback signaling pathway controlling the expression and function of IFNβin the trophoblast that is essential for an effective response during viral and microbial infections.