Temperature is a cryptic factor shaping the geographical pattern of genetic variation in Ceratophyllum demersum across a subtropical freshwater lake

Macrophyte habitats exhibit remarkable heterogeneity,encompassing the spatial variation of abiotic and biotic components such as changes in water conditions and weather as well as anthropogenic stressors.Environmental factors are thought to be important drivers shaping the genetic and epigenetic variation of aquatic plants.However,the links among genetic diversity,epigenetic variation,and environmental variables remain largely unclear,especially for clonal aquatic plants.Here,we performed population genetic and epigenetic analyses in conjunction with habitat discrimination to elucidate the environmental factors driving intraspecies genetic and epigenetic variation in hornwort(Ceratophyllum demersum)in a subtropical lake.Environmental factors were highly correlated with the genetic and epigenetic variation of C.demersum,with temperature being a key driver of the genetic variation.Lower temperature was detected to be correlated with greater genetic and epigenetic variation.Genetic and epigenetic variation were positively driven by water temperature,but were negatively affected by ambient air temperature.These findings indicate that the genetic and epigenetic variation of this clonal aquatic herb is not related to the geographic feature but is instead driven by environmental conditions,and demonstrate the effects of temperature on local genetic and epigenetic variation in aquatic systems.

Rational fusion design inspired by cell-penetrating peptide:SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease induced by multiple interconnected mechanisms.Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology.However,clinical translation of peptide drugs is greatly hampered by their low permeability into brain.Herein,a hybrid peptide HNSS is generated by merging two therapeutic peptides(SS31 and S-14 G Humanin(HNG)),using a different approach from the classical shuttle-therapeutic peptide conjugate design.HNSS demonstrated increased bio-permeability,with a 2-fold improvement in brain distribution over HNG,thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides.HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting,ROS scavenging and p-STAT3 activation.Meanwhile,HNSS with increased Aβaffinity greatly inhibited Aβoligomerization/fibrillation,and interrupted Aβinteraction with neuron/microglia by reducing neuronal mitochondrial Aβdeposition and promoting microglial phagocytosis of Aβ.In3×Tg-AD transgenic mice,HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance.This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification,providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer’s disease(AD)collectively culminate in neuronal deterioration.In the context of AD,autophagy dysfunction,a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes.Therefore,multidimensional autophagy regulation strategies co-manipulating“autophagy induction”and“lysosome degradation”in dual targets(neuron and microglia)are more reliable for AD treatment.Accordingly,we designed an RP-1 peptide-modified reactive oxygen species(ROS)-responsive micelles(RT-NM)loading rapamycin or gypenoside XVII.Guided by RP-1 peptide,the ligand of receptor for advanced glycation end products(RAGE),RT-NM efficiently targeted neurons and microglia in AD-affected region.This nanocombination therapy activated the whole autophagy-lysosome pathway by autophagy induction(rapamycin)and lysosome improvement(gypenoside XVII),thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes,and promoting Aβ phagocytosis.Resultantly,it decreased aberrant protein burden,alleviated neuroinflammation,and eventually ameliorated memory defects in 3×Tg-AD transgenic mice.Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

氟代亚氨基糖的合成与糖苷酶抑制活性

亚氨基糖由于具有重要的糖苷酶抑制活性、抗病毒和抗肿瘤活性等已经在新药创制中显示出巨大的发展潜力。系统研究此类化合物的构效关系有望发现高活性和高选择性的先导化合物。氟代是考察构效关系的常用方法之一。本文总结了氟代亚氨基糖的合成方法与化合物的糖苷酶抑制活性。合成方法中氟的来源包括含氟砌块、氟代糖或氟代试剂,三种合成策略各有优缺点与适用范围。基于氟代亚氨基糖的糖苷酶抑制活性研究,本文初步归纳了一些有代表性的重要亚氨基糖的构效关系,明确了糖环完整性对化合物糖苷酶抑制活性的重要意义。在此基础上对亚氨基糖的侧链或并环环系修饰则可能分别影响抑制谱和糖苷酶抑制活性。氟代亚氨基糖的研究成果是对亚氨基糖化学的重要贡献,以氟代为工具,必将进一步完善与修正亚氨基糖的构效关系,为设计合成具有潜在药物活性的亚氨基糖类化合物提供依据,并极大促进相关的新药创制工作。

Modulating autophagic flux via ROS-responsive targeted micelles to restore neuronal proteostasis in Alzheimer’s disease

Compromised autophagy and defective lysosomal clearance significantly contribute to impaired neuronal proteostasis,which represents a hallmark of Alzheimer’s disease(AD)and other age-related neurodegenerative disorders.Growing evidence has implicated that modulating autophagic flux,instead of inducing autophagosome formation alone,would be more reliable to rescue neuronal proteostasis.Concurrently,selectively enhancing drug concentrations in the leision areas,instead of the whole brain,will maximize therapeutic efficacy while reduing non-selective autophagy induction.Herein,we design a ROS-responsive targeted micelle system(TT-NM/Rapa)to enhance the delivery efficiency of rapamycin to neurons in AD lesions guided by the fusion peptide TPL,and facilitate its intracellular release via ROS-mediated disassembly of micelles,thereby maximizing autophagic flux modulating efficacy of rapamycin in neurons.Consequently,it promotes the efficient clearance of intracellular neurotoxic proteins,β-amyloid and hyperphosphorylated tau proteins,and ameliorates memory defects and neuronal damage in 3×Tg-AD transgenic mice.Our studies demonstrate a promising strategy to restore autophagic flux and improve neuronal proteostasis by rationally-engineered nano-systems for delaying the progression of AD.

Crosstalk between the B7/CD28 and EGFR pathways:Mechanisms and therapeutic opportunities

Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,head and neck cancer,pancreatic cancer,and breast cancer.Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy,but patients inevitably experience acquired resistance.Although immune checkpoint inhibitors(ICIs)targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types,their efficacy is limited in cancers harboring activating gene alterations of EGFR.Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3,B7x and HHLA2,is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment(TME).In this review,we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways.Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies.We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers,as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.

On-resin peptide modification of methionine residue by employing 2-bromoacetate derivatives

On-resin peptide modification renders an easy-to-operate method that combines solid-phase peptide synthesis efficiency and avoids tedious purification procedures. Herein, we report the transition-metal-free and redox-neutral approach for solid-phase Met diversification with substrate diversity, which could be applied to synthesize cyclic peptides of different sizes.

A dynamic stiffness-based framework for harmonic input estimation and response reconstruction considering damage

In structural health monitoring(SHM),the measurement is point-wise but structures are continuous.Thus,input estimation has become a hot research subject with which the full-field structural response can be calculated with a finite element model(FEM).This paper proposes a framework based on the dynamic stiffness theory,to estimate harmonic input,reconstruct responses,and to localize damages from seriously deficient measurements.To begin,Fourier transform converts the dynamic equilibrium equation to an equivalent static one in the frequency domain,which is underdetermined since the dimension of measurement vector is far less than the FEM-node number.The principal component analysis has been adopted to“compress”the under-determined equation,and formed an over-determined equation to estimate the unknown input.Then,inverse Fourier transform converts the estimated input in the frequency domain to the time domain.Applying this to the FEM can reconstruct the target responses.If a structure is damaged,the estimated nodal force can localize the damage.To improve the damage-detection accuracy,a multi-measurement-based indicator has been proposed.Numerical simulations have validated that the proposed framework can capably estimate input and reconstruct multi-types of full-field responses,and the damage indicator can localize minor damages even with the existence of noise.