Texture development and tensile properties of Mg?Yb binary alloys during hot extrusion and subsequent annealing

Ytterbium(Yb)containing magnesium alloys have aroused extensive interest due to their excellent mechanical properties after thermomechanical processing and heat treatment.Unfortunately,the sole effect of Yb addition on the microstructure and mechanical properties of pure Mg matrix remains uncertain to date.In this work,the effects of Yb concentration on the texture development and tensile properties of pure Mg matrix during hot extrusion and the subsequent annealing were systematically investigated.The results revealed that the constitutional supercooling induced by Yb addition refined the as-cast microstructure but exerted a negligible effect on the original columnar grain morphology.When extruded at 300°C,the dynamic recrystallization(DRX)process was considerably retarded.The in-grain misorientation axes(IGMA)analysis combined with TEM observation indicated that non-basal slips operated with increasing Yb concentration.Specifically,the prismaticslip should be robustly activated in Mg-1.0 Yb extrudate,promoting the formation of the texture with{10?10}plane normal to the extrusion direction(ED),while for the Mg?2.0 Yb counterpart,the increased activity of pyramidal<c+a>slip and the relaxation of basal/<c+a>dislocations generated an ED-tilted texture component.The preferential grain growth dominated the subsequent annealing texture development at 400°C when a comparable grain size was achieved.An obvious ED-tilted texture intensity with the peak around<12 13>was observed in Mg-2.0 Yb alloy,which was primarily caused by grains with the basal orientation vanished and with the non-basal orientations intensified due to a higher concentration of Yb solute.Favored by the grain refinement,the Mg-2.0 Yb extrudate exhibited a high tensile yield strength of 304±3.5 MPa,while the subsequently annealed counterpart presented a favorable elongation to failure of 14.8±1.2%,which mainly due to the homogeneous grain structure,weak ED-tilted texture,and dissolution of coarse phases after high-temperature annealing.

pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma

Photodynamic therapy(PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation,but the strong hydrophobicity and poor tumor selectivity of photosensitizers,as well as the oxygen-consuming properties of PDT,leading to unsatisfactory therapeutic outcomes.Herein,a tumor acidic microenvironment activatable dissolving microneedle(DHA@HPFe-MN)was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification.The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin(PpIX)-ADH-hyaluronic acid(HA)conjugate HA-ADH-PpIX with“iron reservoir”PA-Fe 3+complex in the needle tip via acylhydrazone bond formation,and dihydroartemisinin(DHA)was concurrently loaded in the hydrogel network.HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect.DHA@HPFe-MN with sharp needle tip,efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites,where the acidic pH triggered the degradation of microneedles,enabling Fe-activated and DHA-mediated oxidation treatment,as evidenced by abundant reactive oxygen species(ROS)generation.Moreover,under light irradiation,a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation.Importantly,the Fe-catalyzed ROS production of DHA was oxygen-independent,which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells.This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.

Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways

Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain.The ketogenic diet,a widely recognized therapeutic intervention for refractory epilepsy,has recently been proposed as a potential treatment for a variety of neurological diseases,including Alzheimer's disease.However,the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear.The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease.Male amyloid precursor protein/presenilin 1(APP/PS1)mice were randomly assigned to either a ketogenic diet or control diet group,and received their respective diets for a duration of 3 months.The findings show that ketogenic diet administration enhanced cognitive function,attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice,and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway.Collectively,these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation.This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.

Downregulation of hsa_circ_0002198 inhibits keloid fibroblast activities in vitro by reducing NLRP3 inflammasome activity

The levels of hsa circular RNA_0002198(hsa_circ_0002198)have been found to be significantly upregulated in keloid dermal fibroblasts.However,the functional role of hsa_circ_0002198 in keloid fibroblasts and the underlying molecular mechanism for its effects have not been reported.In this study,the levels of hsa_circ_0002198 and nucleotide-binding and oligomerization domain,leucine rich repeat and pyrin domain containing 3(NLRP3)expression in keloid scar tissues and adjacent normal skin tissues were determined by quantitative real-time PCR and western blotting,respectively.In vitro models of keloid tissue were created by culturing primary keloid fibroblasts obtained from patients.A series of functional experiments,including CCK-8 assays,Transwell assays,and ELISA assays were performed to analyze the functional role of hsa_circ_0002198/NLRP3.Our data showed that hsa_circ_0002198 and NLRP3 were upregulated in keloid scar tissues when compared with adjacent normal tissues.Knockdown of hsa_circ_0002198 expression significantly suppressed cell proliferation,migration,and invasion,and those effects could be partially reversed by forced NLRP3 overexpression in keloid fibroblasts.At the molecular level,knockdown of hsa_circ_0002198 downregulated the levels of Col I,α-SMA,and NLRP3 proteins,as well as the levels of TGF-β,IL-1ß,and IL-33,but upregulated caspase 3 expression in keloid fibroblasts.All those effects were partially reversed after NLRP3 overexpression.In conclusion,our results suggest hsa_circ_0002198 as a potential target for treating keloid lesions.

Switchable hidden spin polarization and negative Poisson's ratio in two-dimensional antiferroelectric wurtzite crystals

Two-dimensional(2D)antiferroelectric materials have raised great research interest over the last decade.Here,we reveal a type of 2D antiferroelectric(AFE)crystal where the AFE polarization direction can be switched by a certain degree in the 2D plane.Such 2D functional materials are realized by stacking the exfoliated wurtzite(wz)monolayers with“self-healable”nature,which host strongly coupled ferroelasticity/antiferroelectricity and benign stability.The AFE candidates,i.e.,Zn X and Cd X(X=S,Se,Te),are all semiconductors with direct bandgap atΓpoint,which harbors switchable antiferroelectricity and ferroelasticity with low transition barriers,hidden spin polarization,as well as giant in-plane negative Poisson's ratio(NPR),enabling the co-tunability of hidden spin characteristics and auxetic magnitudes via AFE switching.The 2D AFE wz crystals provide a platform to probe the interplay of 2D antiferroelectricity,ferroelasticity,NPR,and spin effects,shedding new light on the rich physics and device design in wz semiconductors.

Analysis on herbal medicines utilized for treatment of COVID-19

As coronavirus disease 2019(COVID-19)pandemic poses a substantial global public health threat,traditional Chinese medicine(TCM)was used in 91.50%of the COVID-19 cases in China,showing encouraging results in improving symptom management and reducing the deterioration,mortality,and recurrence rates.A total of 166 modified herbal formulae consisting of 179 single herbal medicines were collected for treating COVID-19 in China.Glycyrrhizae Radix et Rhizome,Scutellariae Radix,and Armeniacae Semen Amarum are the most frequently utilized in clinics,most of which are antipyretic(47,26.26%),expectorant and cough-suppressing(22,12.29%),and dampness-resolving(21,11.73%)from traditional descriptions.A total of 1212 chemical components containingβ-sitosterol,stigmasterol,and quercetin were primarily selected.Additionally,using complex system entropy and unsupervised hierarchical clustering,8 core herbal combinations and 10 new formulae emerged as potentially useful candidates for COVID-19.Finally,following scaffold analysis,self-organizing mapping(SOM)and cluster analysis,12 clusters of molecules yielded 8 pharmacophore families of structures that were further screened as pharmacological targets in human metabolic pathways for inhibiting coronavirus.This article aims to make more easily accessible and share historical herbal knowledge used in contemporary treatments in a modern manner to assist researchers contain the global spread of COVID-19.

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Microglia activation is observed in various neurodegenerative diseases.Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity.Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions.

Emerging role of tumor cell plasticity in modifying therapeutic response

Resistance to cancer therapy is a major barrier to cancer management.Conventional views have proposed that acquisition of resistance may result from genetic mutations.However,accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance,the latter of which is the focus that will be discussed here.Such non-mutational processes are largely driven by tumor cell plasticity,which renders tumor cells insusceptible to the drug-targeted pathway,thereby facilitating the tumor cell survival and growth.The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial–mesenchymal transition,acquisition properties of cancer stem cells,and transdifferentiation potential during drug exposure.From observations in various cancers,this concept provides an opportunity for investigating the nature of anticancer drug resistance.Over the years,our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased.This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs,which are likely to improve patient outcomes in clinical practice.

Redox regulation in tumor cell epithelial-mesenchymal transition:molecular basis and therapeutic strategy

Epithelial–mesenchymal transition(EMT)is recognized as a driving force of cancer cell metastasis and drug resistance,two leading causes of cancer recurrence and cancer-related death.It is,therefore,logical in cancer therapy to target the EMT switch to prevent such cancer metastasis and recurrence.Previous reports have indicated that growth factors(such as epidermal growth factor and fibroblast growth factor)and cytokines(such as the transforming growth factor beta(TGF-β)family)are major stimulators of EMT.However,the mechanisms underlying EMT initiation and progression remain unclear.Recently,emerging evidence has suggested that reactive oxygen species(ROS),important cellular secondary messengers involved in diverse biological events in cancer cells,play essential roles in the EMT process in cancer cells by regulating extracellular matrix(ECM)remodeling,cytoskeleton remodeling,cell–cell junctions,and cell mobility.Thus,targeting EMT by manipulating the intracellular redox status may hold promise for cancer therapy.Herein,we will address recent advances in redox biology involved in the EMT process in cancer cells,which will contribute to the development of novel therapeutic strategies by targeting redox-regulated EMT for cancer treatment.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant

The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p53^(72P)-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)that otherwise bound to p53^(72P),leading to subsequent nuclear translocation of PGC-1αand activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p53^(72P)-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p53^(72P)interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p53^(72P)variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p53^(72P)variant.Therefore,our findings identified a gain of function of the p53^(72P)variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53^(72P)-PSAT1 perturbation.

FN-λ： A new spotlight in innate immunity against influenza virus infection

Influenza virus is a long-lasting and severe threat to human health. Seasonal flu epidemics, which are caused by the co- circulating influenza A viruses （IAVs） and influenza B viruses （IBVs）, occur annually and lead to tens of millions of respiratory illnesses and up to half a million human deaths worldwide each year （Ginsberg et al., 2009）. Influenza pandemics are more devastating. The 2009 swine-originated H1N1 virus, which caused the latest influenza pandemic, spread from Mexico and U.S.