ROR2 promotes invasion and chemoresistance of triple-negative breast cancer cells by activating PI3K/AKT/mTOR signaling

Objective:This study aimed to investigate the role of receptor tyrosine kinase-like orphan receptor 2(ROR2)in triple-negative breast cancer(TNBC).Methods:ROR2 expression in primary TNBC and metastatic TNBC tissues was analyzed by immunohistochemical staining and PCR.ROR2 expression in TNBC cell lines was detected by PCR and Western blot analysis.The migration,invasion and chemosensitivity of TNBC cells with overexpression or knockdown of ROR2 were examined.Results:ROR2 expression was high in metastatic TNBC tissues.ROR2 knockdown suppressed the migration,invasion and chemoresistance of TNBC cells.ROR2 overexpression in MDA-MB-435 cells promoted the migration,invasion,and chemoresistance.Moreover,ROR2 knockdown in HC1599 and MDA-MB-435 adriamycin-resistant cells enhanced chemosensitivity to adriamycin.ROR2 could activate PI3K/AKT/mTOR signaling in TNBC cells.Conclusion:ROR2 is upregulated and promotes metastatic phenotypes of TNBC by activating PI3K/AKT/mTOR signaling.

Strontium-incorporated bioceramic scaffolds for enhanced osteoporosis bone regeneration

The restoration of bone defects caused by osteoporosis remains a challenge for surgeons.Strontium ranelate has been applied in preventative treatment approaches due to the biological functions of the trace element strontium(Sr).In this study,we aimed to fabricate bioactive scaffolds through Sr incorporation based on our previously developed modified amino-functional mesoporous bioactive glass(MBG)and to systematically investigate the bioactivity of the resulting scaffold in vitro and in vivo in an osteoporotic rat model.The results suggested that Sr-incorporated amino-functional MBG scaffolds possessed favorable biocompatibility.Moreover,with the incorporation of Sr,osteogenic and angiogenic capacities were upregulated in vitro.The in vivo results showed that the Sr-incorporated amino-functional MBG scaffolds achieved better bone regeneration and vessel formation.Furthermore,bioinformatics analysis indicated that the Sr-incorporated amino-functional MBG scaffolds could reduce reactive oxygen species levels in bone marrow mesenchymal stem cells in the osteoporotic model by activating the cAMP/PKA signaling pathway,thus playing an anti-osteoporosis role while promoting osteogenesis.This study demonstrated the feasibility of incorporating trace elements into scaffolds and provided new insights into biomaterial design for facilitating bone regeneration in the treatment of osteoporosis.

NGS-metabarcoding revealing novel foraminiferal diversity in the Western Pacific Magellan Seamount sediments

Seamount is a unique deep-sea ecosystem widely distributed in the world.Its biodiversity is vibrant due to its specific geographical and hydrological conditions.However,the diversity and features of foraminifera in such an environment have rarely been studied.We extracted environmental DNA(eDNA)in sedime nts and amplified the partial small subunit ribo somal DNA(SSU rDNA)of fo raminife ra to understand the foraminiferal diversity from four sites in Magellan Seamount(Western Pacific Ocean).Partial S SU rDNA sequencing was conducted and 912979 foraminiferal reads were obtained and gathered into 266 operational taxonomic units(OTUs).In the available dataset,a high proportion of rare OTUs and low identity OTUs in each studied sample showed that the Magellan Seamount foraminiferal community might have a high genetic novelty.The relative abundance of foraminifera varied between replicates probably due to the existence of bias in amplification process and patchiness of the deep-sea floor.It showed that the Magellan Seamount has a relatively high benthic foraminiferal diversity characterized mainly by monothalamiids(76.37%of total reads)in association with rotaliids(19.03%of total reads),including planktic foraminiferal sequences(38.58%of rotaliids;7.36%of total reads).The remaining reads were assigned to miliolids(0.83%of total reads)and textulariids(0.66%of total reads),and 3.11%of total reads are unassigned to a specific family.The co mparative analysis with foraminiferal assemblage s from coastal and deep-sea environme nts indicated that seamounts could aggregate species from a nearby deep-sea.

Sonic Hedgehog stimulates migration of MCF-7 breast cancer cells through Rac1

As one of the most common tumors in women, breast cancer has drawn considerable interest from investigators and clinicians in recent years. Despite early diagnosis and best therapeutic regimens available, the prognosis of malignant or metastatic breast cancer patients is still not optimistic. Hedgehog signaling, a classical pathway indispensable to embryonic development, participates in the growth of a variety of tumors. In the present study,the effect of Sonic Hedgehog(Shh) on breast cancer cells was investigated. We identified that Shh signal stimulated the migration of MCF-7 breast cancer cells. Smo and Gli1 were involved in Shh-stimulated migration of MCF-7 cells. Activating Smo and Gli1 induced cell migration, which was blocked by their specific antagonists.The effect of Shh signaling on MCF-7 cells was independent of Wnt5 a, Dvl2 and Rab35, but directly dependent on Rac1. In conclusion, our study suggested that Shh promotes breast cancer cell migration via Rac1 independently of the non-canonical Wnt signaling pathway, which may represent a rational molecular target for combination medication in breast cancer.

Phase separation of GRP7 facilitated by FERONIAmediated phosphorylation inhibits mRNA translation to modulate plant temperature resilience

Changes in ambient temperature profoundly affect plant growth and performance.Therefore,the molecu-larbasis of plant acclimation to temperature fluctuation is of great interest.In this study,we discovered that GLYCINE-RICH RNA-BINDING PROTEIN 7(GRP7)contributes to cold and heat tolerance in Arabidopsis thaliana.We found that exposure to a warm temperature rapidly induces GRP7 condensates in planta,which can be reversed by transfer to a lower temperature.Cell biology and biochemical assays revealed that GRP7 undergoes liquid-liquid phase separation(LLPS)in vivo and in vitro.LLPS of GRP7 in the cyto-plasm contributes to the formation of stress granules that recruit RNA,along with the translation machinery component eukaryotic initiation factor 4E1(elF4E1)and the mRNA chaperones COLD SHOCK PROTEIN 1(CSP1)and CSP3,to inhibit translation.Moreover,natural variations in GRP7 affecting the residue phos-phorylated by the receptorkinase FERONIA alter its capacity to undergo LLPS and correlate with the adap-tation of some Arabidopsis accessions to a widertemperature range.Taken together,ourfindings illustrate the role of translational control mediated by GRP7 LLPS to confer plants with temperature resilience.

A novel FGFR1 inhibitor CYY292 suppresses tumor progression,invasion,and metastasis of glioblastoma by inhibiting the Akt/GSK3β/snail signaling axis

Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,including proliferation,survival,migration,and dif-ferentiation.FGFR1 was predominantly expressed in GBM tissues,and FGFR1 expression was negatively correlated with overall survival.We rationally designed a novel small molecule CYY292,which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro.CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1.CYY292 dose-depen-dently inhibited cell proliferation,epithelial-mesenchymal transition,stemness,invasion,and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells,and this effect was prevented by pharmacological inhibitors and critical gene knockdown.In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547.CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models.This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292,which targets FGFR1,on downstream signaling pathways directly reducing GBM cell growth,invasion,and metastasis and thus impairing the recruitment,activation,and function of immune cells.

Corrigendum to"A novel FGFR1 inhibitor CYY292 suppresses tumor progression,invasion,and metastasis of glioblastoma by inhibiting the Akt/GSK3β/snail signaling axis"[Genes&Diseases 11(2024)479-494]

The authors regret that in Figure 3C,the Western Blot(WB)image representing GAPDH levels was mistakenly chosen as the same image for ERK(indicated by the red dotted-line rectangle).We have attached the original WB strip for GAPDH to demonstrate that this was an unintentional error in image selection.Additionally,we noticed that the Transwell images in the two upper panels of the right column in Figure 4J are misleading due to errors in image selection.We have attached the original data to show that this was also an unintentional error.We assure you that these two corrections do not alter the scientificconclusionof thearticle.

Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu

TypeⅡdiabetes mellitus(TIIDM)remains a challenging clinical issue for both dentists and orthopedists.By virtue of persistent hyperglycemia and altered host metabolism,the pathologic diabetic micromilieu with chronic inflammation,advanced glycation end products accumulation,and attenuated biomineralization severely impairs bone regeneration efficiency.Aiming to“remodel”the pathologic diabetic micromilieu,we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles(Sr-MBGNs)and gelatin methacrylate(GelMA).Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr,Ca,and Si ions enhancing osteogenic,angiogenic,and immunomodulatory properties.In addition to angiogenic and anti-inflammatory outcomes,this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen,promoting cell focal adhesion,modulating osteoblast differentiation,and boosting the release of OCN,the noncollagenous proteins(intrafibrillar mineralization dependent),and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis.This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the“barren”diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.

Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment

Bone morphogenetic protein(BMP-2)has been approved by the FDA to promote bone regeneration,but uncertain osteogenic effect and dose-dependent side effects may occur.Osteoimmunomodulation plays an important role in growth factor-based osteogenesis.Here,we explored how proinflammatory signals affect the dose-dependent osteogenic potential of BMP-2.We observed that the expression level of local IL-1βdid not increase with the dose of BMP-2 in the mouse osteogenesis model.A low dose of BMP-2 could not promote new bone formation,but trigger the release of IL-1βfrom M1 macrophages.As the dose of BMP-2 increased,the IL-1βexpression and M1 infiltration in local microenvironment were inhibited by IL-1Ra from MSCs under osteogenic differentiation induced by BMP-2,and new bone tissues formed,even excessively.Anti-inflammatory drugs(Dexamethasone,Dex)promoted osteogenesis via inhibiting M1 polarization and enhancing BMP-2-induced MSC osteo-differentiation.Thus,we suggest that the osteogenic effect of BMP-2 involves macrophage-MSC interaction that is dependent on BMP-2 dose and based on IL-1R1 ligands,including IL-1βand IL-1Ra.The dose of BMP-2 could be reduced by introducing immunoregulatory strategies.

高电磁干扰屏蔽和低反射的柔性Ag/BaFe_(12)O_(19)微纤维/聚酰亚胺复合薄膜

高屏蔽效率和低反射特性的先进电磁干扰屏蔽(EMI SE)材料在降低二次电磁辐射污染方面具有巨大的潜力.本研究采用气流纺丝法制备了具有优异EMI SE的梯度导电Ag/BaFe_(12)O_(19)超细纤维/聚酰亚胺(GCABP)复合薄膜.梯度导电结构有效地减少了电磁波的反射.BaFe_(12)O_(19)微纤维的掺入进一步提高了薄膜的EMI SE.在厚度为100μm时,复合膜的EMI SE可达98.9 dB,吸收系数(A)为0.75,证实了GCABP膜是一种吸波型EMI屏蔽材料.聚酰亚胺(PI)保护Ag超细纤维和BaFe12O19超细纤维,确保GCABP薄膜在极端环境下的稳定性.此外,GCABP薄膜表现出优异的热管理性能,如其在1.4 V的低电压下表面温度高达315℃,响应时间达到5.4 s,循环加热能力稳定,整体可靠性好.鉴于其出色的综合性能,GCABP薄膜在国防工业和航空航天等领域具有巨大的应用潜力.

Orchestration of energy metabolism and osteogenesis by Mg^(2+)facilitates low-dose BMP-2-driven regeneration

The clinical application of bone morphogenetic protein-2(BMP-2)is limited by several factors,including ineffectiveness at low doses and severe adverse effects at high doses.To address these efficacy and safety limitations,we explored whether orchestration of energy metabolism and osteogenesis by magnesium ion(Mg^(2+))could reduce the dose and thereby improve the safety of BMP-2.Our results demonstrated that rapid metabolic activation triggered by BMP-2 was indispensable for subsequent osteogenesis.Moreover,inadequate metabolic stimulation was shown to be responsible for the ineffectiveness of low-dose BMP-2.Next,we identified that Mg^(2+),as an"energy propellant",substantially increased cellular bioenergetic levels to support the osteogenesis via the Akt-glycolysis-Mrs2-mitochondrial axis,and consequently enhanced the osteoinductivity of BMP-2.Based on the mechanistic discovery,microgel composite hydrogels were fabricated as low-dose BMP-2/Mg^(2+)codelivery system through microfluidic and 3D printing technologies.An in vivo study further confirmed that rapid and robust bone regeneration was induced by the codelivery system.Collectively,these results suggest that this bioenergetic-driven,cost-effective,low-dose BMP-2-based strategy has substantial potential for bone repair.

Secondary prevention medication persistence and prognosis of acute ischaemic stroke or transient ischaemic attack

Introduction The risk of disability and mortality is high among recurrent stroke,which highlights the importance of secondary prevention measures.We aim to evaluate medication persistence for secondary prevention and the prognosis of acute ischaemic stroke or transient ischaemic attack(TIA)in China.Methods Patients with acute ischaemic stroke or TIA from the China National Stroke Registry II were divided into 3 groups based on the percentage of persistence in secondary prevention medication classes from discharge to 3 months after onset(level I:persistence=0%,level II:0%<persistence<100%,level III:persistence=100%).The primary outcome was recurrent stroke.The secondary outcomes included composite events(stroke,myocardial infarction or death from cardiovascular cause),all-cause death and disability(modified Rankin Scale score=3–5)from 3 months to 1 year after onset.Recurrent stroke,composite events and all-cause death were performed using Cox regression model,and disability was identified through logistic regression model using the generalised estimating equation method.Results 18344 patients with acute ischaemic stroke or TIA were included,315(1.7%)of whom experienced recurrent strokes.Compared with level I,the adjusted HR of recurrent stroke for level II was 0.41(95%CI 0.31 to 0.54)and level III 0.37(0.28 to 0.48);composite events for level II 0.41(0.32 to 0.53)and level III 0.38(0.30 to 0.49);all-cause death for level II 0.28(0.23 to 0.35)and level III 0.20(0.16–0.24).Compared with level I,the adjusted OR of disability for level II was 0.89(0.77 to 1.03)and level III 0.82(0.72 to 0.93).Conclusions Persistence in secondary prevention medications,especially in all classes of medications prescribed by the physician,was associated with lower hazard of recurrent stroke,composite events,all-cause death and lower odds of disability in patients with acute ischaemic stroke or TIA.

On-chip multiplexed single-cell patterning and controllable intracellular delivery

Conventional electroporation approaches show limitations in the delivery of macromolecules in vitro and in vivo.These limitations include low efficiency,noticeable cell damage and nonuniform delivery of cells.Here,we present a simple 3D electroporation platform that enables massively parallel single-cell manipulation and the intracellular delivery of macromolecules and small molecules.A pyramid pit micropore array chip was fabricated based on a silicon wet-etching method.A controllable vacuum system was adopted to trap a single cell on each micropore.Using this chip,safe single-cell electroporation was performed at low voltage.Cargoes of various sizes ranging from oligonucleotides(molecular beacons,22 bp)to plasmid DNA(CRISPR-Cas9 expression vectors,>9 kb)were delivered into targeted cells with a significantly higher transfection efficiency than that of multiple benchmark methods(e.g.,commercial electroporation devices and Lipofectamine).The delivered dose of the chemotherapeutic drug could be controlled by adjusting the applied voltage.By using CRISPR-Cas9 transfection with this system,the p62 gene and CXCR7 gene were knocked out in tumor cells,which effectively inhibited their cellular activity.Overall,this vacuum-assisted micropore array platform provides a simple,efficient,high-throughput intracellular delivery method that may facilitate on-chip cell manipulation,intracellular investigation and cancer therapy.

急性缺血性脑卒中MSU与常规救治疗效的对比分析

目的对比分析应用移动卒中单元(MSU)与常规救治模式对急性缺血性脑卒中(AIS)的治疗效果。方法选取河南大学附属南石医院脑病重症科自2019年10月至2020年1月收治的AIS患者60例,采用随机数字表法将患者分为MSU组(30例)和常规组(30例)。MSU组采用装配了16排移动CT的MSU在卒中发生现场进行神经功能学评估、脑部移动CT扫描诊断及重组组织型纤溶酶原激活物阿替普酶(rt-PA)静脉溶栓治疗;常规组采用常规救治模式,由120现场急救并转运患者至医院,在急诊科进行神经功能学评估、CT脑扫描成像,专家会诊确诊,入住卒中专科进行rt-PA静脉溶栓治疗。对比分析2组患者首次医学接触时间、完成CT脑扫描时间、rt-PA静脉溶栓时间,以及溶栓治疗前后神经功能缺损程度变化和临床疗效。结果MSU组的治疗总有效率高于常规组,差异具有统计学意义(P<0.05)。MSU组首次医疗接触至完成头颅CT检查时间明显少于常规组(平均时间缩短28.72 min),首次医疗接触至静脉溶栓开始时间明显少于常规组(平均时间缩短34.81 min),2组比较差异均具有统计学意义(P<0.05)。MSU组治疗后的美国国立卫生研究院卒中量表评分优于常规组,差异有统计学意义(P<0.05)。结论AIS运用MSU模式进行rt-PA静脉溶栓治疗,可以显著缩短CT脑扫描时间和rt-PA静脉溶栓时间,对改善患者神经功能和提高临床疗效作用显著。

Supramolecular Nanofibers/Hydrogels of the Conjugates of Nucleobase,Saccharide,and Amino Acids

Three new hydrogelators based on the conjugates of three naturally occurring biological building blocks:nu-cleobase,saccharide,and amino acids,were explored.Being synthesized via a facile solid phase peptide synthesis route,the hydrogelators self-assemble in water to afford supramolecular nanofibers and hydrogels.Transmission electron microscopy,oscillation rheometry,and circular dichroism reveal that the hydrogels consist of largely he-lix-based nanofibers of the widths of 5-12 nm and exhibit storage moduli up to 1 kPa.These hydrogelators also exhibit excellent cell-compatibility.This work illustrates a new platform for constructing molecular soft materials for nanobiotechnology.