肺癌细胞中GTSE1与细胞周期的关系及潜在调控机制

细胞周期的调控对于维持细胞正常功能至关重要,尤其在肺癌等疾病的发展中。细胞周期由四个主要阶段组成(G1、S、G2和M期),这些阶段通过一系列精确的分子事件来确保细胞正确增殖和分裂。在肺癌细胞中,细胞周期失调可导致癌细胞无序增殖和侵袭能力增强。G2和S期表达-1(G2and S-phase expressed 1,GTSE1)是一种在细胞质中发现的调节蛋白,它在多种癌细胞的细胞周期分布中起着关键作用,并参与了细胞增殖和凋亡等过程。GTSE1通过与细胞周期蛋白依赖激酶抑制因子1A(cyclin-dependent kinase inhibitor 1A,p21)的相互作用,维持p21的稳定性,进而抑制细胞周期蛋白依赖性激酶1/2(cyclin-dependent kinase 1/2,CDK1/2)的活性,影响细胞周期的进程。此外,GTSE1还参与肿瘤蛋白53(tumor protein 53,p53)信号通路的调控。在双微体同源基因2(mouse double minute 2 homolog,MDM2)的协助下,GTSE1能够将p53从细胞核转运至胞质,并促进其泛素化降解,从而影响细胞周期和细胞死亡相关信号通路。本文综述了GTSE1在肺癌细胞中的表达情况和对肺癌的影响,以及其参与细胞周期调控的潜在机制。

Lycium barbarum glycopeptide(wolfberry extract)slows N-methyl-N-nitrosourea-induced degradation of photoreceptors

Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation:A multicenter,case-series study in China

Objective:To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor(EGFR)21L858R mutant non-small cell lung cancer(NSCLC)patients in China and to explore the factors influencing the efficacy and safety.Methods:A longitudinal,consecutive case-series,multicenter study with mixed prospective and retrospective data was conducted.The primary endpoint was progression-free survival(PFS),and the secondary endpoints included duration of treatment(DOT),overall survival(OS),objective response rate(ORR),disease control rate(DCR)and safety.Results:A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included.The median follow-up time for these patients was 20.4 months.Among 134 patients with evaluable lesions,the ORR was 70.9%and the DCR was 96.3%.The median PFS was 16.3[95%confidence interval(95%CI),13.7−18.9]months.Multivariate Cox regression analysis suggested that the baseline brain metastasis(BM)status[with vs.without BM:hazard ratio(HR),1.331;95%CI,0.720−2.458;P=0.361]and initial doses(45 mg vs.30 mg:HR,0.837;95%CI,0.427−1.641;P=0.604)did not significantly affect the median PFS.The median DOT was 21.0(95%CI,17.5−24.6)months and the median OS was not reached.Genetic tests were performed in 64 patients after progression,among whom 29(45.3%)patients developed the EGFR 20T790M mutation.In addition,among the 46 patients who discontinued dacomitinib treatment after progression,31(67.4%)patients received subsequent third-generation EGFR-tyrosine kinase inhibitors.The most common grade 3−4 adverse events were rash(10.4%),diarrhea(9.1%),stomatitis(7.1%)and paronychia(4.5%).The incidence of grade 3−4 rash was significantly higher in the 45 mg group than that in the 30 mg group(21.9%vs.7.5%,P=0.042).Conclusions:First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

磺酰腙的高效快速合成及其抗菌性能初探——推荐一个医学本科院校化学创新实验

在有机化学实验教学过程中,实验内容通常是完成某一化合物的合成或提取,缺少对目标化合物的结构鉴定和性质检验。为了提高有机化学实验教学质量,培养学生的科研素养和创新能力。以商业易得的醛、酮和对甲苯磺酰肼为反应原料,于室温无溶剂条件下,利用研磨方法在1 min内高效快速合成磺酰腙,并对产物进行结构表征和性质研究。产物应用于抗菌实验研究时,化合物3i和3h对大肠杆菌有最好的抑制效果。实验涉及合成、TLC检测和柱色谱层析等操作,可以锻炼学生在有机化合物合成、纯化及结构鉴定等方面的操作技能。要求学生独立查阅文献,熟练掌握Origin、ChemDraw和MestRec等软件的使用,可以提升学生分析问题并解决问题的能力。改进的实验以提高学生综合素质为宗旨,适用于有机化学基础实验教学。

Interfacial stress characterization of GaN epitaxial layer with sapphire substrate by confocal Raman spectroscopy

As an important wide-bandgap semiconductor,gallium nitride(GaN)has attracted considerable attention.This paper describes the use of confocal Raman spectroscopy to characterize undoped GaN,n-type GaN,and p-type GaN through depth profiling using 405-,532-,and 638-nm wavelength lasers.The Raman signal intensity of the sapphire substrate at different focal depths is studied to analyze the depth resolution.Based on the shift of the E2 H mode of the GaN epitaxial layer,the interfacial stress for different types of GaN is characterized and calculated.The results show that the maximum interfacial stress appears approximately at the junction of the GaN and the sapphire substrate.Local interfacial stress analysis between the GaN epitaxial layer and the substrate will be very helpful in furthering the applications of GaN devices.

Confocal photoluminescence characterization of silicon-vacancy color centers in 4H-SiC fabricated by a femtosecond laser

Silicon-vacancy(VSi)centers in silicon carbide(SiC)are expected to serve as solid qubits,which can be used in quantum computing and sensing.As a new controllable color center fabrication method,femtosecond(fs)laserwriting has been gradually applied in the preparation of VSi in SiC.In this study,4H-SiCwas directlywritten by an fs laser and characterized at 293 K by atomic force microscopy,confocal photoluminescence(PL),and Raman spectroscopy.PL signals of VSi were found and analyzed using 785 nm laser excitation by means of depth profiling and two-dimensional mapping.The influence of machining parameters on the VSi formation was analyzed,and the three-dimensional distribution of VSi defects in the fs laser writing of 4H-SiC was established.

The Evolution of Microtubule End-Binding Protein 1 (EB1) and Roles in Regulating Microtubule Behavior

All organisms must transmit genetic information to offspring through cell division, and mitotic spindle participates in the process. Spindle dynamics through depolymerization or polymerization of microtubules generates the driving force required for chromosome movements in mitosis. To date, studies have shown that microtubule arrays control the directions of cell division and diverse microtubule-associated proteins regulate cell division. But a clear picture of how microtubules and microtubule-associated proteins modulate cell division remains unknown. Depletion of end-binding protein 1 by RNA-mediated inhibition shows that one of the microtubule-associated proteins, end-binding protein 1, plays a crucial role in mitotic spindle formation and promotes microtubule dynamics and is needed for the proper segregation of mitotic chromosomes during anaphase in Drosophila cells. Here, we review the properties of end-binding protein 1 and the roles of end-binding protein 1 in regulating microtubule behavior and in cell cycle.

Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade

Background:Immune checkpoint blockade(ICB)has revolutionized the treatment of various cancer types.Despite significant preclinical advancements in understanding mechanisms,identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging.Recent evidence,both preclinical and clinical,underscores the pivotal role of the extracellular matrix(ECM)in modulating immune cell infiltration and behaviors.This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.Methods:We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy.This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses.We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas(TCGA)dataset and 1,084 inhouse samples.Additionally,novel therapeutic targets were identified based on these established immuno-collagenic subtypes.Results:Our categorization divided tumors into three subtypes:“soft&hot”(low collagen activity and high immune infiltration),“armored&cold”(high collagen activity and low immune infiltration),and“quiescent”(low collagen activity and immune infiltration).Notably,“soft&hot”tumors exhibited the most robust response to ICB therapy across various cancer types.Mechanistically,inhibiting collagen augmented the response to ICB in preclinical models.Furthermore,these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types.Additionally,an unbiased approach identified B7 homolog 3(B7-H3),an available drug target,as strongly expressed in“armored&cold”tumors,relating with poor prognosis.Conclusion:This study introduces histopathology-based universal immunocollagenic subtypes capable of predicting ICB responses across diverse cancer types.These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Photoluminescence and Raman Spectroscopy Study on Color Centers of Helium Ion-Implanted 4H-SiC

Color centers in silicon carbide(SiC)are promising candidates for quantum technologies.However,the richness of the polytype and defect configuration of SiC makes the accurate control of the types and position of defects in SiC still challenging.In this study,helium ion-implanted 4H-SiC was characterized by atomic force microscopy(AFM),confocal photoluminescence(PL),and confocal Raman spectroscopy at room temperature.PL signals of silicon vacancy were found and analyzed using 638-nm and 785-nm laser excitation by means of depth profiling and SWIFT mapping.Lattice defects(C-C bond)were detected by continuous laser excitation at 532 nm and 638 nm,respectively.PL/Raman depth profiling was helpful in revealing the three-dimensional distribution of produced defects.Differences in the depth profiling results and SRIM simulation results were explained by considering the depth resolution of the confocal measurement setup,helium bubbles,as well as swelling.

肽基多孔材料及其应用

多肽自组装形成的多孔结构是新一代多孔材料,在催化、传感、分离和药物递送等领域具有很好的应用前景.肽基多孔材料的孔内充满氨基酸侧链,因此可以通过合理设计或修改肽序列来调节其孔径大小和性能.功能基团和金属离子的引入进一步扩展了多肽基多孔材料的结构与性能.在这篇综述中,我们讨论了肽基多孔材料的设计、合成、组装及其性能,并综述了近年来其在不同领域的应用.

Hierarchical metal-peptide assemblies with chirality-encoded spiral architecture and catalytic activity

We report the coordination assembly of the ferrocene-diphenylalanine(Fc-FF)with divalent copper ions(Cu^(2+))into metalpeptide assemblies(MPAs)with hierarchical spiral architectures.The MPA particles are composed of helically organized nanofibers which can be correlated to the logarithmic spirals.The MPAs are hierarchically porous with abundant Fc and Cu2+active sites and show much higher catalytic activity than natural laccase toward the decolorization reaction.Moreover,a series of hierarchical structures of the MPAs can be synthesized by controlling the temperature and enantiomeric excess(ee).The peptide enantiomers with higher ee values will self-assemble into highly complex and ordered structures,which show higher surface area and porosity and thus enhanced catalytic activity compared with those assembled by peptides with lower ee values.The results provide new insights into the vital role of chirality in directing the self-assembly of biomolecules into highly ordered complex functional structures.

Low temperature one-pot synthesis of 1,1-diethoxyethane from ethanol on Bi/BiCeO_(x)with strong metal-support interactions

The direct conversion of ethanol to 1,1-diethoxyethane(DEE)through one-pot dehydrogenation-acetalization has attracted broad interest from both academia and industry.Based on thermodynamics,the oxidative dehydrogenation of alcohol to acetaldehyde requires high temperature to activate oxygen to realize the C-H cleavage,while the acetalization of acetaldehyde with ethanol is exothermic reversible reaction favorable at low temperature.The mismatching of the reaction condition for the two consecutive steps makes it a great challenge to achieve both high ethanol conversion and high DEE selectivity.This work reports a highly efficient bi-functional catalysis by Bi/BiCeO_(x)for one-pot oxidative dehydrogenation-acetalization route from ethanol to DEE under 150℃and ambient pressure,affording a selectivity of 98.5%±0.5%to DEE at an ethanol conversion of 87.0%±1.0%.An efficient tandem catalysis has been achieved on the interfacial Bi^(δ)+-Ov-Ce^(III)sites in Bi/BiCeO_(x)established by strong metal-support interaction,in which Biδ+-Ov-sites contribute to the oxidative dehydrogenation of ethanol at mild temperature,and-Ov-CeIII sites to the subsequent acetalization between the generated acetaldehyde and ethanol.

Resection of high-grade glioma involving language areas assisted by multimodal techniques under general anesthesia:a retrospective study

Background Multimodal techniques-assisted resection of glioma under general anesthesia(GA)has been shown to achieve similar clinical outcomes as awake craniotomy(AC)in some studies.In this study,we aim to validate the use of multimodal techniques can achieve the maximal safe resection of high-grade glioma involving language areas(HGILAs)under GA.Methods HGILAs cases were reviewed and collected between January 2009 and December 2020 in our center.Patients were separated into multimodal group(using neuronavigation,intraoperative MRI combined with direct electrical stimulation[DES]and neuromonitoring[IONM])and conventional group(neuronavigation alone)and clinical outcomes were compared between groups.Studies of HGILAs were reviewed systematically and the meta-analysis results of previous(GA or AC)studies were compared with our results.Results Finally,there were 263 patients in multimodal group and 137 patients in conventional group.Compared to the conventional group,the multimodal group achieved the higher median EOR(100%versus 94.32%,P<0.001)and rate of gross total resection(GTR)(73.8%versus 36.5%,P<0.001)and the lower incidence of permanent language deficit(PLD)(9.5%versus 19.7%,P=0.004).The multimodal group achieved the longer median PFS(16.8 versus 10.3 months,P<0.001)and OS(23.7 versus 15.7 months,P<0.001)than the conventional group.The multimodal group achieved a higher rate of GTR than the cohorts in previous multimodal studies under GA and AC(73.8%versus 55.7%[95%CI 32.0-79.3%]versus 53.4%[35.5-71.2%]).The multimodal group had a lower incidence of PLD than the cohorts in previous multimodal studies under GA(9.5%versus 14.0%[5.8-22.1%])and our incidence of PLD was a little higher than that of previous multimodal studies under AC(9.5%versus 7.5%[3.7-11.2%]).Our multimodal group also achieved a relative longer survival than previous studies.Conclusions Surgery assisted by multimodal techniques can achieve maximal safe resection for HGILAs under GA.Further prospective studies are needed to compare GA with AC for HGILAs.

Dysregulation of circular RNAs in inflammation and cancers

Emerging lines of evidence have shown that the production of the covalently closed single-stranded circular RNAs is not splicing errors,but rather a regulated process with distinct biogenesis and turnover.Circular RNAs are expressed in a cell type-and tissue-specific manner and often localize to specific subcellular regions or organelles for functions.The dysregulation of circular RNAs from birth to death is linked to the pathogenesis and progression of diverse diseases.This review outlines how aberrant circular RNA biogenesis,subcellular location,and degradation are linked to disease progression,focusing on metaflammation and cancers.We also discuss potential therapeutic strategies and obstacles in targeting such disease-related circular RNAs.

Dynamic Load Restoration Considering the Interdependencies Between Power Distribution Systems and Urban Transportation Systems

After a major outage,mobile emergency resources(MERs)can be dispatched via the transportation system(TS)for service restoration to critical loads in the power distribution system(PDS).In this case study,the efficiency of service restoration in the PDS is associated with the traffic efficiency of the TS,and vice versa,because the PDS and TS are mutually coupled through traffic lights and MERs.This paper proposes a service restoration method considering interdependency between the PDS and TS,which is formulated as a mixed-integer linear program(MILP).The objective includes maximizing the efficiency of both PDS restoration and TS.By solving the MILP,the dynamic load restoration and MER dispatch strategies can be obtained.For the PDS,the availability of MERs,including mobile sources and repair crews,relates to their dispatch in the TS,and their relationship is formulated as mathematical models.For the TS,the dynamic traffic flow is modeled using the cell transmission model and the effect of traffic lights is considered.Case studies validate the effectiveness of the proposed method.

Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis

Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.

Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging

O-linked N-acetyl-glucosamine glycosylation(O-GlcNAcylation)of intracellular proteins is a dynamic process broadly implicated in age-related disease,yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process.O-GlcNAc transferase(OGT)and the opposing enzyme O-GlcNAcase(OGA)control this nutrient-sensing protein modification in cells.Here,we show that global O-GlcNAc levels are increased in multiple tissues of aged mice.In aged liver,carbamoyl phosphate synthetase 1(CPS1)is among the most heavilyO-GlcNAcylated proteins.CPS1O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of theO-GlcNAc pathway.High glucose stimulates CPS1O-GlcNAcylation and inhibits CPS1 activity.Liver-specific deletion of OGT potentiates CPS1 activity and renders CPS1 irresponsive to further stimulation by a prolonged fasting.Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction,implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.

Metabolic engineering of Yarrowia lipolytica for scutellarin production

Scutellarin related drugs have superior therapeutic effects on cerebrovascular and cardiovascular diseases.Here,an optimal biosynthetic pathway for scutellarin was constructed in Yarrowia lipolytica platform due to its excellent metabolic potential.By integrating multi-copies of core genes from different species,the production of scutellarin was increased from 15.11 mg/L to 94.79 mg/L and the ratio of scutellarin to the main by-product was improved about 110-fold in flask condition.Finally,the production of scutellarin was improved 23-fold and reached to 346 mg/L in fed-batch bioreactor,which was the highest reported titer for de novo production of scutellarin in microbes.Our results represent a solid basis for further production of natural products on unconventional yeasts and have a potential of industrial implementation.

Earthworm biomass and population structure are negatively associated with changes in organic residue nitrogen concentration during vermicomposting

Vermicomposting is an efficient and environmentally friendly technology to dispose of agricultural organic residues.The efficiency of organic residue decomposition during vermicomposting is directly affected by the biomass and population structure of earthworms.In this study,we investigated how the earthworm biomass and population structure responded to changes in the physicochemical properties of six types of organic residue(cattle dung,herbal waste,rice straw,soybean straw,garden waste,and tea residues)during vermicomposting.Each type of organic residues was placed in a pot with earthworms Eisenia fetida,and the physicochemical properties of the organic residues and earthworm growth dynamics were recorded at 0,30,60,and 90 d of vermicomposting.The biomass and population structure of earthworms were stable or increased in rice straw,garden waste,and cattle dung within 60 d of vermicomposting,whereas in tea residues and herb waste,very little earthworm activity(3 adults and 2 cocoons)was recorded on day 30.Among the physicochemical parameters,the substrate C/N ratio was negatively correlated with earthworm growth dynamics.Decomposing organic residues showed higher NH_(4)^(+)-N and NH_(3)^(-)-N concentrations but a lower total organic carbon content,which negatively affected earthworm growth and reproduction.We recommend that chemical properties of vermicomposting systems should be monitored regularly.At the threshold levels of decomposing organic residue NH_(4)^(+)-N and NH_(3)^(-)-N concentrations,earthworms should be removed and the vermicompost can be harvested.Small-and large-scale farmers thus need to monitor the physicochemical properties of vermicompost to sustain active earthworm populations.

Self-assembly of Fibonacci number spirals in amyloid-like nanofibril films

Fibonacci number spiral patterns can be found in nature,particularly in plants,such as the sunflowers and phyllotaxis.Here,we demonstrated this pattern can be reproduced spontaneously within self-assembling peptide nanofibril films.By high-temperature water vapor annealing of an amorphous film containing both peptide and cationic diamines,well-defined amyloid-like nanofibrils can be assembled spontaneously,during which the nanofibrils will hierarchically stack with each other following the Fibonacci number patterns.The formation of the patterns is a selftemplated process,which involves stepwise chiral amplification from the molecular scale to the nano-and micro-scales.Moreover,by controlling the diameter,length,and handedness of the nanofibrils,various complex hierarchical structures could be formed,including vertically aligned nanoarray,mesoscale helical bundles,Fibonacci number spirals,and then helical toroids.The results provide new insights into the chiral self-assembly of simple biological molecules,which can advance their applications in optics and templated synthesis.