2,6-二甲氧基-1,4-苯醌通过抑制NLRP3炎症小体活化缓解小鼠的感染性休克

目的 探究发酵小麦胚芽提取物主要活性成分2,6-二甲氧基-1,4-苯醌(DMQ)抑制NLRP3炎症小体活化并缓解小鼠感染性休克的作用机制。方法 细胞学水平:在BMDM细胞中,经脂多糖(LPS)预处理、DMQ干预后,利用尼日利亚菌素(Nigericin)、ATP、尿酸钠结晶(MSU)分别活化经典NLRP3炎症小体以及胞内转染LPS活化非经典NLRP3炎症小体。利用聚脱氧腺苷酸(Poly A:T)活化AIM2炎症小体。在THP-1细胞中,利用Nigericin活化经典NLRP3炎症小体,通过Western blotting和ELISA方法测定NLRP3炎症小体活化产物的表达水平。蛋白分子水平:利用免疫共沉淀探究DMQ阻断NLRP3炎症小体活化的具体机制。动物水平:将8周龄雄性C57BL/6J小鼠随机分为空白对照组、感染性休克LPS组、DMQ 20 mg/kg治疗组、DMQ 40 mg/kg治疗组,6只/组,待DMQ治疗组小鼠预注射相应浓度DMQ后,对照组小鼠注射无菌PBS,其余3组小鼠腹腔注射相同剂量LPS,利用ELISA检测DMQ干预对LPS诱导的小鼠感染性休克模型中血清和腹腔灌洗液中TNF-α和IL-1β分泌水平的影响。DMQ预处理后注射LPS观察记录小鼠36 h内的生存状态并绘制生存曲线。结果 DMQ可有效抑制小鼠BMDM细胞和人THP-1细胞中经典NLRP3炎症小体活化(P<0.05),在小鼠BMDM细胞中对非经典NLRP3炎症小体活化也起到有效抑制作用(P<0.05),DMQ对AIM2炎症小体活化无影响(P>0.05)。进一步实验结果揭示DMQ可阻断ASC和NLRP3之间的相互作用。DMQ治疗组可显著降低小鼠血清和腹腔液中IL-1β的分泌水平(P<0.05)并延长小鼠生存时间(P<0.05)。结论 发酵小麦胚芽提取物主要活性成分DMQ通过阻断ASC和NLRP3之间的相互作用有效抑制NLRP3炎症小体活化并缓解LPS诱导的小鼠感染性休克。

Isolation and <i>Ex Vivo</i>Expansion of Human Hematopoietic Stem Cells Derived from Umbilical Cord Blood

Umbilical cord blood (UCB) is a current major source of hematopoietic stem cells (HSCs) for cell transplantation therapy. Cell transplantation with HSCs derived from UCB is advantageous over transplantation with HSCs from adult tissues. However, the low number of HSC derived from a single unit of UCB limits its application. Thus, ex vivo expansion is a good option to create more UCB HSCs for clinical application. The strategies for HSC expansion in vitro focus on mimicking the composition and structure of HSC natural niche by enhancing self-renewal and inhibiting lineage differentiation of HSCs. In the past decade, the mechanisms of the interaction between HSC and the natural niche have been deeply investigated. This great progress in basic research has led to advancements in UCB HSC ex vivo expansion. In addition, the biological characteristics of the originally isolated UCB HSCs correlate with outcome of subsequent ex vivo expansion. In this paper, we summarize the late progress achieved in isolation and ex vivo expansion of UCB HSCs. Importantly, we attempt to provide an impact and practicable procedure to expand UCB HSC in vitro from isolation of original HSCs to identification of expanded HSCs.

Molecular dynamics studies on spreading of nanofluids promoted by nanoparticle adsorption on solid surface

Abstract Spreading of nanofluids on solid substrate was studied via molecular dynamics simulations. Simulation models for two immiscible fluids （oil and water based nanofiuids） confined in a slit between two planar solid walls were set up. The influence of the volume concentration of the nanoparticles on the three-phase contact line motion was investigated. We found that the larger volume concentration results in more visible nanoparticle adsorption on solid surface. This effect further induces an advancing displacement of the contact line compared with the meniscus profiles in low concentration case and that with the absence of nanoparticles. These findings are consistent with the previous experimental and theoretical results and provide the atomic-scale understanding on nanofluid spreading.

LSD1调控颗粒细胞自噬并抑制Wt1参与FSH调节的有腔卵泡形成

In a growing follicle,the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication.Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development,the underlying mechanisms require substantial study.According to our study,along with FSH-induced antral follicles(AFs)formation,both lysine-specific demethylase 1(LSD1)protein levels and autophagy increased simultaneously in granulosa cells(GCs)in a time-dependent manner,we therefore evaluated the importance of LSD upon facilitating the formation of AFs correlated to autophagy in GCs.Conditional knockout of Lsdl in GCs resulted in significantly decreased AF number and subfertility in females,accompanied by marked suppression of the autophagy in GCs.On the one hand,depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog(WT1),at both the protein and mRNA levels.WT1 prevented the expression of FSH receptor(Fshr)in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction.On the other hand,depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs.We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity.Therefore,the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment

Although DNA mutation drives stem cell aging,how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood.Here,using a mouse model of irradiation-induced premature aging and middle-aged mice,we show that DNA mutation accumulation in hematopoietic stem cells(HSCs)during aging upregulates their surface expression of major histocompatibility complex class II(MHCII).MHCII upregulation increases the chance for recognition by bone marrow(BM)-resident regulatory T cells(Tregs),resulting in their clonal expansion and accumulation in the HSC niche.On the basis of the establishment of connexin 43(Cx43)-mediated gap junctions,BM Tregs transfer cyclic adenosine monophosphate(cAMP)to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A(PKA)signaling.Importantly,targeting the HSC–Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs.These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.

纳米限域毛细凝聚: 对150年前的开尔文方程的修正

毛细凝聚是指在限域毛细通道内的气体,不必达到过饱和状态即可发生凝聚从而转变成液体的现象.水蒸气为什么会凝聚呢?我们可以简单认为,空气只能承载一定量的水蒸气,当空气中的水蒸气多到超过一个临界点,多余的那部分会从空气中跑出来,凝聚成水.对小的通道,情况又有不同:受表面张力和弯曲界面的影响,水在小通道内会更容易凝聚:没达到饱和蒸气压的时候,水就凝聚了.早在150年前,著名的英国科学家威廉·汤姆森(William Thomson,后来被册封为开尔文勋爵)从理论上描述了毛细管内弯曲的液气界面引起的蒸气压变化,被称为开尔文方程,这是固液界面润湿领域三大经典理论之一[1].

Molecular mechanism of adsorption/desorption hysteresis:dynamics of shale gas in nanopores

Understanding the adsorption and desorption behavior of methane has received considerable attention since it is one of the crucial aspects of the exploitation of shale gas.Unexpectedly,obvious hysteresis is observed from the ideally reversible physical sorption of methane in some experiments.However,the underlying mechanism still remains an open problem.In this study,Monte Carlo(MC) and molecular dynamics(MD) simulations are carried out to explore the molecular mechanisms of adsorption/desorption hysteresis.First,a detailed analysis about the capillary condensation of methane in micropores is presented.The influence of pore width,surface strength,and temperature on the hysteresis loop is further investigated.It is found that a disappearance of hysteresis occurs above a temperature threshold.Combined with the phase diagram of methane,we explicitly point out that capillary condensation is inapplicable for the hysteresis of shale gas under normal temperature conditions.Second,a new mechanism,variation of pore throat size,is proposed and studied.For methane to pass through the throat,a certain energy is required due to the repulsive interaction.The required energy increases with shrinkage of the throat,such that the originally adsorbed methane cannot escape through the narrowed throat.These trapped methane molecules account for the hysteresis.Furthermore,the hysteresis loop is found to increase with the increasing pressure and decreasing temperature.We suggest that the variation of pore throat size can explain the adsorption/desorption hysteresis of shale gas.Our conclusions and findings are of great significance for guiding the efficient exploitation of shale gas.

Molecular transport under extreme confinement

Mass transport through the nanoporous medium is ubiquitous in nature and industry.Unlike the macroscale transport phenomena which have been well understood by the theory of continuum mechanics,the relevant physics and mechanics on the nanoscale transport still remain mysterious.Recent developments in fabrication of slit-like nanocapillaries with precise dimensions and atomically smooth surfaces have promoted the fundamental research on the molecular transport under extreme confinement.In this review,we summarized the contemporary progress in the study of confined molecular transport of water,ions and gases,based on both experiments and molecular dynamics simulations.The liquid exhibits a pronounced layered structure that extends over several intermolecular distances from the solid surface,which has a substantial influence on static properties and transport behaviors under confinement.Latest studies have also shown that those molecular details could provide some new understanding on the century-old classical theory in this field.

Nature inspired hierarchical structures in nano-cellular epoxy/graphene-Fe3O4 nanocomposites with ultra-efficient EMI and robust mechanical strength

Hierarchical layered structures,whether in a compact form like nacre or a porous manner like bone,are well known for their combined features of high stiffness,strength,and lightweight,inspiring many man-made materials and structures for high performance applications.The use of nacre/bone like hierarchical structures in polymer nanocomposites can achieve excellent mechanical and functional properties with high filler volume fractions after carefully aligning functional nanofillers,although the fabrication and processing remain a great challenge.In this work,a bio-inspired lightweight nano-cellular epoxy/graphene-Fe_(3)O_(4) nanocomposite with high nanofiller loading of 75 wt.%was successfully fabricated by combining features from both nacre and bone structures,via a simple compression molding process together with an eco-friendly supercritical CO_(2) foaming process to achieve robust mechanical strength and excellent electromagnetic interference(EMI)shielding effectiveness(SE)simultaneously.Highly aligned graphene-Fe_(3)O_(4) nanoplatelets with well controlled nanoscale porous structures(52.6 nm)enabled both low density(1.26 g/cm^(3))and high specific EMI SE>5200 dB/cm^(2)/g,as well as preserved tensile strength of 67 MPa.This study provides a sustainable route to fabricate nature mimicked structures with high performance and high flexibility for a wide range of applications,from portable electronics to healthcare devices.

Reprogramming Glial Cells into Functional Neurons for Neuro-regeneration:Challenges and Promise

The capacity for neurogenesis in the adult mammalian brain is extremely limited and highly restricted to a few regions,which greatly hampers neuronal regeneration and functional restoration after neuronal loss caused by injury or disease.Meanwhile,transplantation of exogenous neuronal stem cells into the brain encounters several serious issues including immune rejection and the risk of tumorigenesis.Recent discoveries of direct reprogramming of endogenous glial cells into functional neurons have provided new opportunities for adult neuro-regeneration.Here,we extensively review the experimental findings of the direct conversion of glial cells to neurons in vitro and in vivo and discuss the remaining issues and challenges related to the glial subtypes and the specificity and efficiency of direct cell-reprograming,as well as the influence of the microenvironment.Although in situ glial cell reprogramming offers great potential for neuronal repair in the injured or diseased brain,it still needs a large amount of research to pave the way to therapeutic application.

Using selenium-conjugated polyethylene glycol to enhance the stability of gold nanoparticles in biologically relevant samples

Using stabilizing agents to maintain the physicochemical properties of colloids in complex environments is crucial for their realworld applications. In this article, we describe how selenium-(Se-) terminated polyethylene glycol(PEG) can serve as a highaffinity stabilizing agent for gold nanoparticles(AuNPs). Compared to Au NPs modified with standard thiolated PEG(S-PEG),Se-PEG-coated Au NPs are much more stable under extreme conditions such as high/low pH, high salt content, and high temperatures. We demonstrate that the Se anchor can prevent the dissociation of PEG ligands from Au NP surfaces in living cells,where a higher concentration of biothiols is usually present. These results indicate that Se-PEG is an excellent stabilizing agent that may facilitate further studies on metal NPs for various complex and physiological systems.

Differentiation of embryonic stem cells in adult bone marrow

Embryonic stem cells （ESCs） are a potential source of generating transplantable hematopoietic stem and progenitor cells,which in turn can serve as ＂seed＂ cells for hematopoietic regeneration.In this study,we aimed to gauge the ability of mouse ESCs directly differentiating into hematopoietic cells in adult bone marrow （BM）.To this end,we first derived a new mouse ESC line that constitutively expressed the green fluorescent protein （GFP） and then injected the ESCs into syngeneic BM via intra-tibia.The progeny of the transplanted ESCs were then analyzed at different time points after transplantation.Notably,however,most injected ESCs differentiated into non-hematopoietic cells in the BM whereas only a minority of the cells acquired hematopoietic cell surface markers.This study provides a strategy for evaluating the differentiation potential of ESCs in the BM micro-environment,thereby having important implications for the physiological maintenance and potential therapeutic applications of ESCs.

Optical and electrical properties of a spiral LED filament

This paper introduces a new type of spiral white light-emitting diodes（WLED） filament with high luminous efficiency and uniform optical performance. The optical and thermal properties of the flexible filament were investigated at different stretching heights, namely 0, 1, 2, and 3 cm. The results indicated that the filament showed the best optical characteristics at the stretching height of 2 cm, because of good heat dissipation. In addition, the radiation temperature of the filament was inversely proportional to the output luminous flux. The reliability of the filament at a stretching height of 2 cm was also evaluated after 1000 h of use. The result demonstrated that the luminous flux decay of the bulb was only 0.85%. The flexible spiral WLED filament exhibiting high luminous flux and good reliability could be adapted to promote industrial development in the near future.

Genome transfer for the prevention of female infertility caused by maternal gene mutation

Poor oocyte quality is associated with early embryo developmental arrest and infertility.Maternal gene plays crucial roles in the regulation of oocyte maturation,and its mutation is a common cause of female infertility.However,how to improve oocyte quality and develop effective therapy for maternal gene mutation remains elusive.Here,we use Zar1 as an example to assess the feasibility of genome transfer to cure maternal gene mutationecaused female infertility.We first discover that cytoplasmic deficiency primarily leads to Zar1-null embryo developmental arrest by disturbing maternal transcript degradation and minor zygotic genome activation(ZGA)during the maternal-zygotic transition.We next perform genome transfer at the oocyte(spindle transfer or polar body transfer)and zygote(early pronuclear transfer or late pronuclear transfer)stages to validate the feasibility of preventing Zar1 mutationecaused infertility.We finally demonstrate that genome transfer either at the oocyte or at the early pronuclear stage can support normal preimplantation embryo development and produce live offspring.Moreover,those pups grow to adulthood and show normal fertility.Therefore,our findings provide an effective basis of therapies for the treatment of female infertility caused by maternal gene mutation.

The ZFP541-KCTD19 complex is essential for pachytene progression by activating meiotic genes during mouse spermatogenesis

Meiosis is essential for fertility in sexually reproducing species and this sophisticated process has been extensively studied.Notwithstanding these efforts,key factors involved in meiosis have not been fully characterized.In this study,we investigate the regulatory roles of zinc finger protein 541(ZFP541)and its interacting protein potassium channel tetramerization domain containing 19(KCTD19)in spermatogenesis.ZFP541 is expressed from leptotene to the round spermatid stage,while the expression of KCTD19 is initiated in pachytene.Depletion of Zfp541 or Kctd19 leads to infertility in male mice and delays progression from early to mid/late pachynema.In addition,Zfp541^(-/-)spermatocytes show abnormal programmed DNA double-strand break repair,impaired crossover formation and resolution,and asynapsis of the XY chromosomes.ZFP541 interacts with KCTD19,histone deacetylase 1/2(HDAC1/2),and deoxynucleotidyl transferase terminal-interacting protein 1(DNTTIP1).Moreover,ZFP541 binds to and activates the expression of genes involved in meiosis and post-meiosis including Kctd19;in turn,KCTD19 promotes the transcriptional activation activity of ZFP541.Taken together,our studies reveal that the ZFP541/KCTD19 signaling complex,acting as a key transcription regulator,plays an indispensable role in male fertility by regulating pachytene progression.

Direct cytoplasm delivery of gold nanoparticles for real-time apoptosis detection

Gold nanoparticles(AuNPs)assembled with fluorescent peptides through Au-S bonds(pep-AuNPs)have been widely used in biomolecular detection.However,due to the endo/lysosomal trapping after the nanoprobes enter cells,the direct delivery of AuNP probes into the cytoplasm for real-time imaging remains a difficult barrier for many cytoplasm-targeting agents.Here,we prepare AuNP@gel by wrapping a multi-functional nanogel structure on the surface of a single AuNP probe by in-situ polymerization in order to directly deliver AuNP probes into the cell cytoplasm.Compared with the pep-AuNP probes,which are trapped inside lysosomes for long periods,the AuNP@gel probes use the proton-sponge effect to effectively disrupt endo/lysosomal membranes and remain in the cytoplasm.In addition,the AuNP@gel probes rapidly escape from endo/lysosomes to avoid the complex environment that interferes with the stability of the AuNP probes and the lysosomal-storage trigger the upregulation of oxidative stress into the cells.The nanogel structure enables the AuNP probes to avoid some detrimental effects and to achieve high-fidelity fluorescence signals in the cells.Compared to traditional strategies for lysosomal escape,this one-step in-situ polymerization procedure avoids the complicated modification of additional ligands and is generally applicable to peptide-,DNA-,and polymerlinked AuNP probes.

RNF219 interacts with CCR4-NOT in regulating stem cell differentiation

Regulation of RNA stability plays a crucial role in gene expression control.Deadenylation is the initial rate-limiting step for the majority of RNA decay events.Here,we show that RING finger protein 219(RNF219)interacts with the CCR4-NOT deadenylase complex.RNF219-CCR4-NOT exhibits deadenylation activity in vitro.RNA-seq analyses identify some of the 2-cell-specific genes and the neuronal genes significantly downregulated upon RNF219 knockdown,while upregulated after depletion of the CCR4-NOT subunit CNOTIO in mouse embryonic stem(ES)cells.RNF219 depletion leads to impaired neuronal lineage commitment during ES cell differentiation.Our study suggests that RNF219 is a novel interacting partner of CCR4-NOT and required for maintenance of ES cell pluripotency.

Developmental genes during placentation:insights from mouse mutants

Placenta,a temporary organ first formed during the development of a new life is essential for the survival and growth of the fetus in eutherian mammals.It serves as an interface for the exchange of nutrients,gases and wastes between the maternal and fetal compartments.During the past decades,studies employing gene-engineered mouse mutants have revealed a wide range of signaling molecules governing the trophoblast development and function during placentation under various pathophysiological conditions.Here,we summarize the recent progress with particular respect to the involvement of developmental genes during placentation.

Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis

Background:The rapid turnover of the intestinal epithelium is driven by the proliferation and differentiation of intestinal stem cells(ISCs).The dynamics of the F-actin cytoskeleton are critical for maintaining intercellular force and the signal transduction network.However,it remains unclear how direct interference with actin polymerization impacts ISC homeostasis.This study aims to reveal the regulatory effects of the F-actin cytoskeleton on the homeostasis of intestinal epithelium,as well as the potential risks of benproperine(BPP)as an anti-tumor drug.Methods:Phalloidin fluorescence staining was utilized to test F-actin polymerization.Flow cytom-etry and IHC staining were employed to discriminate different types of intestinal epithelial cells.Cell proliferation was assessed through bromo-deoxyuridine(BrdU)and 5-ethynyl-2-deoxyuridine(EdU)incorporation assays.The proliferation and differentiation of intestinal stem cells were replicated in vitro through organoid culture.Epithelial migrationwas evaluated through BrdU pulse labeling and chasing in mice.Results:The F-actin content was observed to significantly increase as crypt cells migrated into the villus region.Additionally,actin polymerization in secretory cells,especially in Paneth cells(PCs),was much higher than that in neighboring ISCs.Treatment with the newly identified actin-related protein 2/3 complex subunit 2(ARPC2)inhibitor BPP led to a dose-dependent increase or inhibition of intestinal organoid growth in vitro and crypt cell proliferation in vivo.Compared with the vehicle group,BPP treatment decreased the expression of Lgr5 ISC feature genes in vivo and in organoid culture.Meanwhile,PC differentiation derived from ISCs and progenitors was decreased by inhibition of F-actin polymerization.Mechanistically,BPP-induced actin polymerization inhibition may activate the Yes1-associated transcriptional regulator pathway,which affects ISC proliferation and differentiation.Accordingly,BPP treatment affected intestinal epithelial cell migration in a dose-dependent manner.Conclusion:Our findings indicate that the regulation of cytoskeleton reorganization can affect ISC homeostasis.In addition,inhibiting ARPC2 with the Food and Drug Administration-approved drug BPP represents a novel approach to influencing the turnover of intestinal epithelial cells.