Investigation on the Evolution of Nano-Scale Defects of CL-20 Crystals under Thermal Treatment by Wide/Small-Angle X-ray Scattering

Nano-scale crystal defects extremely affect the security and reliability of the explosive charges of weapons. In order to understand the evolution of nano-scale defects of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaaza-isowurtzitane (CL-20) explosive crystals under thermal treatments, the specific surface, volume fraction and size distribution of the nano-scale defects were studied by using Wide Angle X-ray Scattering (WAXS) and Small Angle X-ray Scattering (SAXS) during the temperature range from 30 °C to 200 °C. The results showed that the number and size of the pores in CL-20 powder did not change significantly during the heating process before phase transformation (30–160 °C). At 170 °C, CL-20 began to convert from ε- to γ- phase, and the specific surface and volume fraction of the nano-scale defects increased significantly. Further investigation of the pore size distribution showed that the number of pores with a small size (radius 9–21 nm) changed particularly significantly, resulting from the cracking of the CL-20 crystal powder during phase transition. At 200 °C, the phase transition was completed and γ-CL-20 was created, and the small-sized pores gradually grew into medium-sized (radius 21–52 nm) pores over time when the temperature was fixed at 200 °C.     

Tomonaga–Luttinger Spin Liquid and Kosterlitz–Thouless Transition in the Spin-1/2 Branched Chains: The Study of Topological Phase Transition

In the present work, we provide a comprehensive numerical investigation of the magnetic properties and phase spectra of three types of spin-1/2 branched chains consisting of one, two and three side spins per unit block with intra-chain interaction and a uniform inter-chain interaction in the presence of an external magnetic field. In a specific magnetic field interval, the low-temperature magnetization of these chains shows a step-like behavior with a pronounced plateau depending on the strength and the type of intra-chain interaction being ferromagnetic or antiferromagnetic. We demonstrate that when inter-chain interaction J1 is antiferromagnetic and intra-chain interaction J2 is ferromagnetic, the magnetization of the models manifests a smooth increase without a plateau, which is evidence of the existence of a Luttinger-like spin liquid phase before reaching its saturation value. On the other hand, when J1 is ferromagnetic and J2 is antiferromagnetic, the low-temperature magnetization of the chain with two branches shows an intermediate plateau at one-half of the saturation magnetization that breaks a quantum spin liquid phase into two regions. The magnetization of the chain with three branches exhibits two intermediate plateaus and two regions of a quantum spin liquid. We demonstrate that the chains with more than one side spin illustrate in their ground-state phase diagram a Kosterlitz–Thouless transition from a gapful phase to a gapless spin liquid phase.     

The Effect of Pore Structure on Impact Behavior of Concrete Hollow Brick,Autoclaved Aerated Concrete and Foamed Concrete

Porous concrete is an energy absorption material, which has been widely used in civil engineering, traffic engineering and disaster reduction engineering. However, the effect of pore structure on the impact behavior of the porous concrete is lacked. In this study, a series of drop-weight impact tests were carried out on three typical types of porous concrete, i.e., concrete hollow brick (CHB), autoclaved aerated concrete (AAC) and foamed concrete (FC), to investigate the effect of pore structures on their impact behavior. For comparison, static load tests were also conducted as references. According to the damage to the samples, the developments of impact force, strain, contact stress–strain relationship and absorbed energy during drop-weight during the impact test were measured and analyzed. The results show that the ratio between the peak impact stress and compressive strength of CHB was 0.44, while that of AAC and FC increased to about 0.6, indicating that the small and uniform pore structure in AAC and FC had a higher resistance against impact load than the hollow cavity of CHB. In addition, the elastic recovery strain in AAC increased by about 0.2% and its strain at peak contact stress increased by about 160% for a comparison of CHB, implying that a small open pore structure could enhance ductility. Besides, the peak contact stress of FC was close to that of AAC during impact loading, while the strain at peak contact stress of FC increased by about 36% compared with AAC, revealing that the closed-pore structure could further enhance the deformation potential. Correspondingly, the energy absorption rates of CHB, AAC and FC were 85.9 kJ/s, 54.4 kJ/s and 49.7 kJ/s, respectively, where AAC decreased by about 58% compared with CHB, and FC decreased by about 10% compared with AAC.     

The acquisition of cold sensitivity during TRPM8 ion channel evolution

To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition.

Given that temperature influences all biological operations, the evolution of thermosensory adaptation is crucial in shaping the specialized temperature-dependent inhabitation of an organism. At the cellular level, thermosensory neurons in the dorsal root ganglia or trigeminal ganglia innervate the skin and transmit temperature information to the spinal cord and the brain. To bestow such neurons with thermal sensitivity, animals have a toolkit of temperature-sensitive ion channels located on the cell membrane at the molecular level. Accordingly, several members of the transient receptor potential (TRP) superfamily with steep thermosensitivity (referred to as thermoTRP) have attracted the general interest in the field of thermal biology, as they sufficiently cause steep changes in depolarizing currents upon either heating or cooling and thus are considered as the primary molecular sensors of temperature (1–4). Therefore, the evolutionary strategy for directly tuning the thermal activation in thermoTRPs can be employed by animals for their specialized thermosensory adaptation, as seen in vampire bats, pit-bearing snakes, platypus, penguins, squirrels, and camels (5–9).As heat sensation (warmth and extreme heat) provides the precondition of a fundamental and conserved biological survival process, the genes that encode heat sensors are considered ancient in many metazoan organisms. The annotation of trpv1 is consistently available in the genomes of fishes, insects, amphibians, reptiles, birds, and mammals. Despite the species-specific temperature-sensitive ranges, a growing number of studies have reported the functional convergence of these heat-sensitive thermoTRP orthologs at the protein level (10), suggesting the essential role of these channels in heat perception across species. Compared to heat sensors, the cold-sensitive thermoTRP likely evolved late. As the most established cold sensor responsive to low temperatures and cooling compounds, transient receptor potential melastatin 8 (TRPM8) was found in somatosensory neurons, and genetic ablation of trpm8 either in the neurons or mice led to a largely decreased cold sensitivity (4, 11–13). Interestingly, cold activation of amphibian TRPM8 has been tested (14), while sequencing efforts indicated the absence of the trpm8 gene in 12 fish species from 10 different orders (15). Several specific domains that may alter TRPM8 cold activation have been reported, including the pore domain, voltage sensing apparatus, and C terminus (8, 16–19). Notably, although the efficacy of cold activation is largely altered by residue substitutions in the pore domain, the channel mutants are still cold sensitive (8). Therefore, these findings based on domain/residue swapping among cold-sensitive TRPM8 orthologs may not draw an overall picture in functionally important domains responsible for cold sensitivity. How did the trpm8 gene originate? How did TRPM8 integrate and modulate cold sensitivity throughout evolution? The answers to such questions probably lead us to understand the evolution of temperature perception and identify the essential structural elements that shape TRPM8 cold activation.In this study, we show the presence of the young trpm8 gene in lobe-finned fishes, believed to be the ancestors that gave rise to all land vertebrates (20). Such a young type of trpm8 derived from the trpm2 exon shuffling was originated and formed during the expansion of lobe-finned fish genomes. By detecting the positive selection-rich domains, we described the formation of the thermosensitive MHR1-3 domain in amphibian and reptile species that enables TRPM8 to undergo conformational changes at low temperatures. Furthermore, we found that the TRPM8 pore domain of terrestrial vertebrates evolved to tune the efficacy of cold activation, in which a cold-sensitive MHR1-3 domain is indispensable to achieve such a modulatory mechanism. Together, our findings suggest that the trpm8 gene origination and formation of the TRPM8 MHR1-3 domain contributed to the transition of vertebrate life from water to land and that the efficacy of cold activation tuned by the TRPM8 pore domain diversified the setting of temperature-adaptive phenotypes in terrestrial vertebrates.     

Application of Iron Tailings-Based Composite Supplementary Cementitious Materials (SCMs) in Green Concrete

How to treat the iron tailings of mining solid waste with high value is an urgent problem on a global scale. In recent years, the application of iron tailings in the building materials industry has attracted the attention of many scholars. The conversion of iron tailings into green building materials helps achieve carbon neutrality and high-value utilization of solid waste, and promotes sustainable development. Although iron tailings have been extensively studied as supplementary cementitious materials, the performance of concrete is not ideal due to its low activity. In this study, the hybrid supplementary cementitious materials system was prepared by iron tailings, phosphorus slag, and steel slag, and the effects of supplementary cementitious materials type, iron tailings content, iron tailings grinding time, and supplementary cementitious materials content on concrete performance were studied. The compressive properties, iron tailings properties, pore structure, interfacial transition zone, and element distribution of hydration products of concrete were tested by compressive strength tests, X-ray Diffractometer (XRD), X-ray Photoelectron Spectroscopy (XPS), Mercury Intrusion Porosimetry (MIP), Backscattering Electron Tests (BSE), and Energy Dispersive Spectrometer (EDS). The results show that further grinding improves the iron tailings activity. There is a synergistic mechanism between steel slag and phosphorus slag in the composite supplementary cementitious materials, which overcomes the low activity defect of iron tailings and produces concrete with a compressive strength exceeding 40 MPa. The composite supplementary cementitious materials can optimize the interfacial transition zone of the concrete interface and reduce the calcium–silicon ratio of the hydration products. However, it will deteriorate the pore structure of the concrete matrix, cause part of the concrete matrix to be damaged and lead to a loss of compressive strength, and the loss is acceptable. This work broadens the methods of comprehensive utilization of iron tailings and also provides a reference for a more detailed understanding of the properties of iron tailings-based concrete.     

A two-component protein condensate of the EGFR cytoplasmic tail and Grb2 regulates Ras activation by SOS at the membrane

We reconstitute a phosphotyrosine-mediated protein condensation phase transition of the ∼200 residue cytoplasmic tail of the epidermal growth factor receptor (EGFR) and the adaptor protein, Grb2, on a membrane surface. The phase transition depends on phosphorylation of the EGFR tail, which recruits Grb2, and crosslinking through a Grb2-Grb2 binding interface. The Grb2 Y160 residue plays a structurally critical role in the Grb2-Grb2 interaction, and phosphorylation or mutation of Y160 prevents EGFR:Grb2 condensation. By extending the reconstitution experiment to include the guanine nucleotide exchange factor, SOS, and its substrate Ras, we further find that the condensation state of the EGFR tail controls the ability of SOS, recruited via Grb2, to activate Ras. These results identify an EGFR:Grb2 protein condensation phase transition as a regulator of signal propagation from EGFR to the MAPK pathway.

Recently, a class of phenomena known as protein condensation phase transitions has begun to emerge in biology. Originally identified in the context of nuclear organization (1) and gene expression (2), a distinct two-dimensional protein condensation on the cell membrane has now been discovered in the T cell receptor (TCR) signaling system involving the scaffold protein LAT (3–5). TCR activation results in phosphorylation of LAT on at least four distinct tyrosine sites, which subsequently recruit the adaptor protein Grb2 and the signaling molecule PLCγ via selective binding interactions with their SH2 domains. Additional scaffold and signaling molecules, including SOS, GADS, and SLP76, are recruited to Grb2 and PLCγ through further specific protein–protein interactions (6, 7). Multivalency among some of these binding interactions can crosslink LAT molecules in a two-dimensional bond percolation network on the membrane surface. The resulting LAT protein condensate resembles the nephrin:NCK:N-WASP condensate (8) in that both form on the membrane surface under control of tyrosine phosphorylation and exert at least one aspect of functional control over signaling output via a distinct type of kinetic regulatory mechanism (9–11). The basic molecular features controlling the LAT and nephrin protein condensates are common among biological signaling machinery, and other similar condensates continue to be discovered (12, 13). The LAT condensation shares downstream signaling molecules with the EGF-receptor (EGFR) signaling system, raising the question if EGFR may participate in a signaling-mediated protein condensation itself.EGFR signals to the mitogen-activated protein kinase (MAPK) pathway and controls key cellular functions, including growth and proliferation (14–16). EGFR is a paradigmatic model system in studies of signal transduction, and immense, collective scientific effort has revealed the inner workings of its signaling mechanism down to the atomic level (17). EGFR is autoinhibited in its monomeric form. Ligand-driven activation is achieved through formation of an asymmetric receptor dimer in which one kinase activates the other to phosphorylate the nine tyrosine sites in the C-terminal tails (17, 18). There is an obvious conceptual connection between EGFR and the LAT signaling system in T cells. The ∼200-residue–long cytoplasmic tail of EGFR resembles LAT in that both are intrinsically disordered and contain multiple sites of tyrosine phosphorylation that recruit adaptor proteins, including Grb2, upon receptor activation (19). Phosphorylation at tyrosine residues Y1068, Y1086, Y1148, and Y1173 in the EGFR tail creates sites to which Grb2 can bind via its SH2 domain. EGFR-associated Grb2 subsequently recruits SOS, through binding of its SH3 domains to the proline-rich domain of SOS. Once at the membrane, SOS undergoes a multistep autoinhibition-release process and begins to catalyze nucleotide exchange of RasGDP to RasGTP, activating Ras and the MAPK pathway (20).While these most basic elements of the EGFR activation mechanism are widely accepted, larger-scale features of the signaling complex remain enigmatic. A number of studies have reported higher-ordered multimers of EGFR during activation, including early observations by Förster Resonance Energy Transfer and fluorescence lifetime studies (21–23), as have more recent studies using single molecule (24, 25) and computational methods (26). Structural analyses and point mutation studies on EGFR have identified a binding interface enabling EGFR asymmetric dimers to associate (27), but the role of these higher-order assemblies remains unclear. At the same time, many functional properties of the signaling system remain unexplained as well. For example, EGFR is a frequently altered oncogene in human cancers, and drugs (including tyrosine kinase inhibitors) targeting EGFR signaling have produced impressive initial patient responses (28). All too often, however, these drugs fail to offer sustained patient benefits, in large part because of poorly understood resistance mechanisms (29). Physical aspects of the cellular microenvironment have been implicated as possible contributors to resistance development (30), and there is a growing realization that EGFR possesses kinase-independent (e.g., signaling independent) prosurvival functions in cancer cells (31). These points fuel speculation that additional layers of regulation over the EGFR signaling mechanism exist, including at the level of the receptor signaling complex itself.Here we report that EGFR undergoes a protein condensation-phase transition upon activation. We reconstituted the cytoplasmic tails of EGFR on supported bilayers and characterized the system behavior upon interaction with Grb2 and SOS, using total internal reflection fluorescence (TIRF) imaging. This experimental platform has been highly effective for revealing both phase-transition characteristics and functional signaling aspects of LAT protein condensates (4, 5, 10, 32–34). Published reports on the LAT system to date have emphasized SOS (or the SOS proline-rich [PR] domain) as a critical crosslinking element. Titrating the SOS PR domain into an initially homogeneous mixture of phosphorylated LAT and Grb2 revealed a sharp transition to the condensed phase, which we have also observed with the EGFR:Grb2:SOS system. Under slightly different conditions, however, we report observations of an EGFR:Grb2 condensation-phase transition without any SOS or other crosslinking molecule. We show that crosslinking is achieved through a Grb2–Grb2 binding interface. Phosphorylation on Grb2 at Y160 as well as a Y160E mutation [both reported to disrupt Grb2–Grb2 binding (35, 36)] were observed to prevent formation of EGFR condensates. We note that the evidence of Grb2–Grb2 binding we observed occurred in the context of EGFR-associated Grb2, which is localized to the membrane surface; free Grb2 dimers are not necessary.The consequence of EGFR condensation on downstream signaling is characterized by mapping the catalytic efficiency of SOS to activate Ras as a function of the EGFR condensation state. SOS is the primary Ras guanine nucleotide exchange factor (GEF) responsible for activating Ras in the EGFR-to-MAPK signaling pathway (37–40). At the membrane, SOS undergoes a multistep process of autoinhibition release before beginning to activate Ras. Once fully activated, SOS is highly processive, and a single SOS molecule can activate hundreds of Ras molecules before disengaging from the membrane (41–43). Autoinhibition release in SOS is a slow process, which necessitates that SOS be retained at the membrane for an extended time in order for Ras activation to begin (5, 10). This delay between initial recruitment of SOS and subsequent initiation of its Ras GEF activity provides a kinetic proofreading mechanism that essentially requires SOS to achieve multivalent engagement with the membrane (e.g., through multiple Grb2 or other interactions) in order for it to activate any Ras molecules.Experimental results described here reveal that Ras activation by SOS is strongly enhanced by EGFR condensation. Calibrated measurements of both SOS recruitment and Ras activation confirmed enhanced SOS catalytic activity on a per-molecule basis, in addition to enhanced recruitment to the condensates. These results suggest that a Grb2-mediated EGFR protein condensation-phase transition is a functional element controlling signal propagation from EGFR downstream to the MAPK signaling pathway.     

艾灸对衰老模型大鼠线粒体DNA含量的影响

目的:探讨艾灸对衰老模型大鼠肝细胞线粒体DNA含量的影响。方法:将36只SD大鼠随机分为3组:青年对照组、衰老模型组、艾灸治疗组。采用25%D-半乳糖溶液125mg/kg·d-1皮下注射复制衰老大鼠模型,采用紫外分光光度法观察艾灸对衰老模型大鼠肝细胞线粒体DNA含量的影响。结果:与青年对照组比较,衰老模型组大鼠肝细胞线粒体DNA含量明显增加(P<0.05);与衰老模型组比较,艾灸治疗组大鼠肝细胞线粒体DNA含量明显减少(P<0.05)。结论:艾灸可以减少肝细胞线粒体DNA的含量,从而起到延缓衰老的作用。     

血管平滑肌细胞表型的成骨转换与血管钙化

血管钙化是血管壁中钙盐沉积的过程,导致血管硬化和失去弹性。它通常发生在中老年人,尤其是患有动脉粥样硬化、高血压、糖尿病和慢性肾脏疾病等疾病患者。血管钙化是一个主动的过程,其中平滑肌细胞的成骨转换是重要事件之一。这些细胞在钙化过程中释放钙离子,导致钙盐的沉积,形成钙化斑块。血管钙化受多种因素调节,包括高磷、高钙水平及氧化应激、机械应力等。此外,中医药研究在减轻血管钙化方面显示出潜力,例如灵芝孢子粉和其衍生物,三七、黄芩素、根皮素、雷公藤甲素等。这些研究为进一步理解和干预血管钙化提供了重要的证据,并揭示了一些潜在的抑制因子,可以作为未来治疗血管钙化的研究方向。     

线粒体H2S供体AP39对心肌梗死大鼠心肌纤维化的影响及其与线粒体动力学的关系

目的]已有研究表明H₂S可拮抗心肌纤维化,但线粒体靶向性H₂S能否拮抗心肌梗死后心肌纤维化,且是否与调控线粒体融合与分裂有关目前并不明确。为了探究这一关系,进行了该研究。 [方法]在动物实验中予以异丙肾上腺素[ISO,50 mg/(kg·d)]腹腔注射构建SD大鼠心肌梗死模型,对各组大鼠行心电图检测,使用线粒体H₂S供体AP39[36 μg/(kg·d)],腹腔注射连续处理SD大鼠4周,使用Masson染色检测心肌纤维化情况,使用Western blot检测相关蛋白表达情况。体外实验以氯化钴(CoCl₂,800 μmol/L)诱导H9c2心肌细胞缺氧损伤,AP39(100 nmol/L)处理H9c2细胞,使用DL-炔丙基甘氨酸(PAG,2 mmol/L)抑制内源性硫化氢合成酶胱硫醚-γ-裂解酶(CSE),并通过荧光探针检测心肌细胞活性氧(ROS)的水平。 [结果]梗死大鼠心肌存在明显间质纤维化,胶原纤维大量堆积,且CSE、线粒体融合蛋白2(MFN2)表达下调,线粒体动力相关蛋白1(DRP1)表达增加,AP39干预后则可明显改善以上变化,而加入CSE抑制剂PAG则可逆转AP39的以上作用。同时在体外实验中发现,以CoCl₂诱导H9c2心肌细胞缺氧损伤时,细胞内ROS水平升高,MFN2表达下调,DRP1表达增加,AP39则可上调MFN2蛋白表达,抑制DRP1表达,降低心肌细胞ROS水平,而PAG则可逆转以上变化。 [结论]线粒体靶向性H₂S供体AP39可以改善心肌梗死大鼠心肌纤维化,且可促进线粒体融合,抑制线粒体过度分裂。     

3D-pCASL和DCE-MRI定量评价烟雾病侧支循环和血管通透性的初步应用

目的 探讨磁共振三维假持续性脉冲自旋标记成像(3D-pCASL)和磁共振动态增强(DCE-MRI)评价烟雾病脑血流侧支循环和血管通透性的应用价值.方法 回顾性分析17例同时进行了常规MRI、3D-pCASL和DCE-MRI检查,并经DSA和/或3D MRA确诊的烟雾病患者资料.选取基底节层面,按照大脑前、中、后动脉供血分布范围,分为10个分区,利用3D-pCASL的血流标记图对10个分区的侧支循环进行评分(0、1、2和3分),并相应分为0,1,2和3组;利用3D-pCASL脑血流图分别计算相应分区的脑血流量(CBF)值;DCE-MRI按照相同选层和分区方法,测定血管容积交换常数(Ktrans)值;对0～3组CBF测值行单因素方差分析,Bonferoni法进行组间两两比较;对Ktrans行Kruskal-WallisH检验(P＜0.01差异有统计学意义).结果 CBF组内差异有统计学意义(F=27.248,P＜0.001),0～3组CBF值分别为32.7 ±10.68、39.11±15.13、57.08±13.99和54.84±15.45 ml·100g-1·min-1,两两比较,除0和1组以及2和3组间差异无统计学意义外,其他组间差异均有统计学意义(所有P ＜0.001);Ktrans组间比较差异无统计学意义(x2 =3.128,P=0.372),0～3组Ktrans值分别为0.021(0.007,0.028),0.019(0.014,0.038),0.020(0.009,039)和0.024 (0.020,0.038),但其中2例合并亚急性梗死的3个分区和1例合并短暂性缺血发作的患者4个分区Ktrans较其他分区增高.结论 运用3D-pCASL和DCE-MRI可定量评价烟雾病脑血流灌注和血管通透性.