Simultaneous macroscale and microscale wave-ion interaction in near-earth space plasmas.

Identifying how energy transfer proceeds from macroscales down to microscales in collisionless plasmas is at the forefront of astrophysics and space physics. It provides information on the evolution of involved plasma systems and the generation of high-energy particles in the universe. Here we report two cross-scale energy-transfer events observed by NASA's Magnetospheric Multiscale spacecraft in Earth's magnetosphere. In these events, hot ions simultaneously undergo interactions with macroscale (~[Formula: see text] km) ultra-low-frequency waves and microscale ([Formula: see text] km) electromagnetic-ion-cyclotron (EMIC) waves. The cross-scale interactions cause energy to directly transfer from macroscales to microscales, and finally dissipate at microscales via EMIC-wave-induced ion energization. The direct measurements of the energy transfer rate in the second event confirm the efficiency of this cross-scale transfer process, whose timescale is estimated to be roughly ten EMIC-wave periods about (1 min). Therefore, these observations experimentally demonstrate that simultaneous macroscale and microscale wave-ion interactions provide an efficient mechanism for cross-scale energy transfer and plasma energization in astrophysical and space plasmas.

Observational evidence of ring current in the magnetosphere of Mercury.

The magnetic gradient and curvature drift of energetic ions can form a longitudinal electric current around a planet known as the ring current, that has been observed in the intrinsic magnetospheres of Earth, Jupiter, and Saturn. However, there is still a lack of observational evidence of ring current in Mercury's magnetosphere, which has a significantly weaker dipole magnetic field. Under such conditions, charged particles are thought to be efficiently lost through magnetopause shadowing and/or directly impact the planetary surface. Here, we present the observational evidence of Mercury's ring current by analysing particle measurements from MErcury Surface, Space Environment, GEochemistry, and Ranging (MESSENGER) spacecraft. The ring current is bifurcated because of the dayside off-equatorial magnetic minima. Test-particle simulation with Mercury's dynamic magnetospheric magnetic field model (KT17 model) validates this morphology. The ring current energy exceeds [Formula: see text] J during active times, indicating that magnetic storms may also occur on Mercury.

A decagonal quasicrystal with rhombic and hexagonal tiles decorated with icosahedral structural units.

The structure of a decagonal quasicrystal in the Zn58Mg40Y2 (at.%) alloy was studied using electron diffraction and atomic resolution Z-contrast imaging techniques. This stable Frank-Kasper Zn-Mg-Y decagonal quasicrystal has an atomic structure which can be modeled with a rhombic/hexagonal tiling decorated with icosahedral units at each vertex. No perfect decagonal clusters were observed in the Zn-Mg-Y decagonal quasicrystal, which differs from the Zn-Mg-Dy decagonal crystal with the same space group P10/mmm. Y atoms occupy the center of 'dented decagon' motifs consisting of three fat rhombic and two flattened hexagonal tiles. About 75% of fat rhombic tiles are arranged in groups of five forming star motifs, while the others connect with each other in a 'zigzag' configuration. This decagonal quasicrystal has a composition of Zn68.3Mg29.1Y2.6 (at.%) with a valence electron concentration (e/a) of about 2.03, which is in accord with the Hume-Rothery criterion for the formation of the Zn-based quasicrystal phase (e/a = 2.0-2.15).

MMS observations of electron scale magnetic cavity embedded in proton scale magnetic cavity.

Magnetic cavities (sometimes referred to as magnetic holes) at electron kinetic scale are thought to be one of the extremely small intermittent structures formed in magnetized turbulent plasmas, where the turbulence energy cascaded down to electron scale may finally be dissipated and consequently energize the electrons. However, the geometry and formation of these structures remain not definitively resolved. Here we discuss an electron scale magnetic cavity embedded in a proton scale magnetic cavity observed by the MMS spacecraft in the magnetosheath. By applying an innovative particle sounding technique, we directly depict the boundary of the electron scale magnetic cavity and uncover the geometry. We find that this structure is nearly circular with a radius of 10.0 km and its formation is due to the diamagnetic current. Investigation of the electron scale structure is only recently made possible by the high spatial and temporal resolution provided by MMS observations.

Ab initio determination of atomic structure of Zn-Zr precipitates in a Mg-Nd-Zn-Zr alloy.

The atomic structure of nanometre-sized Zn-Zr precipitates in a Mg alloy is determined by combining tilt series of micro-beam electron diffraction with atomic resolution Z-contrast imaging. The stoichiometry of the Zn-Zr precipitates is Zn2Zr3 with a primitive tetragonal structure (space group P42/mnm, a = b = 0.761 nm, c = 0.682 nm). There are 20 atoms in the unit cell of tetragonal Zn2Zr3, comprising 12 Zr atoms at the 4d, 4f, 4g positions and eight Zn atoms at the 8j positions.

The function of hyperpolarization-activated cyclic nucleotide-gated channel in diabetic cystopathy.

OBJECTIVE: We aimed at investigating changes in the expression and physiological function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in interstitial cells of Cajal (ICC) in diabetic state. MATERIALS AND METHODS: Twenty adult female Sprague-Dawley (SD) rats were randomly assigned to control and Zucker diabetic fatty (ZDF) group. The protein and mRNA expression of HCN isoforms and C-kit in the rat bladders were detected using Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). The bladder contraction was evaluated using a bladder smooth muscle strip test. Whole cell patch-clamp techniques were used to detect the activity of HCN channels. Immunofluorescent staining was used to the positive expression of HCN and C-kit in ICC. RESULTS: cAMP, as HCN channel-specific stimulant, could increase the frequency and amplitude of spontaneous contractions in both group, while cAMP inducing contraction of ZDF rats, was still significantly lower compared with the control group. Acute bladder ICCs were isolated by collagenase digestion. Classic Ih current pattern was recorded on ICCs while Ih current amplitude of ICCs from ZDF diabetic rats was significantly lower than the control group. The expression and mRNA of HCN1-4 isoforms in ZDF diabetic rats were both significantly lower compared with the control group. Meanwhile, the number of c-kit positive cells in ZDF diabetic rats showed no significant differences compared with controls. The morphological structure of ICC in the bladder of ZDF rats was relatively loose and the number of their cell process was apparently decreased. CONCLUSIONS: The structure of ICCs in ZDF rats was relatively loose, their connection to each other was also diminished. The expression of HCN was down-regulated and its response to cAMP was also decreased. HCN channels in bladder ICCs might regulate detrusor contraction. Changes in HCN expression and activity in bladder ICCs might be one of the most important mechanisms of diabetic cystopathy.

Effect of matrine on reducing damage to bovine mammary epithelial cells induced by Staphylococcus aureus alpha-hemolysin.

Taking bacterial virulence factors as targets is a new therapy for treating host bacterial infection. The aim of this study was to investigate the effect of matrine on α-hemolysin production of Staphylococcus aureus (S. aureus) and reducing the damage to bovine mammary epithelial cells (BMECs) induced by S. aureus α-hemolysin. Subinhibitory concentrations of matrine decreased the production of α-hemolysin in none dose-dependent manner and matrine exhibited a protective effect on S. aureus-induced BMECs injury. The results indicated that the structure of matrine may potentially be used as a basic structure for development of drugs aimed at curing and preventing dairy bovine mastitis.

Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4.

BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4's stability by inhibiting its ubiquitination. PIN1 also catalyses the isomerization of proline 205 of BRD4 and induces its conformational change, which promotes its interaction with CDK9 and increases BRD4's transcriptional activity. Substitution of BRD4 with PIN1-binding-defective BRD4-T204A mutant in gastric cancer cells reduces BRD4's stability, attenuates BRD4-mediated gene expression by impairing its interaction with CDK9 and suppresses gastric cancer cell proliferation, migration and invasion, and tumor formation. Our results identify BRD4 as a new target of PIN1 and suggest that interfering with their interaction could be a potential therapeutic approach for cancer treatment.

Iron overload induces apoptosis of murine preosteoblast cells via ROS and inhibition of AKT pathway.

OBJECTIVE: This study investigates the inhibitory effect of iron overload on MC3T3-E1 cells and its molecular mechanism. METHODS: MC3T3-E1 cells were grown under different concentrations of FAC (ferric ammonium citrate), and the WST-8 assay was used to investigate the proliferation of cells following FAC with or without deferasirox. DCFH-DA fluorescence probe was applied to detect the cellular reactive oxygen species (ROS) level. The apoptotic cells were analyzed with Annexin V-FITC/PI and the Hoechst 33258 nuclear staining assay. The JC-1 staining assay was applied to observe the change in the mitochondrial transmembrane potential. The expression levels of caspase-3, PARP, Bcl-2 family proteins, and AKT kinase were detected with the Western blot assay. RESULTS: Iron overload had a cytotoxic effect on MC3T3-E1 cells in a dosage-dependent way and resulted in increasing level of intracellular ROS. Iron overload induced apoptosis in MC3T3-E1 cells via a caspase-dependent mechanism that is accompanied by mitochondria dysfunction and decreased expression of anti-apoptotic proteins. The expression levels of cleaved-caspase-3 and cleaved-PARP were upregulated, while the expression levels of caspase-9, caspase-7, caspase-3, and PARP were downregulated. Phosphorylation of AKT kinase decreased. CONCLUSION: Iron overload can generate ROS in cells, inhibit AKT kinase and its downstream proteins activity, and subsequently initiate apoptotic events.

The Roles of the Unique Prolyl Isomerase Pin1 in Cancer-Related Viral and Bacterial Infections.

Infection is the process of pathogen invasion, as well as the host reaction to the foreign agents. Proline-directed phosphorylation is a major regulatory mechanism that regulates the function of fundamental proteins involved in infection and infection-induced cancer. Recently, the identification of the phosphorylation-dependent prolyl isomerase Pin1 has uncovered a unique regulatory signaling mechanism controlling protein conformation and function after phosphorylation. Pin1 is the only proline isomerase that specifically recognizes certain Pro-directed Ser/Thr phosphorylation motifs. Pin1 has emerged as a major regulator of cancerrelated viral and bacterial infections notably via activating Toll-like receptor signaling and NF-κB pathways. This paper will specifically review recent findings on the role of Pin1 in cancer-related viral and bacterial infections and also discuss newly discovered Pin1 inhibitors as promising drugs for the prevention and treatment of viral and bacterial infections and associated tumorigenesis.

Ultra-low-frequency wave-driven diffusion of radiation belt relativistic electrons.

Van Allen radiation belts are typically two zones of energetic particles encircling the Earth separated by the slot region. How the outer radiation belt electrons are accelerated to relativistic energies remains an unanswered question. Recent studies have presented compelling evidence for the local acceleration by very-low-frequency (VLF) chorus waves. However, there has been a competing theory to the local acceleration, radial diffusion by ultra-low-frequency (ULF) waves, whose importance has not yet been determined definitively. Here we report a unique radiation belt event with intense ULF waves but no detectable VLF chorus waves. Our results demonstrate that the ULF waves moved the inner edge of the outer radiation belt earthward 0.3 Earth radii and enhanced the relativistic electron fluxes by up to one order of magnitude near the slot region within about 10 h, providing strong evidence for the radial diffusion of radiation belt relativistic electrons.

Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation.

Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.

The presence of tangles composed of phosphorylated tau is one of the neuropathological hallmarks of Alzheimer's disease (AD). Tau, a microtubule (MT)-associated protein, accumulates in AD potentially as a result of posttranslational modifications, such as hyperphosphorylation and conformational changes. However, it has not been fully understood how tau accumulation and phosphorylation are deregulated. In the present study, we identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein. We found that hippocampal DAPK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects. DAPK1 overexpression increased tau protein stability and phosphorylation at multiple AD-related sites. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant or by genetic knockout significantly decreased tau protein stability and abolished its phosphorylation in cell cultures and in mice. Mechanistically, DAPK1-enhanced tau protein stability was mediated by Ser71 phosphorylation of Pin1, a prolyl isomerase known to regulate tau protein stability, phosphorylation, and tau-related pathologies. In addition, inhibition of DAPK1 kinase activity significantly increased the assembly of MTs and accelerated nerve growth factor-mediated neurite outgrowth. Given that DAPK1 has been genetically linked to late onset AD, these results suggest that DAPK1 is a novel regulator of tau protein abundance, and that DAPK1 upregulation might contribute to tau-related pathologies in AD. Therefore, we offer that DAPK1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.

Electromagnetic energy conversion at reconnection fronts.

Earth's magnetotail contains magnetic energy derived from the kinetic energy of the solar wind. Conversion of that energy back to particle energy ultimately powers Earth's auroras, heats the magnetospheric plasma, and energizes the Van Allen radiation belts. Where and how such electromagnetic energy conversion occurs has been unclear. Using a conjunction between eight spacecraft, we show that this conversion takes place within fronts of recently reconnected magnetic flux, predominantly at 1- to 10-electron inertial length scale, intense electrical current sheets (tens to hundreds of nanoamperes per square meter). Launched continually during intervals of geomagnetic activity, these reconnection outflow flux fronts convert ~10 to 100 gigawatts per square Earth radius of power, consistent with local magnetic flux transport, and a few times 10(15) joules of magnetic energy, consistent with global magnetotail flux reduction.

Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications.

Proline-directed protein phosphorylation (pSer/Thr-Pro), a central signaling mechanism in diverse cellular processes in physiology and disease, has been proposed to be subject to further cis-trans conformational regulation by the unique prolyl isomerase Pin1. Until recently, no tool is available to directly detect the cis-trans conformation of Pin1-catalyzed cis-trans conformational changes in vivo. We have developed novel peptide chemistry that enables to generate the first antibodies that can distinguish cis from trans pThr231-Pro conformation in tau (p-tau). Using these conformation-specific antibodies, we have discovered that cis, but not trans, p-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in neurofibrillary degenerated neurons as Alzheimer's disease (AD) progresses, localizing to the dystrophic neurites, an early hallmark change that correlates with synaptic and cognitive deficits. Unlike trans p-tau, the cis not only cannot promote microtubule assembly, but also is more resistant to dephosphorylation and degradation, and prone to aggregation. Pin1 accelerates cis to trans conversion to prevent the accumulation of the pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. These findings develop the first tool to directly detect cis-trans prolyl isomerization, especially after phosphorylation and uncover cis p-tau as the very early pathogenic conformation leading to tau pathology and memory loss in AD. These results also suggest novel conformation-specific diagnoses and therapies for AD and likely others.

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling.

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

Mesenchymal stem cell-based repair of articular cartilage with polyglycolic acid-hydroxyapatite biphasic scaffold.

This study investigates the capacity of a composite scaffold composed of polyglycolic acid-hydroxyapatite (PGA-HA) and autologous mesenchymal stem cells (MSCs) to promote repair of osteochondral defects. MSCs from culture-expanded rabbits were seeded onto a PGA and HA scaffold. After a 72-hour co-culture period, the cell-adhered PGA and HA were joined together, forming an MSCs-PGA-HA composite. Full-thickness cartilage defects in the intercondylar fossa of the femur were then implanted with the MSC-PGA-HA composite, the PGA-HA scaffold only, or they were left empty (n=20). Animals were sacrificed 16 or 32 weeks after surgery and the gross appearance of the defects was evaluated. The specimens were examined histologically for morphologic features, and stained immunohistochemically for type 2 collagen. Specimens of the MSCs-PGA-HA composite implantation group demonstrated hyaline cartilage and a complete subchondral bone formation. At 16 weeks post-implantation, significant integration of the newly formed tissue with surrounding normal cartilage and subchondral bone was observed when compared to the two control groups. At 32 weeks, no sign of progressive degeneration of the newly formed tissue was found. A significant difference in histological grading score was found compared with the control groups. The novel MSCs-seeded, PGA-HA biphasic graft facilitated both articular cartilage and subchondral bone regeneration in an animal model and might serve as a new approach for clinical applications.

Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle.

Pin2/TRF1 was independently identified as a telomeric DNA-binding protein (TRF1) that regulates telomere length, and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its lethal phenotype. We have previously demonstrated that Pin2/TRF1 levels are cell cycle-regulated and its overexpression induces mitotic arrest and then apoptosis. This Pin2/TRF1 activity can be potentiated by microtubule-disrupting agents, but suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is critical in mediating for many, but not all, ATM-dependent phenotypes. Interestingly, Pin2/TRF1 specifically localizes to mitotic spindles in mitotic cells and affects the microtubule polymerization in vitro. These results suggest a role of Pin2/TRF1 in mitosis. However, nothing is known about whether Pin2/TRF1 affects the spindle function in mitotic progression. Here we characterized a new Pin2/TRF1-interacting protein, EB1, that was originally identified in our yeast two-hybrid screen. Pin2/TRF1 bound EB1 both in vitro and in vivo and they also co-localize at the mitotic spindle in cells. Furthermore, EB1 inhibits the ability of Pin2/TRF1 to promote microtubule polymerization in vitro. Given that EB1 is a microtubule plus end-binding protein, these results further confirm a specific interaction between Pin2/TRF1 and the mitotic spindle. More importantly, we have shown that inhibition of Pin2/TRF1 in ataxia-telangiectasia cells is able to fully restore their mitotic spindle defect in response to microtubule disruption, demonstrating for the first time a functional involvement of Pin2/TRF1 in mitotic spindle regulation.

The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor.

Telomerase activity is critical for normal and transformed human cells to escape from crisis and is implicated in oncogenesis. Here we describe a novel Pin2/TRF1 binding protein, PinX1 that inhibits telomerase activity and affects tumorigenicity. PinX1 and its small TID domain bind the telomerase catalytic subunit hTERT and potently inhibit its activity. Overexpression of PinX1 or its TID domain inhibits telomerase activity, shortens telomeres, and induces crisis, whereas depletion of endogenous PinX1 increases telomerase activity and elongates telomeres. Depletion of PinX1 also increases tumorigenicity in nude mice, consistent with its chromosome localization at 8p23, a region with frequent loss of heterozygosity in a number of human cancers. Thus, PinX1 is a potent telomerase inhibitor and a putative tumor suppressor.

A specific interaction between the telomeric protein Pin2/TRF1 and the mitotic spindle.

Pin2/TRF1 was independently identified as a telomeric DNA binding protein (TRF1) [1] and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its ability to induce mitotic catastrophe [2, 3]. Pin2/TRF1 has been shown to bind telomeric DNA as a dimer [3-7] and to negatively regulate telomere length [8-11]. Interestingly, Pin2/TRF1 levels are regulated during the cell cycle, being increased in late G2 and mitosis and degraded as cells exit from mitosis [3]. Furthermore, overexpression of Pin2/TRF1 induces mitotic entry and then apoptosis [12]. This Pin2/TRF1 activity can be significantly potentiated by the microtubule-disrupting agent nocodazole [12] but is suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is important for preventing apoptosis upon DNA damage [13]. These results suggest a role for Pin2/TRF1 in mitosis. However, nothing is known about how Pin2/TRF1 is involved in mitotic progression. Here, we describe a surprising physical interaction between Pin2/TRF1 and microtubules in a cell cycle-specific manner. Both expressed and endogenous Pin2/TRF1 proteins were localized to the mitotic spindle during mitosis. Furthermore, Pin2/TRF1 directly bound microtubules via its C-terminal domain. Moreover, Pin2/TRF1 also promoted microtubule polymerization in vitro. These results demonstrate for the first time a specific interaction between Pin2/TRF1 and microtubules in a mitosis-specific manner, and they suggest a new role for Pin2/TRF1 in modulating the function of microtubules during mitosis.