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The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

Zygomorphic flowers, with bilateral (dorsoventral) symmetry, are considered to have evolved several times independently in flowering plants. In Antirrhinum majus, floral dorsoventral symmetry depends on the activity of two TCP-box genes, CYCLOIDEA (CYC) and DICHOTOMA (DICH). To examine whether the same molecular mechanism of floral asymmetry operates in the distantly related Rosid clade of eudicots, in which asymmetric flowers are thought to have evolved independently, we investigated the function of a CYC homologue LjCYC2 in a papilionoid legume, Lotus japonicus. We showed a role for LjCYC2 in establishing dorsal identity by altering its expression in transgenic plants and analyzing its mutant allele squared standard 1 (squ1). Furthermore, we identified a lateralizing factor, Keeled wings in Lotus 1 (Kew1), which plays a key role in the control of lateral petal identity, and found LjCYC2 interacted with Kew1, resulting in a double mutant that bore all petals with ventralized identity to some extents. Thus, we demonstrate that CYC homologues have been independently recruited as determinants of petal identities along the dorsoventral axis in two distant lineages of flowering plants, suggesting a common molecular origin for the mechanisms controlling floral zygomorphy.dorsoventral axis ͉ floral development ͉ keeled wings in Lotus ͉ LjCYC2 ͉ squared standard

A polyglutamine expansion located in the N terminus of huntingtin (N-htt) causes Huntington's disease (HD). How the mutation causes cell death is unknown. Several recent observations implicate altered huntingtin (htt) processing in the pathogenesis of HD. In the HD brain, mutant N-htt fragments aggregate in the nucleus and cytoplasm (1); the expression of mutant N-htt fragments in vitro causes cell death (2, 3). These findings suggest that proteolysis in the N-terminal region of htt may be important in HD pathogenesis. Furthermore, htt cleavage by caspase 3 could contribute to neurodegeneration in HD. Htt can serve as a substrate for caspase activity. Two proximate caspase 3-sensitive sites and one caspase 6-sensitive site are distal to the polyglutamine tract at aspartate residues 513, 552, and 589, respectively, in the wild-type (wt) protein (4-6). Caspase 3-cleaved N-htt products have been observed in vitro after exogenous expression of human htt in HEK 293 cells (4) and clonal striatal neurons (7). Treatment with the broad acting caspase inhibitor Z-VAD-FMK attenuates caspase 3 cleavage of htt and increases cell survival (6, 7). Enhanced immunoreactivity for caspases has been reported in HD striatal neurons compared with control brain, § supporting the involvement of caspase activation in HD pathogenesis. However, there is no evidence for htt proteolysis by caspases in the brain. No non-caspase proteases have been identified that produce a limited proteolysis of htt. Thus, despite the presence of N-htt fragments in adult and juvenile HD brain (1), the proteolytic pathway involved in the production of mutant N-htt fragments in the brain is unknown. That caspase 3 or other proteases cleave the N terminus of mutant htt in the HD brain would provide strong support that N-terminal htt proteolysis is a critical factor in HD pathogenesis.Here, we demonstrate that caspase 3-cleaved N-htt fragments occur in the control and HD brain and are similar in size to fragments produced in vitro after exogenous expression of human wt and mutant htt in mouse clonal striatal cells (7,8). The wt and mutant caspase 3-cleaved N-htt fragments in brain varied in size with polyglutamine length and were preferentially enriched in membrane fractions. Partial proteolysis of the caspase 3-cleaved N-htt fragments by calpain produced smaller Nterminal fragments. We speculate that caspase 3 cleavage regulates the proteolysis of wt and mutant htt in the brain and increases the association of N-terminal htt with membranes. Calpain-induced proteolysis of the caspase 3-cleaved mutant N-htt fragment may lead to the formation of mutant N-htt fragments that can aggregate and form inclusions. Materials and MethodsCell Culture and Transfections. The culturing and transfection of mouse clonal striatal cells (X57 cells) have been described in our recent publications (7,8,9). MCF-7 cells were grown according to the suppliers' recommendations [American Tissue Culture Collection (ATCC)]. DNA was introduced by using Superfect Transfection Reagent (Qiagen, ...

Thermoelectric materials are capable of converting waste heat into electricity. The dimensionless figure-of-merit (ZT), as the critical measure for the material’s thermoelectric performance, plays a decisive role in the energy conversion efficiency. Half-Heusler materials, as one of the most promising candidates for thermoelectric power generation, have relatively low ZTs compared to other material systems. Here we report the discovery of p-type ZrCoBi-based half-Heuslers with a record-high ZT of ∼1.42 at 973 K and a high thermoelectric conversion efficiency of ∼9% at the temperature difference of ∼500 K. Such an outstanding thermoelectric performance originates from its unique band structure offering a high band degeneracy (Nv) of 10 in conjunction with a low thermal conductivity benefiting from the low mean sound velocity (vm ∼2800 m s−1). Our work demonstrates that ZrCoBi-based half-Heuslers are promising candidates for high-temperature thermoelectric power generation.

Discovery of thermoelectric materials has long been realized by the Edisonian trial and error approach. However, recent progress in theoretical calculations, including the ability to predict structures of unknown phases along with their thermodynamic stability and functional properties, has enabled the so-called inverse design approach. Compared to the traditional materials discovery, the inverse design approach has the potential to substantially reduce the experimental efforts needed to identify promising compounds with target functionalities. By adopting this approach, here we have discovered several unreported half-Heusler compounds. Among them, the p-type TaFeSb-based half-Heusler demonstrates a record high ZT of ~1.52 at 973 K. Additionally, an ultrahigh average ZT of ~0.93 between 300 and 973 K is achieved. Such an extraordinary thermoelectric performance is further verified by the heat-to-electricity conversion efficiency measurement and a high efficiency of ~11.4% is obtained. Our work demonstrates that the TaFeSb-based half-Heuslers are highly promising for thermoelectric power generation.

Objective-Patent foramen ovale and pulmonary arteriovenous shunts are associated with serious complications such as cerebral emboli, stroke, and migraine with aura. The pathophysiological mechanisms that link these conditions are unknown. We aimed to establish a mechanism linking microembolization to migraine aura in an experimental animal model. Methods-We introduced particulate or air microemboli into the carotid circulation in mice to determine whether transient microvascular occlusion, insufficient to cause infarcts, triggered cortical spreading depression (CSD), a propagating slow depolarization that underlies migraine aura.Results-Air microemboli reliably triggered CSD without causing infarction. Polystyrene microspheres (10μm) or cholesterol crystals (<70μm) triggered CSD in 16 of 28 mice, with 60% of the mice (40% of those with CSD) showing no infarcts or inflammation on detailed histological analysis of serial brain sections. No evidence of injury was detected on magnetic resonance imaging examination (9.4T; T2 weighted) in 14 of 15 selected animals. The occurrence of CSD appeared to be related to the magnitude and duration of flow reduction, with a triggering mechanism that depended on decreased brain perfusion but not sustained tissue damage.Interpretation-In a mouse model, microemboli triggered CSD, often without causing microinfarction. Paradoxical embolization then may link cardiac and extracardiac right-to-left shunts to migraine aura. If translatable to humans, a subset of migraine auras may belong to a spectrum of hypoperfusion disorders along with transient ischemic attacks and silent infarcts. Migraine headaches are among the most common and debilitating conditions and occur in 10 to 12% of the general population. 1 Migraine with aura accounts for 15% of cases, and the aura is characterized most commonly by visual or somatosensory symptoms that often anticipate the onset of headache by 20 to 40 minutes. Certain patients with migraine auras are at greater risk for stroke. 2,3 Despite the multiplicity of potential mechanisms linking migraine aura and stroke, 4 experimental evidence linking the triggering of migraine aura attacks to microvascular dysfunction is lacking. Cortical spreading depression (CSD) may be important to this link.CSD is a slowly propagating intense neuronal and glial depolarization that spreads at a characteristic rate of 3 to 5mm per minute. It is a property of all mammalian cortices, but varies in susceptibility between the rodent and more resistant human brain. 5 A number of high-and low-resolution brain imaging studies have led to the conclusion that CSD causes migraine aura. [6][7][8] For example, during visual aura, a slowly propagating wave of cerebral blood oxygenation level-dependent (BOLD) signal change was recorded in calcarine cortex in a migraineur using near continuous high-resolution functional magnetic resonance imaging (MRI). 6 The observed perturbations of the BOLD signal were retinotopically congruent with the patient's visual percept, and displaye...

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