Disordered Ballistic Bismuth Nano-waveguides for Highly Efficient Thermoelectric Energy Conversion.

Junctions based on electronic ballistic waveguides, such as semiconductor nanowires or nanoribbons with transverse structural variations in the order of a large fraction of their Fermi wavelength, are suggested as highly efficient thermoelectric (TE) devices. Full harnessing of their potential requires a capability to either deterministically induce structural variations that tailor their transmission properties at the Fermi level or alternatively to form waveguides that are disordered (chaotic) but can be structurally modified continuously until favorable TE properties are achieved. Well-established methods to realize either of these routes do not exist. Here, disordered bismuth (Bi) waveguides are reported, which are both formed and structurally tuned by electromigration until their efficiency as TE devices is maximized. In accordance with theory, the conductance of the most efficient TE waveguides is in the sub quantum of conductance regime. The stability of these structures is found to be substantially higher than other actively studied devices such as single molecule junctions.

Water-soluble coenzyme q10 inhibits nuclear translocation of apoptosis inducing factor and cell death caused by mitochondrial complex I inhibition.

The objectives of the study were to explore the mechanism of rotenone-induced cell damage and to examine the protective effects of water-soluble Coenzyme Q10 (CoQ10) on the toxic effects of rotenone. Murine hippocampal HT22 cells were cultured with mitochondrial complex I inhibitor rotenone. Water-soluble CoQ10 was added to the culture media 3 h prior to the rotenone incubation. Cell viability was determined by alamar blue, reactive oxygen species (ROS) production by dihydroethidine (DHE) and mitochondrial membrane potential by tetramethyl rhodamine methyl ester (TMRM). Cytochrome c, caspase-9 and apoptosis-inducing factor (AIF) were measured using Western blotting after 24 h rotenone incubation. Rotenone caused more than 50% of cell death, increased ROS production, AIF nuclear translocation and reduction in mitochondrial membrane potential, but failed to cause mitochondrial cytochrome c release and caspase-9 activation. Pretreatment with water-soluble CoQ10 enhanced cell viability, decreased ROS production, maintained mitochondrial membrane potential and prevented AIF nuclear translocation. The results suggest that rotenone activates a mitochondria-initiated, caspase-independent cell death pathway. Water-soluble CoQ10 reduces ROS accumulation, prevents the fall of mitochondrial membrane potential, and inhibits AIF translocation and subsequent cell death.

Molecular ensemble junctions with inter-molecular quantum interference.

We report of a high yield method to form nanopore molecular ensembles junctions containing ~40,000 molecules, in which the semimetal bismuth (Bi) is a top contact. Conductance histograms of these junctions are double-peaked (bi-modal), a behavior that is typical for single molecule junctions but not expected for junctions with thousands of molecules. This unique observation is shown to result from a new form of quantum interference that is inter-molecular in nature, which occurs in these junctions since the very long coherence length of the electrons in Bi enables them to probe large ensembles of molecules while tunneling through the junctions. Under such conditions, each molecule within the ensembles becomes an interference path that modifies via its tunneling phase the electronic structure of the entire junction. This new form of quantum interference holds a great promise for robust novel conductance effects in practical molecular junctions.

Damage to the blood­brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition.

Hyperglycemia aggravates brain damage caused by cerebral ischemia/reperfusion (I/R) and increases the permeability of the blood­brain barrier (BBB). However, there are relatively few studies on morphological changes of the BBB. The present study aimed to investigate the effect of hyperglycemia on BBB morphological changes following cerebral I/R injury. Streptozotocin­induced hyperglycemic and citrate­buffered saline­injected normoglycemic rats were subjected to 30 min middle cerebral artery occlusion. Neurological deficits were evaluated. Brain infarct volume was assessed by 2,3,5­triphenyltetrazolium chloride staining and BBB integrity was evaluated by Evans blue and IgG extravasation following 24 h reperfusion. Changes in tight junctions (TJ) and basement membrane (BM) proteins (claudin, occludin and zonula occludens­1) were examined using immunohistochemistry and western blotting. Astrocytes, microglial cells and neutrophils were labeled with specific antibodies for immunohistochemistry after 1, 3 and 7 days of reperfusion. Hyperglycemia increased extravasations of Evan's blue and IgG and aggravated damage to TJ and BM proteins following I/R injury. Furthermore, hyperglycemia suppressed astrocyte activation and damaged astrocytic endfeet surrounding cerebral blood vessels following I/R. Hyperglycemia inhibited microglia activation and proliferation and increased neutrophil infiltration in the brain. It was concluded that hyperglycemia­induced BBB leakage following I/R might be caused by damage to TJ and BM proteins and astrocytic endfeet. Furthermore, suppression of microglial cells and increased neutrophil infiltration to the brain may contribute to the detrimental effects of pre­ischemic hyperglycemia on the outcome of cerebral ischemic stroke.

The selenoproteome exhibits widely varying, tissue-specific dependence on selenoprotein P for selenium supply.

Selenoprotein P (Sel P) is a selenium-rich glycoprotein believed to play a key role in selenium (Se) transport throughout the body. Development of a Sel P knockout mouse model has supported this notion and initial studies have indicated that selenium supply to various tissues is differentially affected by genetic deletion of Sel P. Se in the form of the amino acid, selenocysteine, is incorporated into selenoproteins at UGA codons. Thus, Se availability affects not only selenoprotein levels, but also the turnover of selenoprotein mRNAs via the nonsense-mediated decay pathway. We investigated how genetic deletion of Sel P in mice affected levels of the mRNAs encoding all known members of the murine selenoprotein family, as well as three non-selenoprotein factors involved in their synthesis, selenophosphate synthetase 1 (SPS1), SECIS-binding protein 2 (SBP2) and SECp43. Our findings present a comprehensive description of selenoprotein mRNA expression in the following murine tissues: brain, heart, intestine, kidney, liver, lung, spleen and testes. We also describe how abundance of selenoproteins and selenoprotein-synthesis factors are affected by genetic deletion of Sel P in some of these tissues, providing insight into how the presence of this selenoprotein influences selenoprotein mRNA levels, and thus, the selenoproteome.

Streptozotocin-induced diabetes causes astrocyte death after ischemia and reperfusion injury.

Diabetes exacerbates neuronal cell death induced by cerebral ischemia. One contributing factor is enhanced acidosis during ischemia. Astrocytes are vulnerable to hypoxia under acidic conditions in vitro and may be targets of ischemia under diabetic conditions. The objective of this study was to determine whether diabetes would cause damage to astrocytes after an ischemic brain injury in vivo. Diabetic and nondiabetic rats were subjected to 5 min of forebrain ischemia and followed by 30 min, 6 h, or 1 or 3 days of recovery. The results showed that ischemia caused activation of astrocytes in nondiabetic rats. In contrast, diabetes caused astrocyte activation in early stage of reperfusion and astrocyte death in late stage of reperfusion. Remarkable astrocyte death was preceded by increased DNA oxidation. Further studies revealed that increased astrocyte damage coincided with enhanced production of free radicals. These data suggest that hyperglycemic ischemia worsens outcome in astrocytes, as it does in neurons.

Risk factors analysis of mirror aneurysms: A multi-center retrospective study based on clinical and demographic profile of patients.

As a special subgroup of multiple intracranial aneurysms, mirror aneurysms are located bilaterally on the corresponding intracranial arteries. The current study sought to compare the clinical and demographic features of patients harboring mirror aneurysm, and to elucidate the corresponding risk factors. We performed a retrospective cohort study of 2641 intracranial aneurysms patients, who were admitted to our hospitals between January 2005 and June 2014. Patients were subdivided into three groups based on the inclusion criteria: (i) single (n=2250); (ii) non-mirror multiple (n=285); and (iii) mirror aneurysms (n=106). Clinical and demographic files of the three groups were collected and compared, and medical histories including stroke, hyperlipemia, hypertension, hyperglycemia, valvular heart disease were considered as potential risk factors. Potential morphological reasons for mirror cerebral aneurysms rupture, including aneurysms size, irregular walls and cerebral hemispheric dominance, were also compared. Our data showed that the male to female ratio of mirror aneurysms patients was 1:3.61, which was significantly different from that of single aneurysm (1:1.27) and multiple aneurysms (1:2.00). The prevalence of mirror aneurysms in women is higher than that in men (P<0.001). Older patients (especially 60-69 years old) also appear to be more vulnerable to mirror aneurysm than single aneurysm (P<0.001). In 84 mirror aneurysm patients the aneurysms were located on the internal carotid arteries (79.2%), most typically at the PComA or in the Cavernous ICA. Patients with medical history of hyperlipemia appear to have an increased risk of harboring mirror aneurysms. Larger aneurysm size and presence of an irregular aneurysm wall appear to be the morphological factors that predispose for mirror aneurysms rupture.

Hyperglycemia increases superoxide production in the CA1 pyramidal neurons after global cerebral ischemia.

Transient global cerebral ischemia results in selective neuronal death in the vulnerable hippocampal CA1 pyramidal neurons in a delayed manner. Hyperglycemia accelerates and exacerbates neuronal damage in this region. The object of this study was to determine whether hyperglycemia-enhanced damage is associated with increased production of superoxide anion after ischemia. The results showed that hyperglycemic ischemia caused a significant increase of superoxide production in the hippocampal CA1 neurons compared to normoglycemic animals after 18 h of recirculation, suggesting that enhanced superoxide anion production may mediate the hyperglycemia-accelerated and -enhanced neuronal death in the hippocampal CA1 area after ischemia and reperfusion.

Diabetes activates cell death pathway after transient focal cerebral ischemia.

It is well known that diabetes aggravates brain damage in experimental and clinical stroke subjects. Diabetes accelerates maturation of neuronal damage, increases infarct volume, and induces postischemic seizures. The mechanism by which diabetes increases ischemic brain damage is still elusive. Our previous experiments indicate that mitochondria dysfunction may play a role in neuronal death. The objective of this study is to determine whether streptozotocin-induced diabetes activates cell death pathway after a brief period of focal cerebral ischemia. Both diabetic and nondiabetic rats were subjected to 30 min of transient middle cerebral artery occlusion, followed by 0, 0.5, 3, and 6 h of reperfusion. We first determined the pathological outcomes after 7 days of recovery by histopathology, and then detected key components of programmed cell death pathway using immunocytochemistry coupled with confocal laser-scanning microscopy and Western blot analysis. The results show that the cytosolic cytochrome c increased mildly after reperfusion in nondiabetic samples. This increase was markedly enhanced in diabetic rats in both ischemic focus and penumbra. Subsequently, caspase-3 was activated and poly-ADP ribose polymerase (PARP) was cleaved. Our results suggest that activation of apoptotic cell death pathway may play a pivotal role in exaggerating brain damage in diabetic subjects.

Diabetes increases expression of ICAM after a brief period of cerebral ischemia.

The objective of present study was to determine whether leukocyte-endothelial cell adhesive molecule, intercellular cell adhesion molecule-1 (ICAM-1) was increased after ischemia in diabetic rats. The immunohistochemistry of ICAM showed that numbers of ICAM-1 positively stained microvessels in the cortex were markedly increased at 3 days of reperfusion in diabetic, but not in non-diabetic rats. These were further confirmed by Western analysis. Western analyses also showed that interlukin-1beta (IL-1beta), but not TNF-alpha, was increased at 3 days of the reperfusion in diabetic rats. The results suggest that inflammatory responses may mediate diabetic hyperglycemia-aggravated brain damage induced by ischemia and reperfusion.

Induction of heat shock proteins by hyperglycemic cerebral ischemia.

Hyperglycemia worsens the neuronal death induced by cerebral ischemia. A previous study demonstrated that diabetic hyperglycemia suppressed the expression of heat shock protein 70 (HSP70) in the liver. The objective of this study is to determine whether hyperglycemia exacerbates ischemic brain damage by suppressing the expression of heat shock proteins (HSPs) in the brain. Both normoglycemic and hyperglycemic rats were subjected to a transient global cerebral ischemia of 15 min and followed by 0.5, 1 and 3 h of reperfusion. The expression of stress-related genes and levels of HSP proteins were determined by DNA microarray, immunocytochemistry and Western blot analyses. The results showed that hyperglycemic ischemia upregulated the expressions of hsp70, hsp90A, hsp90B, heat shock cognate 71 kD protein (hsc70) and mthsp70. Protein levels of HSP70 and HSP60 were enhanced by hyperglycemia compared with normoglycemia. The results suggested that hyperglycemia-exacerbated ischemic brain damage is not mediated by the suppression of the HSPs. The increased levels of HSPs and mthsp70 suggest that the cell and the mitochondrion had strong stress responses to hyperglycemic ischemia.

Bongkrekic acid ameliorates ischemic neuronal death in the cortex by preventing cytochrome c release and inhibiting astrocyte activation.

Mitochondrial release of cytochrome c (cyt-c) plays a critical role in initiating cell death after cerebral ischemia. The objective of this study was to determine whether bongkrekic acid (BKA) ameliorates ischemic neuronal damage by inhibiting the release of cyt-c. These results showed that a 10min period of global ischemia caused neuronal death, increased the release of cyt-c and activated astrocytes in the cortex and CA1. BKA treatment reduced ischemic-induced neuronal death, prevented cyt-c release and inhibited astrocyte activation in the cortex, but not in the CA1. These results suggest that the neuroprotective effect of BKA is associated with its ability to prevent cyt-c release and to inhibit astrocyte activation.

LOXL null mice demonstrate selective dentate structural changes but maintain dentate granule cell and CA1 pyramidal cell potentiation in the hippocampus.

Lysyl oxidase-like protein (LOXL), part of the lysyl oxidase copper-dependent amine oxidase family, is expressed in the extracellular matrix and in the nucleus. It likely plays a role in cross-linking collagen and elastin, possibly modulating cellular functions. Immunohistochemical studies show the presence of LOXL in the pyramidal cell layer of the hippocampus; and in this study, we report that cells in the granule cell layer have significantly smaller somas in LOXL -/- compared to LOXL +/+ mice. In addition we tested the hypothesis that these structural alterations in the dentate granule layer were associated with synaptic efficacy and thus muted long-term potentiation in mice lacking the protein. Electrical recordings were obtained in 300-mum hippocampal slices in dentate and CA1 pyramidal cell layers in age-matched wild type and LOXL null mice. Potentiation in the CA1 cell layer of 10 LOXL -/- and 8 LOXL +/+ mice was 191.0+/-9.3% and 181.6+/-9.1%, respectively (mean+/-S.E.M.). Dentate potentiation was 120.8+/-7.0% and 121.0+/-3.4% in 11 LOXL -/- and 11 LOXL +/+ mice, respectively. No phenotypic difference in potentiation of population spike amplitude (or in EPSP slope) in either layer was observed. Thus, contrary to expectation, structural changes in the hippocampus of LOXL -/- mice did not affect synaptic remodeling in a manner that impaired the establishment of LTP.

Up-regulation and altered distribution of lysyl oxidase in the central nervous system of mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis.

Mutations of the copper-zinc superoxide dismutase (SOD1) gene can result in the development of amyotrophic lateral sclerosis (ALS). The exact cellular mechanisms causing ALS are not known, but oxidative stress is thought to play a prominent role. Lysyl oxidase (LOX) is one of the genes that are known to be up-regulated in ALS patients. In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope. The results showed that LOX, an extracellular matrix protein, was expressed in the choroid plexus, blood vessel walls, brain matrix, and neurons of normal rat and mice. In neurons, LOX was localized within the cytoplasm. LOX immunoreactivity increased in neurons of the spinal cord, brain stem and cortex, and the Purkinje cells of the cerebellum in transgenic G93A SOD1 (mSOD1) mouse model of ALS. In situ hybridization indicated that LOX gene expression was enhanced in the neurons of the spinal cord, brain stem, cortex, caudoputamen and cerebellum in mSOD1 mice compared with wild type controls. LOX enzyme activity was increased in mSOD1 mice. An increase in the amount of LOX mRNA, protein and enzyme activity was coincidental with late stage ALS, indicating that LOX may be associated with the progression of the neurodegenerative process in the mSOD1 model of ALS.

Overexpression of selenoprotein H reduces Ht22 neuronal cell death after UVB irradiation by preventing superoxide formation.

Selenoproteins have been shown to exhibit a variety of biological functions, including antioxidant functions, maintaining cellular redox balance, and heavy metal detoxification. UV irradiation-induced damage is partially mediated by increased oxygen radical production. The present study is designed to examine the antioxidative effects of human selenoprotein H (hSelH) after brief period of UVB irradiation on the murine hippocampal neuronal cell line Ht22. Ht22 cells were stably transfected with the hSelH gene or with MSCV empty vector and exposed to UVB irradiation with or without the presence of serum. The results showed that cell viability was significantly higher in hSelH-transfected cells compared to the MSCV vector-transfected cells after 24 h of recovery with or without the presence of serum in the media. Further studies revealed that while the number of superoxide anion (O2*-) positive cells was increased following a 7 mJ/cm(2) of UVB irradiation and 5 h of recovery, overexpression of hSelH significantly reduced superoxide production. These results suggest that hSelH overexpression protects cells from UVB irradiation-induced cell death by reducing the O2*- formation.

Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals.

Mitochondria play a critical role in the pathogenesis of cerebral ischemia. Acute hyperglycemia has been shown to activate the mitochondria-initiated cell death pathway after an intermediate period of ischemia. The objective of the present study was to determine if diabetic hyperglycemia induced by streptozotocin activates the cell death pathway after a brief period of global ischemia. Five minutes of global ischemia was induced in nondiabetic and diabetic rats. Brain samples were collected after 30 min, 6 h, 1, 3, and 7 days of recirculation as well as from sham-operated controls. Histopathological examination in the hippocampal CA1, CA3, hilus, and dentate gyrus regions, as well as in the cortical and thalamic areas, showed that neuronal death in diabetic animals increased compared to nondiabetic ischemic controls. Neuronal damage maturation occurred after 7 days of recovery in nondiabetic rats, while it was shortened to 3 days of recovery in diabetic animals. Western blot analyses revealed that release of cytochrome c markedly increased after 1 and 3 days of reperfusion in diabetic rats. Caspase-3 activation was evident in the nuclear fraction of the cortex of diabetic rats after 3 days recovery and it was preceded by activation of caspase-9, but not activation of caspase-8. Electron microscopy demonstrated that chromatin condensation and mitochondrial swelling were features of the diabetes-mediated ischemic neuronal damage. However, no apoptotic bodies were observed in any sections examined. These results suggest that a brief period of global ischemia in diabetic animals activates a neuronal cell death pathway involving cytochrome c release, caspase-9 activation, and caspase-3 cleavage, all of which are most likely initiated by early mitochondria damage.

Transient forebrain ischemia induced phosphorylation of cAMP-responsive element-binding protein is suppressed by hyperglycemia.

Hyperglycemia enhances brain damage due to transient cerebral ischemic stroke. The hyperglycemia-mediated detrimental effect is probably due to mitochondrial dysfunction and the resulting promotion of cell death pathways. In this study, we determined whether hyperglycemia suppresses cell survival signals that involve the cAMP-responsive element-binding protein (CREB) and activating transcription factor (ATF-2). Total and phosphorylated CREB and ATF-2 were measured in the cingulate cortex and dentate gyrus, two structures that are ischemia-resistant under normoglycemic conditions but become ischemia-vulnerable under hyperglycemic conditions, using immunocytochemistry and Western blot analysis. Samples were collected from normo-operated and hyperglycemic rats subjected to 15 min of ischemia followed by reperfusion. Transient ischemia induced a persistent phosphorylation of CREB in normoglycemic animals. Hyperglycemia suppressed phosphorylation of CREB in hyperglycemia-recruited areas. Ischemia also induced a transient increase of phospho-ATF-2 in the cingulated cortex that was suppressed by hyperglycmia. We conclude that suppression of neuronal survival signals by hyperglycemia may contribute to the mechanism of converting ischemia-resistant structures into vulnerable ones.