Phonon-assisted tunneling in asymmetric resonant tunneling structures

Based on the dielectric continuum model, we calculated the phonon assisted tunneling (PAT) current of general double barrier resonant tunneling structures (DBRTSs) including both symmetric and antisymmetric ones. The results indicate that the four higher frequency interface phonon modes (especially the one which peaks at either interface of the emitter barrier) dominate the PAT processes, which increase the valley current and decrease the PVR of the DBRTSs. We show that an asymmetric structure can lead to improved performance.Comment: 1 paper and 5 figure

HDAC2 in Primary Sensory Neurons Constitutively Restrains Chronic Pain by Repressing α2δ-1 Expression and Associated NMDA Receptor Activity

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), but not HDAC3, at the Cacna2d1 promoter in the DRG. Strikingly, Hdac2 knockdown or conditional knockout in DRG neurons in male and female mice consistently induced long-lasting mechanical pain hypersensitivity, which was readily reversed by blocking NMDA receptors, inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDA receptor interaction at the spinal cord level. Hdac2 deletion in DRG neurons increased histone acetylation levels at the Cacna2d1 promoter, upregulated α2δ-1 in the DRG, and potentiated α2δ-1-dependent NMDA receptor activity at primary afferent central terminals in the spinal dorsal horn. Correspondingly, Hdac2 knockdown-induced pain hypersensitivity was blunted in Cacna2d1 knockout mice. Thus, our findings reveal that HDAC2 functions as a pivotal transcriptional repressor of neuropathic pain via constitutively suppressing α2δ-1 expression and ensuing presynaptic NMDA receptor activity in the spinal cord. HDAC2 enrichment levels at the Cacna2d1 promoter in DRG neurons constitute a unique epigenetic mechanism that governs acute-to-chronic pain transition.SIGNIFICANCE STATEMENT Excess α2δ-1 proteins produced after nerve injury directly interact with glutamate NMDA receptors to potentiate synaptic NMDA receptor activity in the spinal cord, a prominent mechanism of nerve pain. Because α2δ-1 upregulation after nerve injury is long lasting, gabapentinoids relieve pain symptoms only temporarily. Our study demonstrates for the first time the unexpected role of intrinsic HDAC2 activity at the α2δ-1 gene promoter in limiting α2δ-1 gene transcription, NMDA receptor-dependent synaptic plasticity, and chronic pain development after nerve injury. These findings challenge the prevailing view about the role of general HDAC activity in promoting chronic pain. Restoring the repressive HDAC2 function and/or reducing histone acetylation at the α2δ-1 gene promoter in primary sensory neurons could lead to long-lasting relief of nerve pain

Effects of Multi-Surface Modification on Curie temperature of ferroelectric films

Within the framework of mean field theory, we study the effects of multi-surface modification on Curie temperature of ferroelectric films using the transverse Ising model. The general nonlinear equations for Curie temperature of multi-surface ferroelectric films with arbitrary exchange constants and transverse fields are derived by the transfer matrix method. As an example, we consider a film consisting of top surface layers, bulk layers and bottom surface layers. Two types of surface modifications, modifications of a surface exchange constant and a surface transverse field are taken into account. The dependence of Curie temperature on the surface layer numbers, bulk layer numbers, surface exchange constants, surface transverse fields and bulk transverse fields is discussed.Comment: 11 pages, 5 figure

Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects

Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species

The Biochemical and Cellular Basis for Nutraceutical Strategies to Attenuate Neurodegeneration in Parkinson’s Disease

Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson’s disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc dopaminergic (DAergic) neurons and decay of the striatal tract. While genetic mutations or environmental toxins can precipitate pathology, progressive degenerative succession involves a gradual decline in DA neurotransmission/synaptic uptake, impaired oxidative glucose consumption, a rise in striatal lactate and chronic inflammation. Nutraceuticals play a fundamental role in energy metabolism and signaling transduction pathways that control neurotransmission and inflammation. However, the use of nutritional supplements to slow the progression of PD has met with considerable challenge and has thus far proven unsuccessful. This review re-examines precipitating factors and insults involved in PD and how nutraceuticals can affect each of these biological targets. Discussed are disease dynamics (Sections 1 and 2) and natural substances, vitamins and minerals that could impact disease processes (Section 3). Topics include nutritional influences on α-synuclein aggregation, ubiquitin proteasome function, mTOR signaling/lysosomal-autophagy, energy failure, faulty catecholamine trafficking, DA oxidation, synthesis of toxic DA-quinones, o-semiquinones, benzothiazolines, hyperhomocyseinemia, methylation, inflammation and irreversible oxidation of neuromelanin. In summary, it is clear that future research will be required to consider the multi-faceted nature of this disease and re-examine how and why the use of nutritional multi-vitamin-mineral and plant-based combinations could be used to slow the progression of PD, if possible

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead