Serial processing of kinematic signals by cerebellar circuitry during voluntary whisking

Purkinje cells (PCs) in Crus 1 represent whisker movement via linear changes in firing rate, but the circuit mechanisms underlying this coding scheme are unknown. Here we examine the role of upstream inputs to PCs—excitatory granule cells (GCs) and inhibitory molecular layer interneurons—in processing of whisking signals. Patch clamp recordings in GCs reveal that movement is accompanied by changes in mossy fibre input rate that drive membrane potential depolarisation and high-frequency bursting activity at preferred whisker angles. Although individual GCs are narrowly tuned, GC populations provide linear excitatory drive across a wide range of movement. Molecular layer interneurons exhibit bidirectional firing rate changes during whisking, similar to PCs. Together, GC populations provide downstream PCs with linear representations of volitional movement, while inhibitory networks invert these signals. The exquisite sensitivity of neurons at each processing stage enables faithful propagation of kinematic representations through the cerebellum

Translation of the first upstream ORF in the hepatitis B virus pregenomic RNA modulates translation at the core and polymerase initiation codons

The human hepatitis B virus (HBV) has a compact genome encoding four major overlapping coding regions: the core, polymerase, surface and X. The polymerase initiation codon is preceded by the partially overlapping core and four or more upstream initiation codons. There is evidence that several mechanisms are used to enable the synthesis of the polymerase protein, including leaky scanning and ribosome reinitiation. We have examined the first AUG in the pregenomic RNA, it precedes that of the core. It initiates an uncharacterized short upstream open reading frame (uORF), highly conserved in all HBV subtypes, we designated the C0 ORF. This arrangement suggested that expression of the core and polymerase may be affected by this uORF. Initiation at the C0 ORF was confirmed in reporter constructs in transfected cells. The C0 ORF had an inhibitory role in downstream expression from the core initiation site in HepG2 cells and in vitro, but also stimulated reinitiation at the polymerase start when in an optimal context. Our results indicate that the C0 ORF is a determinant in balancing the synthesis of the core and polymerase proteins

Identifying Targets for COPD Treatment Through Gene Expression Analyses

Despite the status of chronic obstructive pulmonary disease (COPD) as a major global health problem, no currently available therapies can limit COPD progression. Therefore, an urgent need exists for the development of new and effective treatments for COPD. An improved understanding in the molecular pathogenesis of COPD can potentially identify molecular targets to facilitate the development of new therapeutic modalities. Among the best approaches for understanding the molecular basis of COPD include gene expression profiling techniques, such as serial analysis of gene expression or microarrays. Using these methods, recent studies have mapped comparative gene expression profiles of lung tissues from patients with different stages of COPD relative to healthy smokers or non-smokers. Such studies have revealed a number of differentially-regulated genes associated with COPD progression, which include genes involved in the regulation of inflammation, extracellular matrix, cytokines, chemokines, apoptosis, and stress responses. These studies have shed new light on the molecular mechanisms of COPD, and suggest novel targets for clinical treatments

Identifying targets for COPD treatment through gene expression analyses

Despite the status of chronic obstructive pulmonary disease (COPD) as a major global health problem, no currently available therapies can limit COPD progression. Therefore, an urgent need exists for the development of new and effective treatments for COPD. An improved understanding in the molecular pathogenesis of COPD can potentially identify molecular targets to facilitate the development of new therapeutic modalities. Among the best approaches for understanding the molecular basis of COPD include gene expression profiling techniques, such as serial analysis of gene expression or microarrays. Using these methods, recent studies have mapped comparative gene expression profiles of lung tissues from patients with different stages of COPD relative to healthy smokers or non-smokers. Such studies have revealed a number of differentially-regulated genes associated with COPD progression, which include genes involved in the regulation of inflammation, extracellular matrix, cytokines, chemokines, apoptosis, and stress responses. These studies have shed new light on the molecular mechanisms of COPD, and suggest novel targets for clinical treatments

Attenuating Diabetic Vascular and Neuronal Defects by Targeting P2rx7.

Retinal vascular and neuronal degeneration are established pathological features of diabetic retinopathy. Data suggest that defects in the neuroglial network precede the clinically recognisable vascular lesions in the retina. Therefore, new treatments that target early-onset neurodegeneration would be expected to have great value in preventing the early stages of diabetic retinopathy. Here, we show that the nucleoside reverse transcriptase inhibitor lamivudine (3TC), a newly discovered P2rx7 inhibitor, can attenuate progression of both neuronal and vascular pathology in diabetic retinopathy. We found that the expression of P2rx7 was increased in the murine retina as early as one month following diabetes induction. Compared to non-diabetic controls, diabetic mice treated with 3TC were protected against the formation of acellular capillaries in the retina. This occurred concomitantly with a maintenance in neuroglial function, as shown by improved a- and b-wave amplitude, as well as oscillatory potentials. An improvement in the number of GABAergic amacrine cells and the synaptophysin-positive area was also observed in the inner retina of 3TC-treated diabetic mice. Our data suggest that 3TC has therapeutic potential since it can target both neuronal and vascular defects caused by diabetes

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.P30 AG013280 - NIA NIH HHS; T32 AG000057 - NIA NIH HH

Photon assisted Levy flights of minority carriers in n-InP

We study the photoluminescence spectra of n-doped InP bulk wafers, both in the reflection and the transmission geometries relative to the excitation beam. From the observed spectra we estimate the spatial distribution of minority carriers allowing for the spectral filtering due to re-absorption of luminescence in the wafer. This distribution unambiguously demonstrates a non-exponential drop-off with distance from the excitation region. Such a behavior evidences an anomalous photon-assisted transport of minority carriers enhanced owing to the high quantum efficiency of emission. It is shown that the transport conforms very well to the so-called Levy-flights process corresponding to a peculiar random walk that does not reduce to diffusion. The index gamma of the Levy flights distribution is found to be in the range gamma = 0.64 to 0.79, depending on the doping. Thus, we propose the high-efficiency direct-gap semiconductors as a remarkable laboratory system for studying the anomalous transport.Comment: 12 pages, 9 figure

IL-33 deficiency causes persistent inflammation and severe neurodegeneration in retinal detachment.

BACKGROUND: Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and resides in the nuclei of various cell types. In the neural retina, IL-33 is predominately expressed in Müller cells although its role in health and disease is ill-defined. Müller cell gliosis is a critical response during the acute phase of retinal detachment (RD), and in this study, we investigated if IL-33 was modulatory in the inflammatory and neurodegenerative pathology which is characteristic of this important clinical condition. METHODS: RD was induced by subretinal injection of sodium hyaluronate into C57BL/6 J (WT) and IL-33-/- mice and confirmed by fundus imaging and optical coherence tomography (OCT). The expression of inflammatory cytokines, complement components and growth factors was examined by RT-PCR. Retinal neurodegeneration, Müller cell activation and immune cell infiltration were assessed using immunohistochemistry. The expression of inflammatory cytokines in primary Müller cells and bone marrow-derived macrophages (BM-DMs) was assessed by RT-PCR and Cytometric Bead Array. RESULTS: RD persisted for at least 28 days after the injection of sodium hyaluronate, accompanied by significant cone photoreceptor degeneration. The mRNA levels of CCL2, C1ra, C1s, IL-18, IL-1β, TNFα, IL-33 and glial fibrillary acidic protein (GFAP) were significantly increased at day 1 post-RD, reduced gradually and, with the exception of GFAP and C1ra, returned to the basal levels by day 28 in WT mice. In IL-33-/- mice, RD induced an exacerbated inflammatory response with significantly higher levels of CCL2, IL-1β and GFAP when compared to WT. Sustained GFAP activation and immune cell infiltration was detected at day 28 post-RD in IL-33-/- mice. Electroretinography revealed a lower A-wave amplitude at day 28 post-RD in IL-33-/- mice compared to that in WT RD mice. IL-33-/- mice subjected to RD also had significantly more severe cone photoreceptor degeneration compared to WT counterparts. Surprisingly, Müller cells from IL-33-/- mice expressed significantly lower levels of CCL2 and IL-6 compared with those from WT mice, particularly under hypoxic conditions, whereas IL-33-/- bone marrow-derived macrophages expressed higher levels of inducible nitric oxide synthase, TNFα, IL-1β and CCL2 after LPS + IFNγ stimulation compared to WT macrophages. CONCLUSION: IL-33 deficiency enhanced retinal degeneration and gliosis following RD which was related to sustained subretinal inflammation from infiltrating macrophages. IL-33 may provide a previously unrecognised protective response by negatively regulating macrophage activation following retinal detachment

RF MULTIPLIER BASED ON HARMONIC-LOCKED SMFP-LD AND OEO STRUCTURE

We propose and experimentally demonstrate an RF signal multiplier based on optical injection locking in a semiconductor laser followed by an optoelectronic oscillator (OEO). In the proposed scheme, the modulated master laser is injected into a slave laser, a single mode Fabry-Pérot laser diode (SMFP-LD), in such a way that one of the harmonics of the modulated beam is locked to the corresponding mode of the SMFP-LD. By optical beating at the output of the SMFP-LD, stable multiple RF signals with ahigh signal-tonoise ratio (SNR) are generated due to SMFP-LD, which provides a sufficient gain to the RF signal. Further, we employ an OEO structure at the output of the SMFP-LD to optimize one of the generated multiple RF signals which are determined by the electrical bandpass filter (EBPF) and the low noise amplifier (LNF) in the OEO loop. As the gain of the OEO loop is higher than the loss, a high-purity oscillating signal, which is the selected multiple RF frequency, can be generated. In the experiment, a sextuple frequency (20 GHz) of the modulated signal is observed with an SNR and the phase noise of 54.44 dB and −102.44 dBc/Hz@10 kHz, respectively. Compared with other photonic schemes, the proposed method provides high SNR, higher multiplication factor, and low phase nois