Effect of the frequency spectrum of road traffic noise on sleep: A polysomnographic study

Spectrum of sound affects noise annoyance. Spectral differences of road traffic noise (RTN) transmitted indoors are usual because of spectrally different sound insulation of facades. The purpose was to compare the effect of RTN spectrum on sleep. Twenty-one volunteers slept three nights in a sleep laboratory in three sound conditions: low-frequency (LF) RTN, high-frequency (HF) RTN, and quiet (control). The A-weighted equivalent levels were 37, 37, and 17 dB LAeq,8h, respectively. The nocturnal time profiles of LF and HF were equal. Sleep was measured with polysomnography and questionnaires. HF and LF did not differ from each other in respect to their effects on both objective and subjective sleep quality. The duration of deep sleep was shorter, satisfaction with sleep lower, and subjective sleep latency higher in HF and LF than in quiet. Contrary to subjective ratings given right after the slept night, HF was rated as the most disturbing condition for sleep after the whole experiment (retrospective rating). The finding suggests the sound insulation spectrum of the facade construction might play a role regarding the effects of RTN. More research is needed about the effects of spectrum on sleep because the field is very little investigated

Ion beam shaping and downsizing of nanostructures

We report a new approach for progressive and well-controlled downsizing of nanostructures below the 10 nm scale. Low energetic ion beam (Ar+) is used for gentle surface erosion, progressively shrinking the dimensions with ~ 1 nm accuracy. The method enables shaping of nanostructure geometry and polishing the surface. The process is clean room / high vacuum compatible being suitable for various applications. Apart from technological advantages, the method enables study of various size phenomena on the same sample between sessions of ion beam treatment.Comment: 14 pages, 6 figure

Coherent quantum phase slip

A hundred years after discovery of superconductivity, one fundamental prediction of the theory, the coherent quantum phase slip (CQPS), has not been observed. CQPS is a phenomenon exactly dual to the Josephson effect: whilst the latter is a coherent transfer of charges between superconducting contacts, the former is a coherent transfer of vortices or fluxes across a superconducting wire. In contrast to previously reported observations of incoherent phase slip, the CQPS has been only a subject of theoretical study. Its experimental demonstration is made difficult by quasiparticle dissipation due to gapless excitations in nanowires or in vortex cores. This difficulty might be overcome by using certain strongly disordered superconductors in the vicinity of the superconductor-insulator transition (SIT). Here we report the first direct observation of the CQPS in a strongly disordered indium-oxide (InOx) superconducting wire inserted in a loop, which is manifested by the superposition of the quantum states with different number of fluxes. Similarly to the Josephson effect, our observation is expected to lead to novel applications in superconducting electronics and quantum metrology.Comment: 14 pages, 3 figure

Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201

JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length

C-Jun NH2-terminal kinases (JNKs) are essential during brain development, when they regulate morphogenic changes involving cell movement and migration. In the adult, JNK determines neuronal cytoarchitecture. To help uncover the molecular effectors for JNKs in these events, we affinity purified JNK-interacting proteins from brain. This revealed that the stathmin family microtubule-destabilizing proteins SCG10, SCLIP, RB3, and RB3' interact tightly with JNK. Furthermore, SCG10 is also phosphorylated by JNK in vivo on sites that regulate its microtubule depolymerizing activity, serines 62 and 73. SCG10-S73 phosphorylation is significantly decreased in JNK1-/- cortex, indicating that JNK1 phosphorylates SCG10 in developing forebrain. JNK phosphorylation of SCG10 determines axodendritic length in cerebrocortical cultures, and JNK site-phosphorylated SCG10 colocalizes with active JNK in embryonic brain regions undergoing neurite elongation and migration. We demonstrate that inhibition of cytoplasmic JNK and expression of SCG10-62A/73A both inhibited fluorescent tubulin recovery after photobleaching. These data suggest that JNK1 is responsible for regulation of SCG10 depolymerizing activity and neurite elongation during brain development

Workplace productivity and office type: an evaluation of office occupier differences based on age and gender

Purpose Open plan office environments are considered to offer workplace productivity benefits because of the opportunities that they create for interaction and knowledge exchange, but more recent research has highlighted noise, distraction and loss of privacy as significant productivity penalties with this office layout. This study aims to investigate if the purported productivity benefits of open plan outweigh the potential productivity penalties. Design/methodology/approach Previous research suggests that office environments are experienced differently according to the gender and age of the occupier across both open-plan and enclosed configurations. Empirical research undertaken with office occupiers in the Middle East (N=220) led to evaluations to establish the impact different offices had on perceived productivity. Factor analysis was used to establish five underlying components of office productivity. The five factors are subsequently used as the basis for comparison between office occupiers based on age, gender and office type. Findings This research shows that benefits and penalties to workplace productivity are experienced equally across open-plan and enclosed office environments. The greatest impact on perceived workplace productivity however was availability of a variety of physical layouts, control over interaction and the 'downtime' offered by social interaction points. Male occupiers and those from younger generations were also found to consider the office environment to have more of a negative impact on their perceived workplace productivity compared to female and older occupiers. Originality/value The originality of this paper is that it develops the concept of profiling office occupiers with the aim of better matching office provision. This paper aims to establish different occupier profiles based on age, gender and office type. Data analysis techniques such as factor analysis and t-test analysis identify the need for different spaces so that occupiers can choose the most appropriate space to best undertake a particular work task. In addition, it emphasises the value that occupiers place on ‘downtime’ leading to the need for appropriate social space

A review of mid-frequency vibro-acoustic modelling for high-speed train extruded aluminium panels as well as the most recent developments in hybrid modelling techniques

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer

Dynamin I phosphorylation by GSK3 controls activity-dependent bulk endocytosis of synaptic vesicles.

Glycogen synthase kinase 3 (GSK3) is a critical enzyme in neuronal physiology; however, it is not yet known whether it has any specific role in presynaptic function. We found that GSK3 phosphorylates a residue on the large GTPase dynamin I (Ser-774) both in vitro and in primary rat neuronal cultures. This was dependent on prior phosphorylation of Ser-778 by cyclin-dependent kinase 5. Using both acute inhibition with pharmacological antagonists and silencing of expression with short hairpin RNA, we found that GSK3 was specifically required for activity-dependent bulk endocytosis (ADBE) but not clathrin-mediated endocytosis. Moreover we found that the specific phosphorylation of Ser-774 on dynamin I by GSK3 was both necessary and sufficient for ADBE. These results demonstrate a presynaptic role for GSK3 and they indicate that a protein kinase signaling cascade prepares synaptic vesicles for retrieval during elevated neuronal activity

Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

BACKGROUND: Glycogen Synthase Kinase-3 (GSK-3) \u3b1 and \u3b2 are two serine-threonine kinases controlling insulin, Wnt/\u3b2-catenin, NF-\u3baB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK-3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3\u3b1 and GSK-3\u3b2 function in multiple myeloma (MM). METHODS: GSK-3 \u3b1 and \u3b2 expression and cellular localization were investigated by Western blot (WB) and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 \u3b1 and \u3b2 isoforms. Survival signaling pathways were studied with WB analysis. RESULTS: GSK-3\u3b1 and GSK-3\u3b2 were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles: GSK-3\u3b2 knock down decreased MM cell viability, while GSK-3\u3b1 knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of \u3b2-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3\u3b1 knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself. CONCLUSIONS: These data suggest that in MM cells GSK-3\u3b1 and \u3b2 i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors

Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance