HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation

Mitophagy is thought to play a key role in eliminating damaged mitochondria, with diseases such as cancer and neurodegeneration exhibiting defects in this process. Mitophagy is also involved in cell differentiation and maturation, potentially through modulating mitochondrial metabolic reprogramming. Here we examined mitophagy that is induced upon iron chelation and found that the transcriptional activity of HIF1α, in part through upregulation of BNIP3 and NIX, is an essential mediator of this pathway in SH-SY5Y cells. In contrast, HIF1α is dispensable for mitophagy occurring upon mitochondrial depolarisation. To examine the role of this pathway in a metabolic reprogramming and differentiation context, we utilised the H9c2 cell line model of cardiomyocyte maturation. During differentiation of these cardiomyoblasts, mitophagy increased and required HIF1a-dependent upregulation of NIX. Though HIF1a was essential for expression of key cardiomyocyte markers, mitophagy was not directly required. However, enhancing mitophagy through NIX overexpression, accelerated marker gene expression. Taken together, our findings provide a molecular link between mitophagy signalling and cardiomyocyte differentiation and suggest that although mitophagy may not be essential per se, it plays a critical role in maintaining mitochondrial integrity during this energy demanding process.</p

Normalised Root Mean Square and Amplitude of Sidebands of Vibration Response as Tools for Gearbox Diagnosis

Quick assessment of the condition of gearboxes used in helicopters is a safety requirement. One of the most widely used helicopter on-board-mounted condition monitoring system these days is the Health and Usage Monitoring System. It has been specifically designed to monitor the condition of all safety-critical components operating in the helicopter through calculation of so-called condition indicators (CIs) - signal processing routines designed to output a single number that represents the condition of the monitored component. Among number of available parameters, there is a couple of CIs that over the years of testing have earned a reputation of being the most reliable measures of the gear tooth condition. At the same time, however, it has been observed that in some cases, those techniques do not properly indicate the deteriorating condition with the propagation of a gear tooth fault with the period of operation. Hence, three more robust methods have been suggested, which are discussed in this article

Expand+Functional selection and systematic analysis of intronic splicing elements identify active sequence motifs and associated splicing factors

Despite the critical role of pre-mRNA splicing in generating proteomic diversity and regulating gene expression, the sequence composition and function of intronic splicing regulatory elements (ISREs) have not been well elucidated. Here, we employed a high-throughput in vivo Screening PLatform for Intronic Control Elements (SPLICE) to identify 125 unique ISRE sequences from a random nucleotide library in human cells. Bioinformatic analyses reveal consensus motifs that resemble splicing regulatory elements and binding sites for characterized splicing factors and that are enriched in the introns of naturally occurring spliced genes, supporting their biological relevance. In vivo characterization, including an RNAi silencing study, demonstrate that ISRE sequences can exhibit combinatorial regulatory activity and that multiple trans-acting factors are involved in the regulatory effect of a single ISRE. Our work provides an initial examination into the sequence characteristics and function of ISREs, providing an important contribution to the splicing code

Mammalian mitophagy – from <i>in vitro</i> molecules to <i>in vivo</i> models

The autophagic turnover of mitochondria, termed mitophagy, is thought to play an essential role in not only maintaining the health of the mitochondrial network, but also that of the cell and organism as a whole. We have come a long way in identifying the molecular components required for mitophagy through extensive in vitro work and cell line characterisation, yet the physiological significance and context of these pathways remains largely unexplored. This is highlighted by the recent development of new mouse models that have revealed a striking level of variation in mitophagy, even under normal conditions. Here we focus on programmed mitophagy and summarise our current understanding of why, how and where this takes place in mammals

Blocking neutrophil integrin activation prevents ischemia-reperfusion injury.

Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia-reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin's capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia-reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin-mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin-mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia-reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable

Ultra-broadband photon pair preparation by spontaneous four wave mixing in dispersion-engineered optical fiber

We present a study of the spectral properties of photon pairs generated through the process of spontaneous four wave mixing (SFWM) in single mode fiber. Our analysis assumes narrowband pumps, which are allowed to be frequency-degenerate or non-degenerate. Based on this analysis, we derive conditions on the pump frequencies and on the fiber dispersion parameters which guarantee the generation of ultra-broadband photon pairs. Such photon pairs are characterized by: i) a very large degree of entanglement, and ii) a very high degree of temporal synchronization between the signal and idler photons. Through a numerical exercise, we find that the use of photonic crystal fiber (PCF) facilitates the fulfilment of the conditions for ultra-broadband photon pair generation; in particular, the spectral region in which emission occurs can be adjusted to particular needs through an appropriate choice of the PCF parameters. In addition, we present a novel quantum interference effect, resulting from indistinguishable pathways to the same outcome, which can occur when pumping a SFWM source with multiple spectral lines.Comment: 15 pages, 10 figures. To be published in Phys. Rev.

Quantifying hiss-driven energetic electron precipitation: A detailed conjunction event analysis

Abstract We analyze a conjunction event between the Van Allen Probes and the low-altitude Polar Orbiting Environmental Satellite (POES) to quantify hiss-driven energetic electron precipitation. A physics-based technique based on quasi-linear diffusion theory is used to estimate the ratio of precipitated and trapped electron fluxes (R), which could be measured by the two-directional POES particle detectors, using wave and plasma parameters observed by the Van Allen Probes. The remarkable agreement between modeling and observations suggests that this technique is applicable for quantifying hiss-driven electron scattering near the bounce loss cone. More importantly, R in the 100-300 keV energy channel measured by multiple POES satellites over a broad L magnetic local time region can potentially provide the spatiotemporal evolution of global hiss wave intensity, which is essential in evaluating radiation belt electron dynamics, but cannot be obtained by in situ equatorial satellites alone. Key Points Measured and calculated hiss Bw from POES electron measurements agree well Electron ratio measured by POES is able to estimate hiss wave intensity This technique can be used to provide global hiss wave distributio

High-resolution Near-Infrared Images and Models of the Circumstellar Disk in HH 30

We present Hubble Space Telescope (HST) Near-Infrared Camera and Multi-object Spectrometer (NICMOS) observations of the reflection nebulosity associated with the T Tauri star HH 30. The images show the scattered light pattern characteristic of a highly inclined, optically thick disk with a prominent dustlane whose width decreases with increasing wavelength. The reflected nebulosity exhibits a lateral asymmetry in the upper lobe on the opposite side to that reported in previously published Wide Field Planetary Camera 2 (WFPC2) images. The radiation transfer model which most closely reproduces the data has a flared accretion disk with dust grains larger than standard interstellar medium grains by a factor of approximately 2.1. A single hotspot on the stellar surface provides the necessary asymmetry to fit the images and is consistent with previous modeling of the light curve and images. Photometric analysis results in an estimated extinction of Av>~80; however, since the photometry measures only scattered light rather than direct stellar flux, this a lower limit. The radiative transfer models require an extinction of Av = 7,900.Comment: Accepted for publication in Ap.

The reliability of two visual motor integration tests used with children

Occupational therapists often assess the visual motor integration (VMI) skills of children and young people. It is important that therapists use tools with strong psychometric properties. This study aims to examine the reliability of 2 VMI tests. Ninety-two children between the ages of 5 and 17 years (response rate of 31%) completed 2 VMI tests: the Developmental Test of Visual Motor Integration (DTVMI) and the Full Range Test of Visual Motor Integration (FRTVMI). Cronbach\u27s alpha coefficient was used to examine the internal consistency of the 2 VMI tests whereas Spearman\u27s rho correlation was used to evaluate the test&ndash;retest reliability, intrarater reliability, and interrater reliability of the 2 VMI tests. The Cronbach\u27s alpha coefficient for the DTVMI was .82 and .72 for the FRTVMI. The test&ndash;retest reliability coefficient was .73 (p = .000) for the DTVMI and .49 (p = .05) for the FRTVMI. The interrater correlation was significant for both the DTVMI at .94 (p = .000) and FRTVMI at .68 (p = .001). The DTVMI intrarater reliability correlation result was .90 (p = .000) and the FRTVMI at .85 (p = .000). Overall, the DTVMI exhibited a higher level of reliability than the FRTVMI. Both VMI tests appear to exhibit reasonable levels of reliability and are recommended for use with children and young people.<br /

Ruthenium polypyridyl complexes and their modes of interaction with DNA : is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy) L1L2](2-n)?, and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}2{l-H2N(CH2)6NH2}]4?. The ligand tpy is 2,20:60,200-terpyridine and the ligand L1 is a bidentate ligand, namely, apy (2,20-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L2 is a labile monodentate ligand, being Cl-, H2O, or CH3CN. All six species containing a labile L2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds