RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

280 one-opposition near-Earth asteroids recovered by the EURONEAR with the <i>Isaac Newton</i> Telescope

Context. One-opposition near-Earth asteroids (NEAs) are growing in number, and they must be recovered to prevent loss and mismatch risk, and to improve their orbits, as they are likely to be too faint for detection in shallow surveys at future apparitions. Aims. We aimed to recover more than half of the one-opposition NEAs recommended for observations by the Minor Planet Center (MPC) using the Isaac Newton Telescope (INT) in soft-override mode and some fractions of available D-nights. During about 130 h in total between 2013 and 2016, we targeted 368 NEAs, among which 56 potentially hazardous asteroids (PHAs), observing 437 INT Wide Field Camera (WFC) fields and recovering 280 NEAs (76% of all targets). Methods. Engaging a core team of about ten students and amateurs, we used the THELI, Astrometrica, and the Find_Orb software to identify all moving objects using the blink and track-and-stack method for the faintest targets and plotting the positional uncertainty ellipse from NEODyS. Results. Most targets and recovered objects had apparent magnitudes centered around V ~ 22.8 mag, with some becoming as faint as V ~ 24 mag. One hundred and three objects (representing 28% of all targets) were recovered by EURONEAR alone by Aug. 2017. Orbital arcs were prolonged typically from a few weeks to a few years; our oldest recoveries reach 16 years. The O−C residuals for our 1854 NEA astrometric positions show that most measurements cluster closely around the origin. In addition to the recovered NEAs, 22 000 positions of about 3500 known minor planets and another 10 000 observations of about 1500 unknown objects (mostly main-belt objects) were promptly reported to the MPC by our team. Four new NEAs were discovered serendipitously in the analyzed fields and were promptly secured with the INT and other telescopes, while two more NEAs were lost due to extremely fast motion and lack of rapid follow-up time. They increase the counting to nine NEAs discovered by the EURONEAR in 2014 and 2015. Conclusions. Targeted projects to recover one-opposition NEAs are efficient in override access, especially using at least two-meter class and preferably larger field telescopes located in good sites, which appear even more efficient than the existing surveys

Emerging strategies for regeneration of historic urban sites:a systematic literature review

The importance and effectiveness of adaptive reuse as an alternative to the demolition of cultural heritage is well-studied. However, increasing demand in cities to redevelop larger scale urban historic sites requires new strategies to benefit from their inherent values. This paper focuses on strategies of regeneration for historic urban sites. The paper presents a systematic literature review of 45 papers, with case studies geographically concentrated in Europe and Asia, and a focus on residential, commercial, and industrial areas. From the case studies, 46 different regeneration strategies have been deduced. The various strategies are, via content analysis, dissected into a select number of drivers to find commonalities. These key drivers are user participation, top-down, genius loci, sustainability, and conversion. Based on the reflections of the reviewed authors, a performance evaluation assesses the outcomes of these strategies. Further data analysis is conducted at the level of individual drivers as well as their combinations to deduce the most positive-evaluated strategies. Findings show that genius loci contributes to the most positive-evaluated strategies, while top-down driven strategies contribute to the most negative-evaluated strategies. Furthermore, strategies are assessed positively when three or more drivers are considered regardless of their combination. This paper acts as a starting point for further research into the formation of regeneration strategies and into the specific drivers and their combinations or underlying relations. Moreover, it can be of contribution to the practice, to support decision makers and urban planners in developing the appropriate regeneration strategy for historic urban sites

Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1