Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death

LHC Searches for Non-Chiral Weakly Charged Multiplets

Because the TeV-scale to be probed at the Large Hadron Collider should shed light on the naturalness, hierarchy, and dark matter problems, most searches to date have focused on new physics signatures motivated by possible solutions to these puzzles. In this paper, we consider some candidates for new states that although not well-motivated from this standpoint are obvious possibilities that current search strategies would miss. In particular we consider vector representations of fermions in multiplets of $SU(2)_L$ with a lightest neutral state. Standard search strategies would fail to find such particles because of the expected small one-loop-level splitting between charged and neutral states.Comment: 16 pages, 9 figure

Ruthenium-cyclopentadienyl bipyridine-biotin based compounds: Synthesis and biological effect

Prospective anticancer metallodrugs should consider target-specific components in their design in order to overcome the limitations of the current chemotherapeutics. The inclusion of vitamins, which receptors are overexpressed in many cancer cell lines, has proven to be a valid strategy. Therefore, in this paper we report the synthesis and characterization of a set of new compounds [Ru(eta(5)-C5H5)(P(C6H4R)(3))(4,4'-R'-2,2'-bpy)](+) (R = F and R' = H, 3; R = F and R' = biotin, 4; R = OCH3 and R' = H, 5; R = OCH3 and R' = biotin, 6), inspired by the exceptional good results recently obtained for the analogue bearing a triphenylphosphane ligand. The precursors for these syntheses were also described following modified literature procedures, [Ru(eta(5)-C5H3)(P(C6H4R)(3))(2)Cl], where R is -F (1) or -OCH3 (2). The structure of all compounds is fully supported by spectroscopic and analytical techniques and by X-ray diffraction studies for compounds 2, 3, and 5. All cationic compounds are cytotoxic in the two breast cancer cell lines tested, MCF7 and MDA-MB-231, and much better than cisplatin under the same experimental conditions. The cytotoxicity of the biotinylated compounds seems to be related with the Ru uptake by the cells expressing biotin receptors, indicating a potential mediated uptake. Indeed, a biotin-avidin study confirmed that the attachment of biotin to the organometallic fragment still allows biotin recognition by the protein. Therefore, the biotinylated compounds might be potent anticancer drugs as they show cytotoxic effect in breast cancer cells at low dose dependent on the compounds' uptake, induce cell death by apoptosis and inhibit the colony formation of cancer cells causing also less severe side effects in zebrafish.This work was financed by the Portuguese Foundation for Science and Technology (Fundacao para a Crencia e Tecnologia, FCT) within the scope of Projects UID/QUI/00100/2019 and PTDC/QUI-QIN/28662/2017. This work was supported by the strategic program UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF through the COMPETE2020 -Programa Operacional Competitividade e Intemacionalizacao (POCI). A.V. acknowledges the Investigator FCT2013 Initiative for the Project IF/01302/2013 and CEEC-IND/01974/2017 (acknowledging FCT, as well as POPH and FSE, the European Social Fund). L.C.-R, A.R.B. and A.P. thank FCT for their Ph.D. Grants (SFRH/BD/100515/2014, SFRH/BD/139271/2018, and SFRH/BD/139412/2018, respectively). L.C.-R also acknowledges Fulbright Research Grant 2017/2018 with the support of FCT. Brittany Karas acknowledges NJAES-RutgersNJ01201 and NIEHS Training Grant T32-ES 007148 and B.T.B. and C.D. acknowledge NIH-NIEHS P30 ES005022. K.R.C. acknowledges NJAES Project 01202 (W2045) and NIH ES005022

Teagasc submission made in response to the Consultation Paper on Interim Review of Ireland’s Nitrates Derogation 2019

Teagasc SubmissionSubmission to governmentThis submission was made in response to the consultation process run jointly by the Department of Housing, Planning, Community and Local Government (DHPCLG) and the Department of Agriculture, Food and the Marine (DAFM) inviting views and comments on proposals for the Interim Review of Ireland’s Nitrates Derogation Programme in 2019. It has been prepared by Teagasc’s Water Quality Working Group in consultation with the Gaseous Emissions Working Group. These working groups have members drawn from both the Knowledge Transfer and Research Directorates of Teagasc. It was prepared following consultation with colleagues across Teagasc using their collective knowledge and expertise in agri-environmental science and practice and the implementation of the Good Agricultural Practice (GAP) and Nitrates Derogation Regulations.https://www.teagasc.ie/publications/2019/teagasc-submission-made-in-response-to-the-consultation-paper-on-interim-review-of-irelands-nitrates-derogation-2019.ph

UBVRI Light Curves of 44 Type Ia Supernovae

We present UBVRI photometry of 44 type-Ia supernovae (SN Ia) observed from 1997 to 2001 as part of a continuing monitoring campaign at the Fred Lawrence Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics. The data set comprises 2190 observations and is the largest homogeneously observed and reduced sample of SN Ia to date, nearly doubling the number of well-observed, nearby SN Ia with published multicolor CCD light curves. The large sample of U-band photometry is a unique addition, with important connections to SN Ia observed at high redshift. The decline rate of SN Ia U-band light curves correlates well with the decline rate in other bands, as does the U-B color at maximum light. However, the U-band peak magnitudes show an increased dispersion relative to other bands even after accounting for extinction and decline rate, amounting to an additional ~40% intrinsic scatter compared to B-band.Comment: 84 authors, 71 pages, 51 tables, 10 figures. Accepted for publication in the Astronomical Journal. Version with high-res figures and electronic data at http://astron.berkeley.edu/~saurabh/cfa2snIa

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Harmonization and standardization of nucleus pulposus cell extraction and culture methods

BACKGROUND: In vitro studies using nucleus pulposus (NP) cells are commonly used to investigate disc cell biology and pathogenesis, or to aid in the development of new therapies. However, lab-to-lab variability jeopardizes the much-needed progress in the field. Here, an international group of spine scientists collaborated to standardize extraction and expansion techniques for NP cells to reduce variability, improve comparability between labs and improve utilization of funding and resources. METHODS: The most commonly applied methods for NP cell extraction, expansion, and re-differentiation were identified using a questionnaire to research groups worldwide. NP cell extraction methods from rat, rabbit, pig, dog, cow, and human NP tissue were experimentally assessed. Expansion and re-differentiation media and techniques were also investigated. RESULTS: Recommended protocols are provided for extraction, expansion, and re-differentiation of NP cells from common species utilized for NP cell culture. CONCLUSIONS: This international, multilab and multispecies study identified cell extraction methods for greater cell yield and fewer gene expression changes by applying species-specific pronase usage, 60-100 U/ml collagenase for shorter durations. Recommendations for NP cell expansion, passage number, and many factors driving successful cell culture in different species are also addressed to support harmonization, rigor, and cross-lab comparisons on NP cells worldwide

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

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