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The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS. [ABSTRACT FROM AUTHOR]

The Cradle of Humankind (Cradle) in South Africa preserves a rich collection of fossil hominins representing Australopithecus, Paranthropus and Homo.sup.1. The ages of these fossils are contentious.sup.2-4 and have compromised the degree to which the South African hominin record can be used to test hypotheses of human evolution. However, uranium-lead (U-Pb) analyses of horizontally bedded layers of calcium carbonate (flowstone) provide a potential opportunity to obtain a robust chronology.sup.5. Flowstones are ubiquitous cave features and provide a palaeoclimatic context, because they grow only during phases of increased effective precipitation.sup.6,7, ideally in closed caves. Here we show that flowstones from eight Cradle caves date to six narrow time intervals between 3.2 and 1.3 million years ago. We use a kernel density estimate to combine 29 U-Pb ages into a single record of flowstone growth intervals. We interpret these as major wet phases, when an increased water supply, more extensive vegetation cover and at least partially closed caves allowed for undisturbed, semi-continuous growth of the flowstones. The intervening times represent substantially drier phases, during which fossils of hominins and other fossils accumulated in open caves. Fossil preservation, restricted to drier intervals, thus biases the view of hominin evolutionary history and behaviour, and places the hominins in a community of comparatively dry-adapted fauna. Although the periods of cave closure leave temporal gaps in the South African fossil record, the flowstones themselves provide valuable insights into both local and pan-African climate variability. Climate-driven periodicity of flowstone accretion between 3.2 and 1.3 million years ago in Cradle of Humankind caves reveals that the presence of hominin fossils reflects accumulation in open caves during intermittent, substantially drier phases., Author(s): Robyn Pickering [sup.1] [sup.2] , Andy I. R. Herries [sup.3] [sup.4] , Jon D. Woodhead [sup.5] , John C. Hellstrom [sup.5] , Helen E. Green [sup.5] , Bence Paul [...]

There are many processes that affect the measured concentration of elements determined by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Depending on the element of interest, a range of corrections are required to account for sensitivity drift and downhole effects, as well as other sources of inaccuracy. Here, we present a new method of calibrating LA-ICP-MS measurements taking into consideration time-dependent sensitivity changes to produce a three-dimensional calibration surface through time. These 3D calibration surfaces result in up to 20% improvements in our example dataset for some elements. To ensure calibration surfaces that are created using multiple reference materials are not degraded by matrix effects a median yield correction factor is determined relative to a primary reference material. We also introduce sensitivity modelling for elements without accepted values or where interferences may affect calibration. In addition to the correction of drift, we further demonstrate a correction for downhole fractionation effects can improve the precision of spot analyses by up to 20% in our example dataset. A flexible solution to the sum normalisation approach is briefly introduced for calibration of multi-phase samples using different calibration parameters, along with a residual correction based on compositional affinity to a reference material. Combined, these new methodologies can improve the accuracy and precision of concentration determinations by LA-ICP-MS in a wide variety of applications. [ABSTRACT FROM AUTHOR]

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis of μ-droplets is becoming an attractive alternative for detecting and quantifying elements in biological samples. With minimal sample preparation required and detection limits comparable to solution nebulisation ICP-MS, μ-droplets have substantial advantages over traditional elemental detection, particularly for low volumes, such as aliquots taken from samples required for multiple independent biochemical assays, or fluids and tissues where elements of interest exist at native concentrations not suited to the necessary dilution steps required for solution nebulisation ICP-MS. However, the characteristics of μ-droplet residue deposition are heavily dependent on the matrix, and potential effects on signal suppression or enhancement have not been fully characterised. We present a validated and flexible high-throughput method for quantification of elements in μ-droplets using LA-ICP-MS imaging and matrix-matched external calibrants. Imaging the entire μ-droplet area removes analytical uncertainty arising from the often-heterogenous distribution when compared to radial or bisecting line scans that capture only a small portion of the droplet residue. We examined the effects of common matrices found in a standard biochemistry workflow, including native protein and salt contents, as well as reagents used in typical preparation steps for concurrent biochemical assays, such as total protein quantification and enzyme activity assays. We found that matrix composition results in systemic, concentration-dependent signal enhancement and suppression for carbon, whereas high sodium content has a specific space-charge-like suppression effect on high masses. We confirmed the accuracy of our method using both a certified serum standard (Seronorm™ L1) and independent measurements of analysed samples by solution nebulisation ICP-MS, then tested the specificity and reproducibility by examining spinal cord tissue homogenates from SOD1-G93A transgenic mice with a known molecular phenotype of increased copper- and zinc-binding superoxide dismutase-1 expression and altered copper-to-zinc stoichiometry. The method presented is rapid and transferable to multiple other biological matrices and allows high-throughput analysis of low-volume samples with sensitivity comparable to standard solution nebulisation ICP-MS protocols.ᅟ [ABSTRACT FROM AUTHOR]

The double-spike approach for correction of instrumental mass bias in mass spectrometry data is well established. However, there is very little consistency within the scientific community in terms of double-spike data reduction. Double-spike solutions require computer calculation, using either geometric or algebraic approaches, and are often performed using spreadsheet calculations that vary from group to group and between isotope systems. Here, we present IsoSpike, a generalised computer procedure for the processing of double-spike mass spectrometry data, built as an add-on for the Iolite data-reduction package (). Use of this software permits visualisation of mass spectrometry data in a time window, and rigorous treatment and screening of data. Additionally, IsoSpike uses an integration-by-integration approach where the double-spike calculations are performed on every integration within an analysis, providing straightforward quantification of uncertainties on double-spike-corrected isotope ratios. The advantages of this approach over traditional methods are discussed here. Platinum stable isotope data are presented as an example data set, although the procedure is applicable to any double-spike system. IsoSpike is freely available from . [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound Cu II (atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with Cu II (atsm) showing initial promise., Competing Interests: Declaration of competing interest Collaborative Medicinal Development has licensed intellectual property pertaining to Cu(II)(atsm) from the University of Melbourne where the inventors include ARW and PSD. AIB is a paid consultant for Collaborative Medicinal Development LLC and has a profit share interest in Collaborative Medicinal Development Pty Ltd. PJC and JSB are unpaid consultants for Collaborative Medicinal Development LLC. DJH received research and material support from Agilent Technologies and ESI Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)