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The Heslington brain. (a) All orifices of the dark skull were tightly covered with mud; (b) shows the skull base with the foramen magnum. Illumination of the inner part of the skull as seen through the foramen magnum is shown in the inlay; (c) after opening the skull the sediment covered structure remained intact; (d ) these structures resemble a shrunken brain covered with muddy sediment; (e) careful removal of the sediment uncovers a surface resembling the gyri of a human brain. (Online version in colour.)

The Heslington brain. (a) All orifices of the dark skull were tightly covered with mud; (b) shows the skull base with the foramen magnum. Illumination of the inner part of the skull as seen through the foramen magnum is shown in the inlay; (c) after opening the skull the sediment covered structure remained intact; (d ) these structures resemble a shrunken brain covered with muddy sediment; (e) careful removal of the sediment uncovers a surface resembling the gyri of a human brain. (Online version in colour.)

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Human proteins have not been reported to survive in free nature, at ambient temperature, for long periods. Particularly, the human brain rapidly dissolves after death due to auto-proteolysis and putrefaction. The here presented discovery of 2600-year-old brain proteins from a radiocarbon dated human brain provides new evidence for extraordinary lon...

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... The success of brain preservation is likely due to the formation of protein aggregates that provide protection against degradation. 422,424 While soft tissues still remain relatively rare in comparison to other sample types, protein markers for health, age, and life history could potentially be developed. ...
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Paleoproteomics, the study of ancient proteins, is a rapidly growing field at the intersection of molecular biology, paleontology, archaeology, paleoecology, and history. Paleoproteomics research leverages the longevity and diversity of proteins to explore fundamental questions about the past. While its origins predate the characterization of DNA, it was only with the advent of soft ionization mass spectrometry that the study of ancient proteins became truly feasible. Technological gains over the past 20 years have allowed increasing opportunities to better understand preservation, degradation, and recovery of the rich bioarchive of ancient proteins found in the archaeological and paleontological records. Growing from a handful of studies in the 1990s on individual highly abundant ancient proteins, paleoproteomics today is an expanding field with diverse applications ranging from the taxonomic identification of highly fragmented bones and shells and the phylogenetic resolution of extinct species to the exploration of past cuisines from dental calculus and pottery food crusts and the characterization of past diseases. More broadly, these studies have opened new doors in understanding past human-animal interactions, the reconstruction of past environments and environmental changes, the expansion of the hominin fossil record through large scale screening of nondiagnostic bone fragments, and the phylogenetic resolution of the vertebrate fossil record. Even with these advances, much of the ancient proteomic record still remains unexplored. Here we provide an overview of the history of the field, a summary of the major methods and applications currently in use, and a critical evaluation of current challenges. We conclude by looking to the future, for which innovative solutions and emerging technology will play an important role in enabling us to access the still unexplored "dark" proteome, allowing for a fuller understanding of the role ancient proteins can play in the interpretation of the past.
... The hook effect is partially caused by the formation of protein aggregates that contribute to the extraordinary long-term stability of GFAP. These aggregates can last for millennia at ambient temperature, as exemplified by the Heslington brain 31 . The formation of pathological GFAP aggregates in vivo can accompany lethal neurological disorders such as Alexander disease 2 . ...
Article
Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.
... For the analysis of sNfL using Simoa SR-X technology, the consequence of a deviation from standard procedure (i.e. processing blood immediately and freezing at − 70; single use of aliquots) has not been reported to this extent and in three different cohorts [16][17][18] . Therefore, we studied two important and mutable pre-analytic variables: the effect of delayed freezing (up to 24 h) and repeated thawing and re-freezing (up to three cycles). ...
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Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24 h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24 h (mean absolute difference 0.2 pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7 pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4–8 °C when samples are frozen within 24 h and single aliquots can be used up to three times. These observations should be considered for planning future studies.
... Yet remarkably, the statement is false. The true curiosity lies in why the brain seems to be the most commonly preserved soft tissue in ancient human remains and, moreover, why it preserves such an extensive proteome (Petzold et al. 2020). ...
... Proteomic data from both the Heslington brain (Petzold et al. 2020) and that of the Iceman (Maixner et al. 2013) offer quantitative information, which is essential for statistical analyses addressing cross contamination and other sources of bias, as well as for empirical validation of spurious findings. Limited by being qualitative and ambiguous, we argue that the proteomic data as reported by Petrone et al. (2020) do not support their conclusion that the find unambiguously represents human brain tissue. ...
... Likewise, the near simultaneous publication of reports on preserved ancient brain tissue (Petrone et al. 2020;Petzold et al. 2020) calls attention to our current lack of understanding of the means by which neural tissues preserve in the archaeological record. In this respect, we welcome the study of Petrone et al. (2020), which both highlights the importance of combining proteomic and lipidomic investigation with analyses of associated skeletal material, and raises the intriguing prospect of a potential role for vitrification in the preservation of ancient biomolecules. ...
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Brain tissue is ubiquitous in the archaeological record. Multiple, independent studies report the finding of black, resinous or shiny brain tissue, and Petrone et al. [2020 "Heat-induced Brain Vitrification from the Vesuvius Eruption in C.E. 79." N Engl J Med. 382: 383-384; doi:10.1056/ NEJMc1909867] raise the intriguing prospect of a role for vitrification in the preservation of ancient biomolecules. However, Petrone et al. (2020) have not made their raw data available, and no detailed laboratory or analytical methodology is offered. Issues of contamination and misinterpretation hampered a decade of research in biomolecular archaeology, such that addressing these sources of bias and facilitating validation of specious findings has become both routine and of paramount importance in the discipline. We argue that the evidence they present does not support their conclusion of heat-induced vitrification of human brain tissue, and that future studies should share palaeoproteomic data in an open access repository to facilitate comparative analysis of the recovery of ancient proteins and patterns of their degradation.
... 105 Pioneering research on the preserved brain matter in an Iron Age skull may also be instrumental in helping doctors better understand the formation of debilitating brain plaques. 106 Particularly in cities, therefore, mindlessly bulldozing the past without analyzing the history first may mean burying a more healthy future. ...
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Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), α‐internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot‐Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of posttranslational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualizations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modeling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease. Likewise Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33 meta‐analyses on Nf body fluid levels. The review concludes with considerations for clinical trial design and an outlook for future research.