Stack-based Typed Assembly Language

In previous work, we presented a Typed Assembly Language (TAL). TAL is sufficiently expressive to serve as a target language for compilers of high-level languages such as ML. This work assumed such a compiler would perform a continuation-passing style transform and eliminate the control stack by heap-allocating activation records. However, most compilers are based on stack allocation. This paper presents STAL, an extension of TAL with stack constructs and stack types to support the stack allocation style. We show that STAL is sufficiently expressive to support languages such as Java, Pascal, and ML; constructs such as exceptions and displays; and optimizations such as tail call elimination and callee-saves registers. This paper also formalizes the typing connection between CPS-based compilation and stack-based compilation and illustrates how STAL can formally model calling conventions by specifying them as formal translations of source function types to STAL types.Engineering and Applied Science

Intensional Polymorphism in Type-erasure Semantics

Intensional polymorphism, the ability to dispatch to different routines based on types at run time, enables a variety of advanced implementation techniques for polymorphic languages, including tag-free garbage collection, unboxed function arguments, polymorphic marshalling, and flattened data structures. To date, languages that support intensional polymorphism have required a type-passing (as opposed to type-erasure) interpretation where types are constructed and passed to polymorphic functions at run time. Unfortunately, type-passing suffers from a number of drawbacks: it requires duplication of constructs at the term and type levels, it prevents abstraction, and it severely complicates polymorphic closure conversion.We present a type-theoretic framework that supports intensional polymorphism, but avoids many of the disadvantages of type passing. In our approach, run-time type information is represented by ordinary terms. This avoids the duplication problem, allows us to recover abstraction, and avoids complications with closure conversion. In addition, our type system provides another improvement in expressiveness; it allows unknown types to be refined in place thereby avoiding certain beta-expansions required by other frameworksEngineering and Applied Science

Generating Bijections between HOAS and the Natural Numbers

A provably correct bijection between higher-order abstract syntax (HOAS) and the natural numbers enables one to define a "not equals" relationship between terms and also to have an adequate encoding of sets of terms, and maps from one term family to another. Sets and maps are useful in many situations and are preferably provided in a library of some sort. I have released a map and set library for use with Twelf which can be used with any type for which a bijection to the natural numbers exists. Since creating such bijections is tedious and error-prone, I have created a "bijection generator" that generates such bijections automatically together with proofs of correctness, all in the context of Twelf.Comment: In Proceedings LFMTP 2010, arXiv:1009.218

Top ten discoveries of the year: Neurodegeneration

As we embark on a new year of scientific inquiry in neurodegenerative disease research, it is helpful to take a look back and consider the contributions in the field with the potential to be the most impactful. The purpose of this review is to highlight recent advances in 2019 which have the potential to be transformative in the field of neurodegenerative neuropathology. Substantive scientific progress rarely occurs as a “eureka moment”, and when possible, we opted to highlight collaborative efforts and research trends. We also included groundbreaking methodologies and tools. The generous increases in federal funding in the United States and elsewhere have massively expanded the total number of active programs researching Alzheimer’s disease. This exacerbates an imbalance, and an effort was made to highlight innovations across disease categories, and not to permit dementia to crowd out movement disorders, motor neuron disease, ataxias, etc. Thus, our overall goal was to highlight some of the most important discoveries, tools or methods that we feel will most likely directly enhance our ability to understand and diagnose neurodegenerative brain diseases. Given space limitations and the targeted readership of this journal, we selected ten topics most relevant to neuropathologists and clinical neuroscientists: 1. A new neurodegenerative disease category, 2. A new approach to probing gene expression on the single cell level, 3. A new approach merging histology and gene expression profiling, 4. A new computational approach using deep machine learning and computer vision, 5. A neuropathological substrate for sleep disturbance in Alzheimer’s disease, 6. A candidate pathogenic agent for Alzheimer’s disease, 7. A comprehensive approach to morphometric analysis of cerebellar neurodegeneration, 8. The strongest evidence yet linking neurodegeneration to contact sports, 9. Mounting evidence for gut to central nervous system transmission in Parkinson’s disease, and 10. A spotlight on glia in Huntington’s disease

Neurodegeneration: 2021 update

This article reviews a collection of manuscripts in the field of neurodegenerative disease chosen from what are considered by the author to be among the 10 most important and potentially impactful topics or research trends of 2020 relevant to the field of experimental and diagnostic neuropathology. A deliberate effort was made to provide balance among disease categories covered. The result is a varied selection that includes not just individual papers but also research topics and trends. The association of COVID-19 with longer-term neurological symptoms has launched a research trend fueled by speculation that the SARS-CoV-2 might trigger neurodegenerative changes. The onslaught of transcriptomic studies has begun to give way to proteomics, with three transformative studies published examining glial contributions to Alzheimer disease, cerebral atherosclerosis in cognitive decline, and the complex sequence of post-translational modifications of the tau protein. Plasma biomarkers for Alzheimer disease have continued to make rapid advances, especially around highly sensitive assays capable of detecting different forms of abnormal hyperphosphorylated tau in peripheral blood. Two studies using cryo-electron microscopy showed the power of the approach by continuing to elucidate the diversity of filamentous tau inclusions, and a third study gave the first glimpse of α-synuclein aggregates at near atomic resolution. Another study continued to delineate how different α-synuclein conformers (“strains”) target specific brain regions and lead to neurodegeneration. In Huntington’s disease, we saw compelling molecular data showing how cells adapt to endoplasmic reticulum stress through the unfolded protein response. Finally, the role of astrocytes in chronic traumatic encephalopathy has emerged as a critical area of interest

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies

Fishing Paper, 1819

Fishing paper for Benjamin Parks, Joseph Crary, Oliver Crary and John [Colcard?]. Joseph Crary was a fisherman out of Prospect, Me. Includes the entire proceeds from fishing for the year and expenses for each fisherman

Neurodegeneration: 2023 update

This paper reviews ten highly impactful studies published in the previous year selected by the author from the neurodegenerative neuropathology literature. As in previous years, the focus is to highlight human tissue-based experimentation most relevant to neuropathologists. A concerted effort was made to balance the selected studies across disease categories, approaches, and methodologies to capture the breadth of the research landscape. Studies include an integrated proteomic and transcriptomic study of Alzheimer disease (AD) and new consensus diagnostic neuropathological criteria for progressive supranuclear palsy. A number of studies looking at TAR DNA-binding protein 43 (TDP-43) are highlighted. One examined interaction between AD and limbic age-related TDP-43 encephalopathy (LATE) and yet another demonstrated how TDP-43 represses cryptic exon inclusion in UNC13A, suggesting a novel pathogenic mechanism. Most surprisingly, three cryogenic electron microscopy (cryo-EM) studies showed that TMEM106B filaments form the core of TDP-43-positive inclusions. Cryo-EM revealed a prion protein amyloid structure from aggregates in Gerstmann-Sträussler-Scheinker disease. There was an elegant functional genomic study cataloging microglial gene expression in the human brain. A study shed light on how APOE influences chronic traumatic encephalopathy. A pathoanatomical study tested the dual hit hypothesis of Lewy body progression throughout the nervous system. And finally, deep learning continues to show its promise with application of a weakly supervised multiple instance learning paradigm to assess aging post-mortem brains

Fluid preservation in brain banking: a review

Fluid preservation is nearly universally used in brain banking to store fixed tissue specimens for future research applications. However, the effects of long-term immersion on neural circuitry and biomolecules are not well characterized. As a result, there is a need to synthesize studies investigating fluid preservation of brain tissue. We searched PubMed and other databases to identify studies measuring the effects of fluid preservation in nervous system tissue. We categorized studies based on the fluid preservative used: formaldehyde solutions, buffer solutions, alcohol solutions, storage after tissue clearing, and cryoprotectant solutions. We identified 91 studies containing 197 independent observations of the effects of long-term storage on cellular morphology. Most studies did not report any significant alterations due to long-term storage. When present, the most frequent alteration was decreased antigenicity, commonly attributed to progressive crosslinking by aldehydes that renders biomolecules increasingly inaccessible over time. To build a mechanistic understanding, we discuss biochemical aspects of long-term fluid preservation. A subset of lipids appears to be chemical altered or extracted over time due to incomplete retention in the crosslinked gel. Alternative storage fluids mitigate the problem of antigen masking but have not been extensively characterized and may have other downsides. We also compare fluid preservation to cryopreservation, paraffin embedding, and resin embedding. Overall, existing evidence suggests that fluid preservation provides maintenance of neural architecture for decades, including precise structural details. However, to avoid the well-established problem of overfixation caused by storage in high concentration formaldehyde solutions, fluid preservation procedures can use an initial fixation step followed by an alternative long-term storage fluid. Further research is warranted on optimizing protocols and characterizing the generalizability of the storage artifacts that have been identified

Postmortem changes in brain cell structure: a review

Brain cell structure is a key determinant of neural function that is frequently altered in neurobiological disorders. Following the global loss of blood flow to the brain that initiates the postmortem interval (PMI), cells rapidly become depleted of energy and begin to decompose. To ensure that our methods for studying the brain using autopsy tissue are robust and reproducible, there is a critical need to delineate the expected changes in brain cell morphometry during the PMI. We searched multiple databases to identify studies measuring the effects of PMI on the morphometry (i.e. external dimensions) of brain cells. We screened 2119 abstracts, 361 full texts, and included 172 studies. Mechanistically, fluid shifts causing cell volume alterations and vacuolization are an early event in the PMI, while the loss of the ability to visualize cell membranes altogether is a later event. Decomposition rates are highly heterogenous and depend on the methods for visualization, the structural feature of interest, and modifying variables such as the storage temperature or the species. Geometrically, deformations of cell membranes are common early events that initiate within minutes. On the other hand, topological relationships between cellular features appear to remain intact for more extended periods. Taken together, there is an uncertain period of time, usually ranging from several hours to several days, over which cell membrane structure is progressively lost. This review may be helpful for investigators studying human postmortem brain tissue, wherein the PMI is an unavoidable aspect of the research