A Door of Hope re-opened : the Fifth Monarchy, King Charles and King Jesus

A Door of Hope was the manifesto of the Fifth Monarchists’ desperate uprising in London in January 1661, a few months after the Restoration of Charles II. While the rising itself is well known, its manifesto has never been examined in detail. Probably based on a sermon to Venner’s congregation, it displays a defiant conviction that the Restoration could be understood as part of God’s providential plan, the next step towards the imminent kingdom of Christ on earth. But it also reaches out to a much wider constituency, all the supporters of the “Good Old Cause”, offering a programme that might appeal to many radicals. And the author draws on secular, republican discourse to buttress his apocalyptic claims, revealing close links between even the most extreme Fifth Monarchists and wider currents of interregnum radicalism

Evidence for Filamentarity in the Las Campanas Redshift Survey

We apply Shapefinders, statistical measures of `shape' constructed from two dimensional partial Minkowski functionals, to study the degree of filamentarity in the Las Campanas Redshift Survey (LCRS). In two dimensions, three Minkowski functionals characterise the morphology of an object, they are: its perimeter (L), area (S), and genus. Out of L and S a single dimensionless Shapefinder Statistic, F can be constructed (0 <=F <=1). F acquires extreme values on a circle (F = 0) and a filament (F = 1). Using F, we quantify the extent of filamentarity in the LCRS by comparing our results with a Poisson distribution with similar geometrical properties and having the same selection function as the survey. Our results unambiguously demonstrate that the LCRS displays a high degree of filamentarity both in the Northern and Southern galactic sections a result that is in general agreement with the visual appearance of the catalogue. It is well known that gravitational clustering from Gaussian initial conditions gives rise to the development of non-Gaussianity reflected in the formation of a network-like filamentary structure on supercluster scales. Consequently the fact that the smoothed LCRS catalogue shows properties consistent with those of a Gaussian random field (Colley 1997) whereas the unsmoothed catalogue demonstrates the presence of filamentarity lends strong support to the conjecture that the large scale clustering of galaxies is driven by gravitational instability.Comment: Accepted for publication in Ap

A Thousand Contradictory Ways: Addiction, Neuroscience, and Expert Autobiography

Neuroscientific accounts of addiction are increasingly influential in health and medical circles. At the same time a diverse, if equally scientifically focused, opposition to addiction neuroscience is emerging. In this struggle over the merits of addiction neuroscience are elements of a uniquely 21st-century public engagement with science. No longer trusted by the public as the unerring source of objective knowledge about the world, science is, at least in some contexts, increasingly treated as just one voice among many. Observing the difficulties this loss of faith in science poses for effective action on pressing issues such as climate change, philosopher Bruno Latour develops a different (ecological) approach to scientific knowledge, one that for the first time allows scientists (and other “moderns”) to understand it for what it really is and locate it “diplomatically” alongside other modes of knowing. In this article, I ask whether a similar innovation is needed to allow more effective understanding of addiction. I explore this question by analyzing two recent, widely discussed, popular books (Marc Lewis’s Memoirs of an Addicted Brain: A Neuroscientist Examines His Former Life on Drugs, 2011 and Carl Hart’s High Price: A Neuroscientist’s Journey of Self-discovery that Challenges Everything You Think You Know About Drugs and Society, 2013) as well as reviews of these books. Written by neuroscientists, and drawing heavily on personal memoir to illustrate and ratify their competing views on drugs and addiction, both books crystallize contemporary dilemmas about science, empiricism, and the nature of evidence and truth. How are we to understand their mix of “scientific fact” and individual self-observation, what does this mix suggest about scientific knowledge, and what are its implications for dominant notions of “evidence-based” drug policy and treatment? I argue that these books both trouble and reinforce our taken-for-granted distinctions between science and personal stories, between objectivity and subjectivity, and note the lost opportunities the books represent for a more searching and productive (Latour might say “ecological”) engagement with science

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Automated deep learning segmentation of high-resolution 7 T postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution of 135 postmortem human brain tissue specimens imaged at 0.3 mm$^{3}$ isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We then segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter. We show generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm^3 and 0.16 mm^3 isotropic T2*w FLASH sequence at 7T. We then compute localized cortical thickness and volumetric measurements across key regions, and link them with semi-quantitative neuropathological ratings. Our code, Jupyter notebooks, and the containerized executables are publicly available at: https://pulkit-khandelwal.github.io/exvivo-brain-upennComment: Preprint submitted to NeuroImage Project website: https://pulkit-khandelwal.github.io/exvivo-brain-upen

Altered Hematopoiesis in Mice Lacking DNA Polymerase μ Is Due to Inefficient Double-Strand Break Repair

Polymerase mu (Polμ) is an error-prone, DNA-directed DNA polymerase that participates in non-homologous end-joining (NHEJ) repair. In vivo, Polμ deficiency results in impaired Vκ-Jκ recombination and altered somatic hypermutation and centroblast development. In Polμ−/− mice, hematopoietic development was defective in several peripheral and bone marrow (BM) cell populations, with about a 40% decrease in BM cell number that affected several hematopoietic lineages. Hematopoietic progenitors were reduced both in number and in expansion potential. The observed phenotype correlates with a reduced efficiency in DNA double-strand break (DSB) repair in hematopoietic tissue. Whole-body γ-irradiation revealed that Polμ also plays a role in DSB repair in non-hematopoietic tissues. Our results show that Polμ function is required for physiological hematopoietic development with an important role in maintaining early progenitor cell homeostasis and genetic stability in hematopoietic and non-hematopoietic tissues

Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a ‘‘cognitive enhancer’ ’ and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (,20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipH HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigr

Numt-Mediated Double-Strand Break Repair Mitigates Deletions during Primate Genome Evolution

Non-homologous end joining (NHEJ) is the major mechanism of double-strand break repair (DSBR) in mammalian cells. NHEJ has traditionally been inferred from experimental systems involving induced double strand breaks (DSBs). Whether or not the spectrum of repair events observed in experimental NHEJ reflects the repair of natural breaks by NHEJ during chromosomal evolution is an unresolved issue. In primate phylogeny, nuclear DNA sequences of mitochondrial origin, numts, are inserted into naturally occurring chromosomal breaks via NHEJ. Thus, numt integration sites harbor evidence for the mechanisms that act on the genome over evolutionary timescales. We have identified 35 and 55 lineage-specific numts in the human and chimpanzee genomes, respectively, using the rhesus monkey genome as an outgroup. One hundred and fifty two numt-chromosome fusion points were classified based on their repair patterns. Repair involving microhomology and repair leading to nucleotide additions were detected. These repair patterns are within the experimentally determined spectrum of classical NHEJ, suggesting that information from experimental systems is representative of broader genetic loci and end configurations. However, in incompatible DSBR events, small deletions always occur, whereas in 54% of numt integration events examined, no deletions were detected. Numts show a statistically significant reduction in deletion frequency, even in comparison to DSBR involving filler DNA. Therefore, numts show a unique mechanism of integration via NHEJ. Since the deletion frequency during numt insertion is low, native overhangs of chromosome breaks are preserved, allowing us to determine that 24% of the analyzed breaks are cohesive with overhangs of up to 11 bases. These data represent, to the best of our knowledge, the most comprehensive description of the structure of naturally occurring DSBs. We suggest a model in which the sealing of DSBs by numts, and probably by other filler DNA, prevents nuclear processing of DSBs that could result in deleterious repair

Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems