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"Roberts, Christopher J."
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The contentious history of the International Bill of Human Rights
\"Traces conflicts about the definition of human rights and shows how a series of contradictions worked their way into the International Bill of Human Rights\"-- Provided by publisher.
Book
Therapeutic protein aggregation: mechanisms, design, and control
•Therapeutic proteins form a variety of aggregate types.•Aggregates are risk factors for patient immune responses.•Aggregation mechanisms depend on protein sequence and environment.•Opportunities exist for predictive design and control of aggregation rates and mechanisms.
Although it is well known that proteins are only marginally stable in their folded states, it is often less well appreciated that most proteins are inherently aggregation-prone in their unfolded or partially unfolded states, and the resulting aggregates can be extremely stable and long-lived. For therapeutic proteins, aggregates are a significant risk factor for deleterious immune responses in patients, and can form via a variety of mechanisms. Controlling aggregation using a mechanistic approach may allow improved design of therapeutic protein stability, as a complement to existing design strategies that target desired protein structures and function. Recent results highlight the importance of balancing protein environment with the inherent aggregation propensities of polypeptide chains.
Journal Article
Injustice ground zero
V. 1: \"Writers Christopher Sebela (SUICIDE SQUAD MOST WANTED) and Brian Buccellato (DETECTIVE COMICS) and artists Pop Mhan (HE-MAN: THE ETERNITY WAR), Tom Derenick (INFINITE CRISIS: FIGHT FOR THE MULTIVERSE) and Daniel Sampere (GREEN ARROW) delve deep inside the twisted mind of Harley Quinn for her unique take on the events of Injustice: Gods Among Us, straight from ground zero! Following the release of the most-anticipated fighting game sequel, Injustice 2, this is the story behind the original hit game Injustice: Gods Among Us ... but this time, told like never before! For her entire career as a criminal, Harley Quinn lived in the shadow of her beloved Joker. But when one joke went too far and drove Superman to kill, Harley found herself on her own for the first time ... and teamed up with the very heroes she used to fight! With Superman now a brutal despot, Batman must lead a team of heroes and villains to form the resistance to the Man of Steel ... and Harley is on the frontlines, whether Batman wants her there or not! For the first time in her life, Harley has her own identity, her own gang and a new sense of purpose. But will Harley throw it all away when her beloved Mr. J seemingly returns from the dead? Or will she take her place as a true hero in this strange new world?\"-- Provided by publisher.
Book
Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy
Though motor neurons selectively degenerate in amyotrophic lateral sclerosis, other cell types are likely involved in this disease. We recently generated rNLS8 mice in which human TDP-43 (hTDP-43) pathology could be reversibly induced in neurons and expected that microglia would contribute to neurodegeneration. However, only subtle microglial changes were detected during disease in the spinal cord, despite progressive motor neuron loss; microglia still reacted to inflammatory triggers in these mice. Notably, after hTDP-43 expression was suppressed, microglia dramatically proliferated and changed their morphology and gene expression profiles. These abundant, reactive microglia selectively cleared neuronal hTDP-43. Finally, when microgliosis was blocked during the early recovery phase using PLX3397, a CSF1R and c-kit inhibitor, rNLS8 mice failed to regain full motor function, revealing an important neuroprotective role for microglia. Therefore, reactive microglia exert neuroprotective functions in this amyotrophic lateral sclerosis model, and definition of the underlying mechanism could point toward novel therapeutic strategies.
Journal Article
Large-bodied birds are over-represented in unstructured citizen science data
Citizen science platforms are quickly accumulating hundreds of millions of biodiversity observations around the world annually. Quantifying and correcting for the biases in citizen science datasets remains an important first step before these data are used to address ecological questions and monitor biodiversity. One source of potential bias among datasets is the difference between those citizen science programs that have unstructured protocols and those that have semi-structured or structured protocols for submitting observations. To quantify biases in an unstructured citizen science platform, we contrasted bird observations from the unstructured iNaturalist platform with that from a semi-structured citizen science platform—eBird—for the continental United States. We tested whether four traits of species (body size, commonness, flock size, and color) predicted if a species was under- or over-represented in the unstructured dataset compared with the semi-structured dataset. We found strong evidence that large-bodied birds were over-represented in the unstructured citizen science dataset; moderate evidence that common species were over-represented in the unstructured dataset; strong evidence that species in large groups were over-represented; and no evidence that colorful species were over-represented in unstructured citizen science data. Our results suggest that biases exist in unstructured citizen science data when compared with semi-structured data, likely as a result of the detectability of a species and the inherent recording process. Importantly, in programs like iNaturalist the detectability process is two-fold—first, an individual organism needs to be detected, and second, it needs to be photographed, which is likely easier for many large-bodied species. Our results indicate that caution is warranted when using unstructured citizen science data in ecological modelling, and highlight body size as a fundamental trait that can be used as a covariate for modelling opportunistic species occurrence records, representing the detectability or identifiability in unstructured citizen science datasets. Future research in this space should continue to focus on quantifying and documenting biases in citizen science data, and expand our research by including structured citizen science data to understand how biases differ among unstructured, semi-structured, and structured citizen science platforms.
Journal Article
Connecting high-temperature and low-temperature protein stability and aggregation
Protein aggregation is a long-standing problem for preservation of proteins in both laboratory settings and for commercial biotechnology products. It is well established that heating (cooling) can accelerate (slow) aggregation by populating (depopulating) unfolded or partially unfolded monomer states that are key intermediates in aggregation processes. However, there is a long-standing question of whether the same mechanism(s) that lead to aggregation under high-temperature stress are relevant for low-temperature stress such as in refrigerated or supercooled liquids. This report shows the first direct comparison of \"hot\" and \"cold\" aggregation kinetics and folding/unfolding thermodynamics, using bovine hemoglobin as a model system. The results suggest that the same mechanism for non-native aggregation holds from \"hot\" to \"cold\" temperatures, with an aggregation temperature-of-maximum-stability slightly below 0°C. This highlights that sub-zero temperatures can induce cold-mediated aggregation, even in the absence of freezing stresses. From a practical perspective, the results suggests the possibility that cold-stress may be a useful alternative to heat-stress for extrapolating predictions of protein shelf life at refrigerated conditions, as well as providing a foundation for more mechanistic studies of cold-stress conditions in future work. A comparison between isochoric and isobaric methods is also briefly discussed.
Journal Article
Aggregation of therapeutic proteins
While significant progress has been made in the past decade, the current understanding of protein aggregation and its consequences is still immature. Aggregation of Therapeutic Proteins provides an up-to-date resource on protein aggregation and its consequences, and available methods to control or slow down the aggregation process
eBook
Sex-specific attenuation of constant light-induced memory impairment and Clock gene expression in brain in hepatic Npas2 knockout mice
NPAS2 (Neuronal PAS Domain Protein 2) is a component of the core circadian clock and the coordinated activity between central brain and peripheral liver clock proteins postulated to be instrumental for linking behaviour and metabolism. We investigated a conditional liver-specific knockout mouse model (
Npas
2-/- or cKO) to explore its function in activity, circadian rhythms and cognition (novel object recognition-NOR). Circadian rhythms showed no genotype differences. Constant-light reduced NOR in floxxed controls but remarkably not in
Npas
2-/- mice, particularly females. Consistent with entrainment of systemic and central circadian biology,
N
pas
2-/- mice showed altered expression of circadian gene
Clock
in frontal cortex. Sex differences independent of genotype were found in expression of circadian genes
Clock
,
Bmal1
and
Reverb-b
in brain. Sex differences in
Clock
were absent in
N
pas
2-/- mice. Females showed greater period length and phase response to constant light independently of genotype. The data suggest that a role for peripheral NPAS2 in constant light-induced memory impairment in females, and potential mediation by altered cortical circadian
Clock
gene expression, merit further investigation. These findings have implications for the interaction between peripheral and central circadian clocks, circadian sex differences and the deleterious effects of constant light on cognition.
Journal Article
Microglial transcriptome analysis in the rNLS8 mouse model of TDP-43 proteinopathy reveals discrete expression profiles associated with neurodegenerative progression and recovery
The microglial reaction is a hallmark of neurodegenerative conditions, and elements thereof may exert differential effects on disease progression, either worsening or ameliorating severity. In amyotrophic lateral sclerosis (ALS), a syndrome characterized by cytoplasmic aggregation of TDP-43 protein and atrophy of motor neurons in the cortex and spinal cord, the transcriptomic signatures of microglia during disease progression are incompletely understood. Here, we performed longitudinal RNAseq analysis of cortical and spinal cord microglia from rNLS8 mice, in which doxycycline-regulatable expression of human TDP-43 (hTDP-43) in the cytoplasm of neurons recapitulates many features of ALS. Transgene suppression in rNLS8 mice leads to functional, anatomical and electrophysiological resolution that is dependent on a microglial reaction that is concurrent with recovery rather than disease onset. We identified basal differences between the gene expression profiles of microglia dependent on localization in spinal cord or cortex. Microglia subjected to chronic hTDP-43 overexpression demonstrated transcriptomic changes in both locations. We noted strong upregulation of
Apoe
,
Axl
,
Cd63
,
Clec7a
,
Csf1
,
Cst7
,
Igf1
,
Itgax
,
Lgals3
,
Lilrb4
,
Lpl
and
Spp1
during late disease and recovery. Importantly, we identified a distinct suite of differentially expressed genes associated with each phase of disease progression and recovery. Differentially expressed genes were associated with chemotaxis, phagocytosis, inflammation, and production of neuroprotective factors. These data provide new insights into the microglial reaction in TDP-43 proteinopathy. Genes differentially expressed during progression and recovery may provide insight into a unique instance in which the microglial reaction promotes functional recovery after neuronal insult.
Journal Article
Notch-Deficient Skin Induces a Lethal Systemic B-Lymphoproliferative Disorder by Secreting TSLP, a Sentinel for Epidermal Integrity
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j-dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations.
Journal Article