Reducing Poverty in California…Permanently

If California were to seriously commit to equalizing opportunity and reducing poverty, how might that commitment best be realized? This is of course a hypothetical question, as there is no evidence that California is poised to make such a serious commitment, nor have many other states gone much beyond the usual lip-service proclamations. There are many reasons for California’s complacency, but an important one is that most people think that poverty is intractable and that viable solutions to it simply don’t exist. When Californians know what needs to be done, they tend to go forward and get it done. When, for example, the state’s roads are in disrepair, there are rarely paralyzing debates about exactly how to go about fixing them; instead we proceed with the needed repairs as soon as the funds to do so are appropriated. The same type of sure and certain prescription might appear to be unavailable when it comes to reducing poverty. It is hard not to be overwhelmed by the cacophony of voices yielding a thick stream of narrow-gauge interventions, new evaluations, and piecemeal proposals.1 Although the research literature on poverty is indeed large and may seem confusing, recent advances have in fact been so fundamental that it is now possible to develop a science-based response to poverty. In the past, the causes of poverty were not well understood, and major interventions, such as the War on Poverty, had to be built more on hunch than science. It is an altogether different matter now. The causes of poverty are well established, and the effects of many possible policy responses to poverty are likewise well established. The simple purpose of this essay is to assemble these advances into a coherent plan that would, if implemented, reduce poverty in California substantially

Why is there so much Poverty in California? The Causes of California’s Sky-High Poverty and the Evidence Behind the Equal Opportunity Plan for Reducing It

The purpose of this report is to describe the current state of poverty in California, to discuss concrete steps that could be taken to reduce poverty in California, and to present the best available evidence on the likely effects of those steps. We take on an important but infrequently-posed question: If California were to seriously commit to reducing poverty, how might that commitment best be realized? This is of course a hypothetical question, as there is no evidence that California is poised to make such a serious commitment, nor have many other states gone much beyond the usual lip service proclamations. It is nonetheless especially striking that California, the highest-poverty state in the country, has not rushed in to rectify the matter.1 There are many reasons for this seeming complacency, but an especially important one is that most people think that poverty is intractable and that viable solutions to it simply don’t exist. When Californians know what needs to be done, they tend to go forward and get it done. When, for example, the state’s roads are in disrepair, there are rarely paralyzing debates about exactly how to go about fixing them; and instead we proceed with the needed repairs as soon as the funds to do so are appropriated. The same type of sure and certain prescription might appear to be unavailable when it comes to fixing poverty. It is hard not to be overwhelmed by the cacaphony of voices yielding a thick stream of narrow-gauge interventions, new evaluations, and piecemeal proposals.

Prion Protein Amino Acid Determinants of Differential Susceptibility and Molecular Feature of Prion Strains in Mice and Voles

The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases

Resistance of Bovine Spongiform Encephalopathy (BSE) Prions to Inactivation

Distinct prion strains often exhibit different incubation periods and patterns of neuropathological lesions. Strain characteristics are generally retained upon intraspecies transmission, but may change on transmission to another species. We investigated the inactivation of two related prions strains: BSE prions from cattle and mouse-passaged BSE prions, termed 301V. Inactivation was manipulated by exposure to sodium dodecyl sulfate (SDS), variations in pH, and different temperatures. Infectivity was measured using transgenic mouse lines that are highly susceptible to either BSE or 301V prions. Bioassays demonstrated that BSE prions are up to 1,000-fold more resistant to inactivation than 301V prions while Western immunoblotting showed that short acidic SDS treatments reduced protease-resistant PrPSc from BSE prions and 301V prions at similar rates. Our findings argue that despite being derived from BSE prions, mouse 301V prions are not necessarily a reliable model for cattle BSE prions. Extending these comparisons to human sporadic Creutzfeldt-Jakob disease and hamster Sc237 prions, we found that BSE prions were 10- and 106-fold more resistant to inactivation, respectively. Our studies contend that any prion inactivation procedures must be validated by bioassay against the prion strain for which they are intended to be used

De Novo Generation of Infectious Prions In Vitro Produces a New Disease Phenotype

Prions are the proteinaceous infectious agents responsible for Transmissible Spongiform Encephalopathies. Compelling evidence supports the hypothesis that prions are composed exclusively of a misfolded version of the prion protein (PrPSc) that replicates in the body in the absence of nucleic acids by inducing the misfolding of the cellular prion protein (PrPC). The most common form of human prion disease is sporadic, which appears to have its origin in a low frequency event of spontaneous misfolding to generate the first PrPSc particle that then propagates as in the infectious form of the disease. The main goal of this study was to mimic an early event in the etiology of sporadic disease by attempting de novo generation of infectious PrPSc in vitro. For this purpose we analyzed in detail the possibility of spontaneous generation of PrPSc by the protein misfolding cyclic amplification (PMCA) procedure. Under standard PMCA conditions, and taking precautions to avoid cross-contamination, de novo generation of PrPSc was never observed, supporting the use of the technology for diagnostic applications. However, we report that PMCA can be modified to generate PrPSc in the absence of pre-existing PrPSc in different animal species at a low and variable rate. De novo generated PrPSc was infectious when inoculated into wild type hamsters, producing a new disease phenotype with unique clinical, neuropathological and biochemical features. Our results represent additional evidence in support of the prion hypothesis and provide a simple model to study the mechanism of sporadic prion disease. The findings also suggest that prion diversity is not restricted to those currently known, and that likely new forms of infectious protein foldings may be produced, resulting in novel disease phenotypes

Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrPSc), a β-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrPC). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease–affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)–affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrPSc as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrPSc-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrPSc–ferritin complexes induces a state of iron bio-insufficiency in prion disease–affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease–associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Cryogenic Orbital Test Bed 3 (CRYOTE3) Overview and Status

CRYOTE3 is a grassroots CFM test effort with contributing government and industry partners focused on developing and testing hardware to produce needed data for model validation and implementation into flight systems

Bioluminescent Imaging Reveals Divergent Viral Pathogenesis in Two Strains of Stat1-Deficient Mice, and in αßγ Interferon Receptor-Deficient Mice

Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1−/− and IFNαßγR−/− mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1−/− mice and in IFNαßγR−/− mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1−/− (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNαßγR−/− mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1−/− and IFNαßγR−/− mice, we infected an additional Stat1−/− strain deleted in the DNA-binding domain (129Stat1−/− (DBD)). These 129Stat1−/− (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNαßγR−/− mice. This lethal pattern was also observed when 129Stat1−/− (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1−/− (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1−/− mouse strains. The data are consistent with the hypothesis that Stat1−/− (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level