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Deluxe Jim Crow : civil rights and American health policy, 1935-1954
\"Plagued by geographic isolation, poverty, and acute shortages of health professionals and hospital beds, the South was dubbed by Surgeon General Thomas Parran \"the nation's number one health problem.\" The improvement of southern, rural, and black health would become a top priority of the U.S. Public Health Service during the Roosevelt and Truman administrations.Karen Kruse Thomas details how NAACP lawsuits pushed southern states to equalize public services and facilities for blacks just as wartime shortages of health personnel and high rates of draft rejections generated broad support for health reform. Southern Democrats leveraged their power in Congress and used the war effort to call for federal aid to uplift the South. The language of regional uplift, Thomas contends, allowed southern liberals to aid blacks while remaining silent on race. Reformers embraced, at least initially, the notion of \"deluxe Jim Crow\"--support for health care that maintained segregation. Thomas argues that this strategy was, in certain respects, a success, building much-needed hospitals and training more black doctors.By the 1950s, deluxe Jim Crow policy had helped to weaken the legal basis for segregation. Thomas traces this transformation at the national level and in North Carolina, where \"deluxe Jim Crow reached its fullest potential.\" This dual focus allows her to examine the shifting alliances--between blacks and liberal whites, southerners and northerners, activists and doctors--that drove policy. Deluxe Jim Crow provides insight into a variety of historical debates, including the racial dimensions of state building, the nature of white southern liberalism, and the role of black professionals during the long civil rights movement\"-- Provided by publisher.
Book
On Multilevel Picard Numerical Approximations for High-Dimensional Nonlinear Parabolic Partial Differential Equations and High-Dimensional Nonlinear Backward Stochastic Differential Equations
Parabolic partial differential equations (PDEs) and backward stochastic differential equations (BSDEs) are key ingredients in a number of models in physics and financial engineering. In particular, parabolic PDEs and BSDEs are fundamental tools in pricing and hedging models for financial derivatives. The PDEs and BSDEs appearing in such applications are often high-dimensional and nonlinear. Since explicit solutions of such PDEs and BSDEs are typically not available, it is a very active topic of research to solve such PDEs and BSDEs approximately. In the recent article (E et al., Multilevel Picard iterations for solving smooth semilinear parabolic heat equations,
arXiv:1607.03295
) we proposed a family of approximation methods based on Picard approximations and multilevel Monte Carlo methods and showed under suitable regularity assumptions on the exact solution of a semilinear heat equation that the computational complexity is bounded by
O
(
d
ε
-
(
4
+
δ
)
)
for any
δ
∈
(
0
,
∞
)
where
d
is the dimensionality of the problem and
ε
∈
(
0
,
∞
)
is the prescribed accuracy. In this paper, we test the applicability of this algorithm on a variety of 100-dimensional nonlinear PDEs that arise in physics and finance by means of numerical simulations presenting approximation accuracy against runtime. The simulation results for many of these 100-dimensional example PDEs are very satisfactory in terms of both accuracy and speed. Moreover, we also provide a review of other approximation methods for nonlinear PDEs and BSDEs from the scientific literature.
Journal Article
Overcoming the curse of dimensionality in the numerical approximation of semilinear parabolic partial differential equations
For a long time it has been well-known that high-dimensional linear parabolic partial differential equations (PDEs) can be approximated by Monte Carlo methods with a computational effort which grows polynomially both in the dimension and in the reciprocal of the prescribed accuracy. In other words, linear PDEs do not suffer from the curse of dimensionality. For general semilinear PDEs with Lipschitz coefficients, however, it remained an open question whether these suffer from the curse of dimensionality. In this paper we partially solve this open problem. More precisely, we prove in the case of semilinear heat equations with gradient-independent and globally Lipschitz continuous nonlinearities that the computational effort of a variant of the recently introduced multilevel Picard approximations grows at most polynomially both in the dimension and in the reciprocal of the required accuracy.
Journal Article
Complete genome sequence analysis of the thermoacidophilic verrucomicrobial methanotroph “Candidatus Methylacidiphilum kamchatkense” strain Kam1 and comparison with its closest relatives
Background: The candidate genus “Methylacidiphilum” comprises thermoacidophilic aerobic methane oxidizers belonging to the Verrucomicrobia phylum. These are the first described non-proteobacterial aerobic methane oxidizers. The genes pmoCAB, encoding the particulate methane monooxygenase do not originate from horizontal gene transfer from proteobacteria. Instead, the “Ca. Methylacidiphilum” and the sister genus “Ca. Methylacidimicrobium” represent a novel and hitherto understudied evolutionary lineage of aerobic methane oxidizers. Obtaining and comparing the full genome sequences is an important step towards understanding the evolution and physiology of this novel group of organisms. Results: Here we present the closed genome of “Ca. Methylacidiphilum kamchatkense” strain Kam1 and a comparison with the genomes of its two closest relatives “Ca. Methylacidiphilum fumariolicum” strain SolV and “Ca. Methylacidiphilum infernorum” strain V4. The genome consists of a single 2,2 Mbp chromosome with 2119 predicted protein coding sequences. Genome analysis showed that the majority of the genes connected with metabolic traits described for one member of “Ca. Methylacidiphilum” is conserved between all three genomes. All three strains encode class I CRISPR-cas systems. The average nucleotide identity between “Ca. M. kamchatkense” strain Kam1 and strains SolV and V4 is ≤95% showing that they should be regarded as separate species. Whole genome comparison revealed a high degree of synteny between the genomes of strains Kam1 and SolV. In contrast, comparison of the genomes of strains Kam1 and V4 revealed a number of rearrangements. There are large differences in the numbers of transposable elements found in the genomes of the three strains with 12, 37 and 80 transposable elements in the genomes of strains Kam1, V4 and SolV respectively. Genomic rearrangements and the activity of transposable elements explain much of the genomic differences between strains. For example, a type 1h uptake hydrogenase is conserved between strains Kam1 and SolV but seems to have been lost from strain V4 due to genomic rearrangements.Conclusions: Comparing three closed genomes of “Ca. methylacidiphilum” spp. has given new insights into the evolution of these organisms and revealed large differences in numbers of transposable elements between strains, the activity of these explains much of the genomic differences between strains.
Journal Article
Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities
Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.
Many interactions between viral and host proteins are mediated by short peptide motifs. Here, using a phage-based viral peptide library, the authors identify 269 peptide-based interactions for 18 coronaviruses, including an interaction between SARS-CoV-2 N and G3BP1/2 that affects stress granules.
Journal Article
A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination
Mutations in the tumour suppressor gene
BRCA2
are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers.
BRCA2 plays a central role in facilitating DNA repair by homologous recombination (HR). Here the authors describe how BRCA2 forms a complex with the protein phosphatase PP2A-B56 in response to DNA damage, which is required for HR.
Journal Article
Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis
Cdk1-mediated phosphorylation of threonine and serine residues on cell cycle regulators needs to be removed after mitosis. Hein
et al.
show that the known preference of the PP2A–B55 phosphatase for threonine provides temporal regulation of mitotic exit.
Protein phosphatase 2A (PP2A) in complex with B55 regulatory subunits reverses cyclin-dependent kinase 1 (Cdk1) phosphorylations at mitotic exit
1
,
2
,
3
,
4
,
5
. Interestingly, threonine and serine residues phosphorylated by Cdk1 display distinct phosphorylation dynamics, but the biological significance remains unexplored. Here we demonstrate that the phosphothreonine preference of PP2A–B55 provides an essential regulatory element of mitotic exit. To allow rapid activation of the anaphase-promoting complex/cyclosome (APC/C) co-activator Cdc20, inhibitory phosphorylation sites are conserved as threonines while serine substitutions delay dephosphorylation and Cdc20 activation. Conversely, to ensure timely activation of the interphase APC/C co-activator Cdh1, inhibitory phosphorylation sites are conserved as serines, and threonine substitutions result in premature Cdh1 activation. Furthermore, rapid translocation of the chromosomal passenger complex to the central spindle is prevented by mutation of a single phosphorylated threonine to serine in inner centromere protein (INCENP), leading to failure of cytokinesis. Altogether, the findings of our work reveal that the inherent residue preference of a protein phosphatase can provide temporal regulation in biological processes.
Journal Article
Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls
During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.
Journal Article