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Book
Avalanche precursors of failure in hierarchical fuse networks
We study precursors of failure in hierarchical random fuse network models which can be considered as idealizations of hierarchical (bio)materials where fibrous assemblies are held together by multi-level (hierarchical) cross-links. When such structures are loaded towards failure, the patterns of precursory avalanche activity exhibit generic scale invariance: irrespective of load, precursor activity is characterized by power-law avalanche size distributions without apparent cut-off, with power-law exponents that decrease continuously with increasing load. This failure behavior and the ensuing super-rough crack morphology differ significantly from the findings in non-hierarchical structures.
Journal Article
Public inquiries, policy learning, and the threat of future crises
In the aftermath of major crises governments turn to public inquiries to learn lessons. Inquiries often challenge established authority, frame heroes and villains in the public spotlight and deliver courtroom-like drama to hungry journalists. As such, they can become high-profile political stories in their own right. Inquiries also have a policy learning mandate with big implications because they are ultimately responsible for identifying policy lessons which, if implemented, should keep us safe from the next big event. However, despite their high-profile nature and their position as the pre-eminent means of learning about crises, we still know very little about what inquiries produce in terms of learning and what factors influence their effectiveness in this0regard. 0In light of this, the question that animates this book is as important as it is simple. Can post-crisis inquiries deliver effective lesson-learning which will reduce our vulnerability to future threats? Conventional wisdom suggests that the answer to this question should be an emphatic no. Outside of the academy, for example, inquiries are regularly vilified as costly wastes of time that illuminate very little while inside social scientists echo similar concerns, regularly describing inquiries as unhelpful. These commentaries, however, lack robust, generalizable evidence to support their claims. This volume provides evidence from the first international comparison of post-crisis inquiries in Australia, Canada, New Zealand, and the United Kingdom, which shows that, contrary to conventional wisdom, the post-crisis inquiry is an effective means of policy learning after crises and that they consistently encourage policy reforms that enhance our resilience to future threats.
Book
Identification of Escherichia coli Host Genes That Influence the Bacteriophage Lambda (λ) T4rII Exclusion (Rex) Phenotype
Despite its historic role in evolving our understanding of modern molecular genetics, the mechanism governing the bacteriophage T4
rII
exclusion (Rex) phenotype has remained a mystery for over six decades. The Rex system is thought...
The T4r
II
exclusion (Rex) phenotype is the inability of T4
rII
mutant bacteriophage to propagate in hosts (
Escherichia coli
) lysogenized by bacteriophage lambda (λ). The Rex phenotype, triggered by T4
rII
infection of a
rex
+
λ lysogen, results in rapid membrane depolarization imposing a harsh cellular environment that resembles stationary phase. Rex “activation” has been proposed as an altruistic cell death system to protect the λ prophage and its host from T4r
II
superinfection. Although well studied for over 60 years, the mechanism behind Rex still remains unclear. We have identified key nonessential genes involved in this enigmatic exclusion system by examining T4r
II
infection across a collection of
rex
+
single-gene knockouts. We further developed a system for rapid, one-step isolation of host mutations that could attenuate/abrogate the Rex phenotype. For the first time, we identified host mutations that influence Rex activity and
rex
+
host sensitivity to T4
rII
infection. Among others, notable genes include
tolA
,
ompA
,
ompF
,
ompW
,
ompX
,
ompT
,
lpp
,
mglC
, and
rpoS
. They are critical players in cellular osmotic balance and are part of the stationary phase and/or membrane distress regulons. Based on these findings, we propose a new model that connects Rex to the σ
S
, σ
E
regulons and key membrane proteins.
Journal Article
How Much Does Ne Vary Among Species?
The population frequency of polymorphic alleles varies in time. This variation has a stochastic component, mainly determined by the size of the considered population,
N
e
: genetic drift...
Genetic drift is an important evolutionary force of strength inversely proportional to
N
e
, the effective population size. The impact of drift on genome diversity and evolution is known to vary among species, but quantifying this effect is a difficult task. Here we assess the magnitude of variation in drift power among species of animals via its effect on the mutation load – which implies also inferring the distribution of fitness effects of deleterious mutations. To this aim, we analyze the nonsynonymous (amino-acid changing) and synonymous (amino-acid conservative) allele frequency spectra in a large sample of metazoan species, with a focus on the primates
vs.
fruit flies contrast. We show that a Gamma model of the distribution of fitness effects is not suitable due to strong differences in estimated shape parameters among taxa, while adding a class of lethal mutations essentially solves the problem. Using the Gamma + lethal model and assuming that the mean deleterious effects of nonsynonymous mutations is shared among species, we estimate that the power of drift varies by a factor of at least 500 between large-
N
e
and small-
N
e
species of animals,
i.e.
, an order of magnitude more than the among-species variation in genetic diversity. Our results are relevant to Lewontin’s paradox while further questioning the meaning of the
N
e
parameter in population genomics.
Journal Article
Investigator and fraud fighter guidebook : operation war stories /
\"Investigator and Fraud Fighter Guidebook provides investigative insight and guidance on how to conduct thorough and complete investigations. The methods taught will allow investigators to solve more cases - even with fewer resources. The author teaches how investigators should perform as many as ten different types of investigations simultaneously: 1. Criminal , 2. Civil, 3. Administrative, 4. ID similar wrongful acts by same suspect, 5. ID other wrongful acts by same suspect, 6. ID others who have committed same wrongs as suspect, 7. Project others who might commit similar acts in future, 8. ID Waste/Abuse, 9. ID Systemic Weaknesses (Cause/Contributing Factors), 10. Consider improvements/corrections to be made (to ensure the wrong does not reoccur)\"-- Provided by publisher.
Book
Modulating Mistranslation Potential of tRNASer in Saccharomyces cerevisiae
Mistranslation, incorporating an amino acid not specified by the “standard” genetic code, has applications in research and synthetic biology. Since mistranslation is toxic, its level must be modulated. Using a serine tRNA with a proline anticodon, we identify...
Transfer RNAs (tRNAs) read the genetic code, translating nucleic acid sequence into protein. For tRNA
Ser
the anticodon does not specify its aminoacylation. For this reason, mutations in the tRNA
Ser
anticodon can result in amino acid substitutions, a process called mistranslation. Previously, we found that tRNA
Ser
with a proline anticodon was lethal to cells. However, by incorporating secondary mutations into the tRNA, mistranslation was dampened to a nonlethal level. The goal of this work was to identify second-site substitutions in tRNA
Ser
that modulate mistranslation to different levels. Targeted changes to putative identity elements led to total loss of tRNA function or significantly impaired cell growth. However, through genetic selection, we identified 22 substitutions that allow nontoxic mistranslation. These secondary mutations are primarily in single-stranded regions or substitute G:U base pairs for Watson–Crick pairs. Many of the variants are more toxic at low temperature and upon impairing the rapid tRNA decay pathway. We suggest that the majority of the secondary mutations affect the stability of the tRNA in cells. The temperature sensitivity of the tRNAs allows conditional mistranslation. Proteomic analysis demonstrated that tRNA
Ser
variants mistranslate to different extents with diminished growth correlating with increased mistranslation. When combined with a secondary mutation, other anticodon substitutions allow serine mistranslation at additional nonserine codons. These mistranslating tRNAs have applications in synthetic biology, by creating “statistical proteins,” which may display a wider range of activities or substrate specificities than the homogenous form.
Journal Article
U.S. inspectors general : truth tellers in turbulent times
\"Inspectors general are important players in the federal government, and their work often draws considerable public attention when one of them uncovers serious misdeeds or mismanagement that make the headlines. This book by two experts in public policy provides a comprehensive, up-to-date examination of how inspectors general have operated in the four decades since Congress established the offices to investigate waste, fraud, and mismanagement at federal agencies and to promote efficiency and effectiveness in government programs. Unique among federal officials, inspectors general are independent of the agencies they monitor, and they report to the executive and legislative branches of government. One key factor in their independence is that they are expected to be non-partisan and carry out their work without regard to partisan interests. The authors of U.S. Inspectors General: Truth Tellers in Turbulent Times emphasize the \"strategic environment\" in which inspectors general work and interact with a variety of stakeholders, inside and outside the government. Their new book is based on in-depth case studies, a survey of inspectors general, and a review of public documents related to the work of inspectors general. It will be of interest to scholars and students of public policy and public management, journalists, and ordinary citizens interested in how the government works, or doesn't work, on their behalf\"-- Provided by publisher.
Book
A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans
Hydrogen sulfide (H
2
S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H
2
S is also toxic, and unregulated accumulation or exposure to environmental H
2
S can be lethal. In
Caenorhabditis elegans
, the hypoxia inducible factor (
hif-1
) coordinates the initial transcriptional response to H
2
S, and is essential to survive exposure to low concentrations of H
2
S. We performed a forward genetic screen to identify mutations that suppress the lethality of
hif-1
mutant animals in H
2
S. The mutations we recovered are specific for H
2
S, as they do not suppress embryonic lethality or reproductive arrest of
hif-1
mutant animals in hypoxia, nor can they prevent the death of
hif-1
mutant animals exposed to hydrogen cyanide. The majority of
hif-1
suppressor mutations we recovered activate the
skn-1
/Nrf2 transcription factor. Activation of SKN-1 by
hif-1
suppressor mutations increased the expression of a subset of H
2
S-responsive genes, consistent with previous findings that
skn-1
plays a role in the transcriptional response to H
2
S. Using transgenic rescue, we show that overexpression of a single gene,
rhy-1
, is sufficient to protect
hif-1
mutant animals in H
2
S. The
rhy-1
gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel,
hif-1
independent, function that promotes survival in H
2
S.
Journal Article