bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiology of the read–write genome
Authors: Shapiro James A. 
Published: June 2014

AbstractDiscoveries in cytogenetics, molecular biology, and genomics have revealed that genome change is an active cell‐mediated physiological process. This is distinctly at variance with the pre‐DNA assumption that genetic changes arise accidentally and sporadically. The discovery that DNA changes arise as the result of regulated cell biochemistry means that the genome is best modelled as a read–write (RW) data storage system rather than a read‐only memory (ROM). The evidence behind this change in thinking and a consideration of some of its implications are the subjects of this article. Specific points include the following: cells protect themselves from accidental genome change with proofreading and DNA damage repair systems; localized point mutations result from the action of specialized trans‐lesion mutator DNA polymerases; cells can join broken chromosomes and generate genome rearrangements by non‐homologous end‐joining (NHEJ) processes in specialized subnuclear repair centres; cells have a broad variety of natural genetic engineering (NGE) functions for transporting, diversifying and reorganizing DNA sequences in ways that generate many classes of genomic novelties; natural genetic engineering functions are regulated and subject to activation by a range of challenging life history events; cells can target the action of natural genetic engineering functions to particular genome locations by a range of well‐established molecular interactions, including protein binding with regulatory factors and linkage to transcription; and genome changes in cancer can usefully be considered as consequences of the loss of homeostatic control over natural genetic engineering functions.
The genome as a developmental organ
Authors: Lamm Ehud 
Published: June 2014

AbstractThis paper applies the conceptual toolkit of Evolutionary Developmental Biology (evo‐devo) to the evolution of the genome and the role of the genome in organism development. This challenges both the Modern Evolutionary Synthesis, the dominant view in evolutionary theory for much of the 20th century, and the typically unreflective analysis of heredity by evo‐devo. First, the history of the marginalization of applying system‐thinking to the genome is described. Next, the suggested framework is presented. Finally, its application to the evolution of genome modularity, the evolution of induced mutations, the junk DNAversusENCODE debate, the role of drift in genome evolution, and the relationship between genome dynamics and symbiosis with microorganisms are briefly discussed.
The evolutionary origin of form and function
Authors: Baverstock Keith , Rönkkö Mauno 
Published: June 2014

AbstractWe regard the basic unit of the organism, the cell, as a complex dissipative natural process functioning under the second law of thermodynamics and the principle of least action. Organisms are conglomerates of information bearing cells that optimise the efficiency of energy (nutrient) extraction from its ecosystem. Dissipative processes, such as peptide folding and protein interaction, yield phenotypic information from which form and function emerge from cell to cell interactions within the organism. Organisms, in Darwin's ‘proportional numbers’, in turn interact to minimise the free energy of their ecosystems. Genetic variation plays no role in this holistic conceptualisation of the life process.
Endogenous bioelectrical networks store non‐genetic patterning information during development and regeneration
Authors: Levin Michael 
Published: June 2014

AbstractPattern formation, as occurs during embryogenesis or regeneration, is the crucial link between genotype and the functions upon which selection operates. Even cancer and aging can be seen as challenges to the continuous physiological processes that orchestrate individual cell activities toward the anatomical needs of an organism. Thus, the origin and maintenance of complex biological shape is a fundamental question for cell, developmental, and evolutionary biology, as well as for biomedicine. It has long been recognized that slow bioelectrical gradients can control cell behaviors and morphogenesis. Here, I review recent molecular data that implicate endogenous spatio‐temporal patterns of resting potentials among non‐excitable cells as instructive cues in embryogenesis, regeneration, and cancer. Functional data have implicated gradients of resting potential in processes such as limb regeneration, eye induction, craniofacial patterning, and head‐tail polarity, as well as in metastatic transformation and tumorigenesis. The genome is tightly linked to bioelectric signaling, via ion channel proteins that shape the gradients, downstream genes whose transcription is regulated by voltage, and transduction machinery that converts changes in bioelectric state to second‐messenger cascades. However, the data clearly indicate that bioelectric signaling is an autonomous layer of control not reducible to a biochemical or genetic account of cell state. The real‐time dynamics of bioelectric communication among cells are not fully captured by transcriptomic or proteomic analyses, and the necessary‐and‐sufficient triggers for specific changes in growth and form can be physiological states, while the underlying gene loci are free to diverge. The next steps in this exciting new field include the development of novel conceptual tools for understanding the anatomical semantics encoded in non‐neural bioelectrical networks, and of improved biophysical tools for reading and writing electrical state information into somatic tissues. Cracking the bioelectric code will have transformative implications for developmental biology, regenerative medicine, and synthetic bioengineering.
The concept of function in modern physiology
Authors: Roux Etienne 
Published: June 2014

AbstractAn overview of the scientific literature shows that the concept of function is central in physiology. However, the concept itself is not defined by physiologists. On the other hand, the teleological, namely, the ‘goal‐directed’ dimension of function, and its subsequent explanatory relevance, is a philosophical problem. Intuitively, the function of a trait in a system explains why this trait is present, but, in the early 1960s, Ernest Nagel and Carl Hempel have shown that this inference cannot be logically founded. However, they showed that self‐regulated systems are teleological. According to the selectionist theories, the function of an item is its effect that has been selected by natural selection, a process that explains its presence. As they restrict the functional attribution of a trait to its past selective value and not its current properties, these theories are inconsistent with the concept of function in physiology. A more adequate one is the causal role theory, for which a function of a trait in a system is its causal contribution to the functional capacity of the system. However, this leaves unsolved the question of the ‘surplus meaning’ of the teleological dimension of function. The significance of considering organisms as ‘purpose‐like’ (teleological) systems may reside not in its explanatory power but in its methodological fruitfulness in physiology. In this view, the teleological dimension of physiological functions is convergent to but not imported from, the teleological dimension of evolutionary biology.
Bioattractors: dynamical systems theory and the evolution of regulatory processes
Authors: Jaeger Johannes , Monk Nick 
Published: June 2014

AbstractIn this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype–phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait – such as attractors with associated basins and their bifurcations – define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self‐organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection.
Mycobacterium tuberculosis Lsr2 Is a Global Transcriptional Regulator Required for Adaptation to Changing Oxygen Levels and Virulence
Authors: Bartek I. L. , Woolhiser L. K. , Baughn A. D. , Basaraba R. J. , Jacobs W. R. , Lenaerts A. J. , Voskuil M. I. 
Published: June 2014

ABSTRACT

To survive a dynamic host environment,
Mycobacterium tuberculosis
must endure a series of challenges, from reactive oxygen and nitrogen stress to drastic shifts in oxygen availability. The mycobacterial Lsr2 protein has been implicated in reactive oxygen defense via direct protection of DNA. To examine the role of Lsr2 in pathogenesis and physiology of
M. tuberculosis
, we generated a strain deleted for
lsr2
. Analysis of the
M. tuberculosis
Δ
lsr2
strain demonstrated that Lsr2 is not required for DNA protection, as this strain was equally susceptible as the wild type to DNA-damaging agents. The
lsr2
mutant did display severe growth defects under normoxic and hyperoxic conditions, but it was not required for growth under low-oxygen conditions. However, it was also required for adaptation to anaerobiosis. The defect in anaerobic adaptation led to a marked decrease in viability during anaerobiosis, as well as a lag in recovery from it. Gene expression profiling of the Δ
lsr2
mutant under aerobic and anaerobic conditions in conjunction with published DNA binding-site data indicates that Lsr2 is a global transcriptional regulator controlling adaptation to changing oxygen levels. The Δ
lsr2
strain was capable of establishing an early infection in the BALB/c mouse model; however, it was severely defective in persisting in the lungs and caused no discernible lung pathology. These findings demonstrate
M. tuberculosis
Lsr2 is a global transcriptional regulator required for control of genes involved in adaptation to extremes in oxygen availability and is required for persistent infection.

IMPORTANCE
M. tuberculosis
causes nearly two million deaths per year and infects nearly one-third of the world population. The success of this aerobic pathogen is due in part to its ability to successfully adapt to constantly changing oxygen availability throughout the infectious cycle, from the high oxygen tension during aerosol transmission to anaerobiosis within necrotic lesions. An understanding of how
M. tuberculosis
copes with these changes in oxygen tension is critical for its eventual eradication. Using a mutation in
lsr2
, we demonstrate that the Lsr2 protein present in all mycobacteria is a global transcriptional regulator in control of genes required for adaptation to changes in oxygen levels.
M. tuberculosis
lacking
lsr2
was unable to adapt to both high and very low levels of oxygen and was defective in long-term anaerobic survival. Lsr2 was also required for disease pathology and for chronic infection in a mouse model of TB.
Genome-Wide Identification of Acinetobacter baumannii Genes Necessary for Persistence in the Lung
Authors: Wang Nengding , Ozer Egon A. , Mandel Mark J. , Hauser Alan R. 
Published: June 2014

ABSTRACT

Acinetobacter baumannii
is a Gram-negative bacterium that causes diseases such as pneumonia, bacteremia, and soft tissue infections in hospitalized patients. Relatively little is known about how
A. baumannii
causes these infections. Thus, we used insertion sequencing (INSeq), a combination of transposon mutagenesis and massively parallel next-generation sequencing, to identify novel virulence factors of
A. baumannii
. To this end, we generated a random transposon mutant library containing 150,000 unique insertions in
A. baumannii
strain ATCC 17978. The INSeq analysis identified 453 genes required for growth in rich medium. The library was then used in a murine pneumonia model, and the relative levels of abundance of mutants before and after selection in the mouse were compared. When genes required for growth in rich medium were removed from the analysis, 157 genes were identified as necessary for persistence in the mouse lung. Several of these encode known virulence factors of
A. baumannii
, such as OmpA and ZnuB, which validated our approach. A large number of the genes identified were predicted to be involved in amino acid and nucleotide metabolism and transport. Other genes were predicted to encode an integration host factor, a transmembrane lipoprotein, and proteins involved in stress response and efflux pumps. Very few genes, when disrupted, resulted in an increase in
A. baumannii
numbers during host infection. The INSeq approach identified a number of novel virulence determinants of
A. baumannii
, which are candidate targets for therapeutic interventions.

IMPORTANCE
A. baumannii
has emerged as a frequent cause of serious infections in hospitals and community settings. Due to increasing antibiotic resistance, alternative approaches, such as antivirulence strategies, are desperately needed to fight
A. baumannii
infections. Thorough knowledge of
A. baumannii
pathogenicity is essential for such approaches but is currently lacking. With the increasingly widespread use of massively parallel sequencing, a class of techniques known as transposon insertion sequencing has been developed to perform comprehensive virulence screens of bacterial genomes
in vivo
. We have applied one of these approaches (INSeq) to uncover novel virulence factors in
A. baumannii
. We identified several such factors, including those predicted to encode amino acid and nucleotide metabolism proteins, an integration host factor protein, stress response factors, and efflux pumps. These results greatly expand the number of
A. baumannii
virulence factors and uncover potential targets for antivirulence treatments.
Detecting Nitrous Oxide Reductase (
nosZ
) Genes in Soil Metagenomes: Method Development and Implications for the Nitrogen Cycle
Authors: Orellana L. H. , Rodriguez-R L. M. , Higgins S. , Chee-Sanford J. C. , Sanford R. A. , Ritalahti K. M. , Löffler F. E. , Konstantinidis K. T. 
Published: June 2014

ABSTRACT

Microbial activities in soils, such as (incomplete) denitrification, represent major sources of nitrous oxide (N
2
O), a potent greenhouse gas. The key enzyme for mitigating N
2
O emissions is NosZ, which catalyzes N
2
O reduction to N
2
. We recently described “atypical” functional NosZ proteins encoded by both denitrifiers and nondenitrifiers, which were missed in previous environmental surveys (R. A. Sanford et al., Proc. Natl. Acad. Sci. U. S. A. 109:19709–19714, 2012, doi:10.1073/pnas.1211238109). Here, we analyzed the abundance and diversity of both
nosZ
types in whole-genome shotgun metagenomes from sandy and silty loam agricultural soils that typify the U.S. Midwest corn belt. First, different search algorithms and parameters for detecting
nosZ
metagenomic reads were evaluated based on
in silico
-generated (mock) metagenomes. Using the derived cutoffs, 71 distinct alleles (95% amino acid identity level) encoding typical or atypical NosZ proteins were detected in both soil types. Remarkably, more than 70% of the total
nosZ
reads in both soils were classified as atypical, emphasizing that prior surveys underestimated
nosZ
abundance. Approximately 15% of the total
nosZ
reads were taxonomically related to
Anaeromyxobacter
, which was the most abundant genus encoding atypical NosZ-type proteins in both soil types. Further analyses revealed that atypical
nosZ
genes outnumbered typical
nosZ
genes in most publicly available soil metagenomes, underscoring their potential role in mediating N
2
O consumption in soils. Therefore, this study provides a bioinformatics strategy to reliably detect target genes in complex short-read metagenomes and suggests that the analysis of both typical and atypical
nosZ
sequences is required to understand and predict N
2
O flux in soils.

IMPORTANCE
Nitrous oxide (N
2
O) is a potent greenhouse gas with ozone layer destruction potential. Microbial activities control both the production and the consumption of N
2
O, i.e., its conversion to innocuous dinitrogen gas (N
2
). Until recently, consumption of N
2
O was attributed to bacteria encoding “typical” nitrous oxide reductase (NosZ). However, recent phylogenetic and physiological studies have shown that previously uncharacterized, functional, “atypical” NosZ proteins are encoded in genomes of diverse bacterial groups. The present study revealed that atypical
nosZ
genes outnumbered their typical counterparts, highlighting their potential role in N
2
O consumption in soils and possibly other environments. These findings advance our understanding of the diversity of microbes and functional genes involved in the nitrogen cycle and provide the means (e.g., gene sequences) to study N
2
O fluxes to the atmosphere and associated climate change.
Management of Fever in Postpneumococcal Vaccine Era: Comparison of Management Practices by Pediatric Emergency Medicine and General Emergency Medicine Physicians
Authors: Khine Hnin , Goldman David L. , Avner Jeffrey R. 
Published: June 2014

Background. The primary objective of this study was to compare management practices of general emergency physicians (GEMPs) and pediatric emergency medicine physicians (PEMPs) for well-appearing young febrile children.Methods. We retrospectively reviewed the charts of well-appearing febrile children aged 3–36 months who presented to a large urban children’s hospital (PED), staffed by PEMPs, or a large urban general emergency department (GED), staffed by GEMPs. Demographics, immunization status, laboratory tests ordered, antibiotic usage, and final diagnoses were collected.Results. 224 cases from the PED and 237 cases from the GED were reviewed. Children seen by PEMPs had significantly less CXRs (23 (10.3%) versus 51 (21.5%),P=0.001) and more rapid viral testing done (102 (45%) versus 40 (17%),P<0.0001). A diagnosis of a viral infection was more common in the PED, while a diagnosis of bacterial infection (including otitis media) was more common in the GED. More GED patients were prescribed antibiotics (41% versus 27%,P=0.002), while more PED patients were treated with oseltamivir (6.7% versus 0.4%,P< 0.001).Conclusions. Our findings identify important differences in the care of the young, well-appearing febrile child by PEMPs and GEMPs and highlight the need for standardization of care.
GPER Mediates Activation of HIF1α/VEGF Signaling by Estrogens
Authors: De Francesco Ernestina Marianna , Pellegrino Michele , Santolla Maria Francesca , Lappano Rosamaria , Ricchio Emilia , Abonante Sergio , Maggiolini Marcello 
Published: June 2014

Abstract
Biological responses to estrogens in normal and malignant tissues are mainly mediated by the estrogen receptors ERα and ERβ, which function as ligand-activated transcription factors. In addition, the G protein–coupled receptor GPR30 (GPER) mediates estrogenic signaling in breast cancer cells and cancer-associated fibroblasts (CAF) that contribute to cancer progression. In this study, we evaluated the role elicited by GPER in the estrogen-regulated expression and function of vascular endothelial growth factor (VEGF) in ER-negative breast cancer cells and CAF. We demonstrated that 17β-estradiol (E2) and the GPER-selective ligand G-1 triggered a GPER/EGFR/ERK/c-fos signaling pathway that leads to increased VEGF via upregulation of HIF1α. In further extending the mechanisms involved in E2-supported angiogenesis, we also showed that conditioned medium from CAF treated with E2 and G-1 promoted human endothelial tube formation in a GPER-dependent manner. In vivo, ligand-activated GPER was sufficient to enhance tumor growth and the expression of HIF1α, VEGF, and the endothelial marker CD34 in a mouse xenograft model of breast cancer. Our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HIF1α-dependent VEGF expression that supports angiogenesis and progression in breast cancer. Cancer Res; 74(15); 4053–64. ©2014 AACR.
Plasma Adipokines and Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Virus–Infected Carriers: A Prospective Study in Taiwan
Authors: Chen Chi-Ling , Yang Wei-Shiung , Yang Hwai-I , Chen Chuen-Fei , You San-Lin , Wang Li-Yu , Lu Sheng-Nan , Liu Chun-Jen , Kao Jia-Horng , Chen Pei-Jer , Chen Ding-Shinn , Chen Chien-Jen 
Published: June 2014

AbstractBackground: Obesity is considered a risk factor for hepatocellular carcinoma (HCC). The relationship between adipocytokine and HCC in hepatitis B virus (HBV) carriers remains unclear. We prospectively investigated the association of adiponectin, leptin, and visfatin levels with HCC.Methods: We conducted a nested case–control study in a community-based cohort with 187 incident HCC and 374 HCC-free HBV carriers. Unconditional logistic regression was conducted to estimate the ORs and 95% confidence intervals (CI).Results: Adiponectin, but not leptin and visfatin, levels were associated with an increased risk of HCC after adjustment for other metabolic factors and HBV-related factors. The risk was increased [OR = 0.51; 95% CI, 0.12–2.11; OR = 4.88 (1.46–16.3); OR = 3.79 (1.10–13.0); OR = 4.13 (1.13–15.1) with each additional quintiles, respectively] with a significant dose–response trend (Ptrend = 0.003). HCC risk associated with higher adiponectin level was higher in HBV carriers with ultrasonographic fatty liver, genotype C infection, higher viral load, and with elevated alanine aminotransferase. Longitudinally, participants with higher adiponectin were less likely to achieve surface antigen of hepatitis B virus (HBsAg) seroclearance and more likely to have persistently higher HBV DNA. Eventually, they were more likely to develop liver cirrhosis [OR = 1.65 (0.62–4.39); OR = 3.85 (1.47–10.1); OR = 2.56 (0.96–6.84); OR = 3.76 (1.33–10.7) for the second, third, fourth, and fifth quintiles, respectively; Ptrend = 0.017] before HCC.Conclusions: Elevated adiponectin levels were independently associated with an increased risk of HCC.Impact: Adiponectin may play different roles in the virus-induced and metabolic-related liver diseases, but the underlying mechanism remains unknown. Cancer Epidemiol Biomarkers Prev; 23(8); 1659–71. ©2014 AACR.