bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of dynamically and statistically downscaled seasonal climate forecasts for the cold season over the United States
Authors: Yoon Jin‐Ho , Ruby Leung L. , Correia James
Published: October 2012

This study compares two approaches, dynamical and statistical downscaling, for their potential to improve regional seasonal forecasts for the United States (U.S.) during the cold season. In the MultiRCM Ensemble Downscaling (MRED) project, seven regional climate models (RCMs) are used to dynamically downscale the Climate Forecast System (CFS) seasonal prediction over the conterminous U.S. out to 5 months for the period of 1982–2003. The simulations cover December to April of next year with 10 ensemble members from each RCM with different initial and boundary conditions from the corresponding ensemble members. These dynamically downscaled forecasts are compared with statistically downscaled forecasts produced by two bias correction methods applied to both the CFS and RCM forecasts. Results of the comparison suggest that the RCMs add value in seasonal prediction application, but the improvements largely depend on location, forecast lead time, variables, and skill metrics used for evaluation. Generally, more improvements are found over the Northwest and North Central U.S. for the shorter lead times. The comparison results also suggest a hybrid forecast system that combines both dynamical and statistical downscaling methods have the potential to maximize prediction skill.
A network model for prediction and diagnosis of sediment dynamics at the watershed scale
Authors: Patil Sopan , Sivapalan Murugesu , Hassan Marwan A. , Ye Sheng , Harman Ciaran J. , Xu Xiangyu
Published: October 2012

We present a semi‐distributed model that simulates suspended sediment export from a watershed in two stages: (1) delivery of sediments from hillslope and bank erosion into the river channel, and (2) propagation of the channel sediments through the river network toward the watershed outlet. The model conceptualizes a watershed as the collection of reaches, or representative elementary watersheds (REW), that are connected to each other through the river network, and each REW comprises a lumped representation of a hillslope and channel component. The flow of water along the stream network is modeled through coupled mass and momentum balance equations applied in all REWs and sediment transport within each REW is simulated through the sediment balance equations. Every reach receives sediment inputs from upstream REWs (if present) and from the erosion of adjacent hillslopes, banks and channel bed. We tested this model using 12 years (1982–1993) of high temporal resolution data from Goodwin Creek, a 21.3 km2 watershed in Mississippi, USA. The model yields good estimates of sediment export patterns at the watershed outlet, with Pearson correlation coefficient (R value) of 0.85, 0.87, and 0.95 at daily, monthly, and annual resolution, respectively. Furthermore, the model shows that the dynamics of sediment transport are controlled to a large extent by the differences in the behavior of coarse and fine sediment particles, temporary channel storage, and the spatial variability in climatic forcing. These processes have a bearing on the patterns of sediment delivery with increasing scale.
Role of surface‐water and groundwater interactions on projected summertime streamflow in snow dominated regions: An integrated modeling approach
Authors: Huntington Justin L. , Niswonger Richard G.
Published: October 2012

Previous studies indicate predominantly increasing trends in precipitation across the Western United States, while at the same time, historical streamflow records indicate decreasing summertime streamflow and 25th percentile annual flows. These opposing trends could be viewed as paradoxical, given that several studies suggest that increased annual precipitation will equate to increased annual groundwater recharge, and therefore increased summertime flow. To gain insight on mechanisms behind these potential changes, we rely on a calibrated, integrated surface and groundwater model to simulate climate impacts on surface water/groundwater interactions using 12 general circulation model projections of temperature and precipitation from 2010 to 2100, and evaluate the interplay between snowmelt timing and other hydrologic variables, including streamflow, groundwater recharge, storage, groundwater discharge, and evapotranspiration. Hydrologic simulations show that the timing of peak groundwater discharge to the stream is inversely correlated to snowmelt runoff and groundwater recharge due to the bank storage effect and reversal of hydraulic gradients between the stream and underlying groundwater. That is, groundwater flow to streams peaks following the decrease in stream depth caused by snowmelt recession, and the shift in snowmelt causes a corresponding shift in groundwater discharge to streams. Our results show that groundwater discharge to streams is depleted during the summer due to earlier drainage of shallow aquifers adjacent to streams even if projected annual precipitation and groundwater recharge increases. These projected changes in surface water/groundwater interactions result in more than a 30% decrease in the projected ensemble summertime streamflow. Our findings clarify causality of observed decreasing summertime flow, highlight important aspects of potential climate change impacts on groundwater resources, and underscore the need for integrated hydrologic models in climate change studies.
Computer-Based and Paper-Based Reading Comprehension in Adolescents With Typical Language Development and Language-Learning Disabilities
Authors: Srivastava Pradyumn , Gray Shelley
Published: October 2012

Purpose

With the global expansion of technology, our reading platform has shifted from traditional text to hypertext, yet little consideration has been given to how this shift might help or hinder students' reading comprehension. The purpose of this study was to compare reading comprehension of computer-based and paper-based texts in adolescents with and without language-learning disabilities (LLD).

Method

Fourteen adolescents with LLD and 25 adolescents with typical language development (TLD) read literary texts in computer-based and paper-based formats and then answered reading comprehension questions.

Results

The LLD group scored significantly lower than the TLD group on the reading comprehension measure, but there were no significant between-group differences for reading or answering time. In addition, there were no significant within-group differences for the computer-based or paper-based conditions. Predictors for reading comprehension varied by group and condition.

Conclusion

Neither group appeared to be affected by the additional cognitive load imposed by hypertext in the computer-based condition; however, the load between conditions may not have been sufficient to differentially impact reading comprehension. Based on the regression analyses, it appears that working memory, oral language, and decoding differed in their contribution to reading comprehension for each group and condition.
Stuttering in School-Age Children: A Comprehensive Approach to Treatment
Authors: Yaruss J. Scott , Coleman Craig E. , Quesal Robert W.
Published: October 2012

Purpose

This letter, prepared through a close collaboration between the authors and more than 100 colleagues, responds to a paper by the editor of
Language, Speech, and Hearing Services in Schools
that highlighted the need for research on treatment for stuttering in school-age children.

Method

Our response addresses 3 themes: First, we offer agreement with the editor’s call for research because more evidence about treatment for children who stutter is certainly needed. Second, we provide an overview of recent literature, demonstrating that the majority of current treatments include strategies for helping children improve speech fluency
in addition to
helping them increase acceptance of their stuttering and diminish the negative consequences of the disorder. Third, we present several strategies designed to help clinicians respond to the individual needs of children who stutter in a data-based, comprehensive manner that focuses on minimizing the adverse impact of stuttering on children’s educational endeavors, and on their lives as a whole.

Conclusion

Much has been learned about the factors that contribute to the successful treatment of stuttering in school-age children, and evidence will continue to accumulate. Meanwhile, speech-language pathologists can help children increase their fluency while simultaneously minimizing the adverse impact of their speaking difficulties and helping them improve their overall communication.
Training Secondary School Teachers in Instructional Language Modification Techniques to Support Adolescents With Language Impairment: A Randomized Controlled Trial
Authors: Starling Julia , Munro Natalie , Togher Leanne , Arciuli Joanne
Published: October 2012

Purpose

This study evaluated the efficacy of a collaborative intervention where a speech-language pathologist (SLP) trained mainstream secondary school teachers to make modifications to their oral and written instructional language. The trained teachers' uptake of techniques in their whole-class teaching practices and the impact this had on the language abilities of students with language impairment (LI) were evaluated.

Method

Two secondary schools were randomly assigned to either a trained or a control condition. A cohort of 13 teachers (7 trained and 6 control) and 43 Year 8 students with LI (21 trained and 22 control) were tested at pre, post, and follow-up times—teachers by structured interview and students by standardized spoken and written language assessments.

Results

Significantly increased use of the language modification techniques by the trained teachers was observed when compared to the control group of untrained teachers, with this increased use maintained over time. Results from the trained group of students showed a significant improvement in written expression and listening comprehension relative to the control group of students.

Conclusion

This randomized controlled trial is one of the first investigations to evaluate a collaborative intervention that links changes in mainstream secondary teachers' instructional language practices with improvements in the language abilities of adolescents with LI.
When a School-Age Child Stutters, Let’s Focus on the Primary Problem
Authors: Nippold Marilyn A.
Published: October 2012

Purpose

In this reply to Yaruss, Coleman, and Quesal (2012), I explain why it is reasonable for speech-language pathologists to focus their attention on helping school-age children who stutter (CWS) achieve natural-sounding fluent speech. I also emphasize the necessity for clinical researchers to conduct high-quality treatment efficacy studies of school-age CWS.
SYSCO's best business practices (BBPs)
Authors: O'Leary Daniel E
Published: October 2012

The purpose of this paper is to present a case about SYSCO's ‘Best Business Practices’ (BBPs). The analysis focuses on both the system and the impact of the system, particularly the measurable effects and the overall organizational impact. Perhaps, the most interesting issue is how a system for BBPs is used to manage a highly decentralized firm, and push the individual corporate entities to better performance, without requiring specific processes or best practices. Use of the system is illustrated through an example.
Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress
Authors: Gerashchenko Maxim V. , Lobanov Alexei V. , Gladyshev Vadim N.
Published: October 2012

Information on unique and coordinated regulation of transcription and translation in response to stress is central to the understanding of cellular homeostasis. Here we used ribosome profiling coupled with next-generation sequencing to examine the interplay between transcription and translation under conditions of hydrogen peroxide treatment in
Saccharomyces cerevisiae
. Hydrogen peroxide treatment led to a massive and rapid increase in ribosome occupancy of short upstream ORFs, including those with non-AUG translational starts, and of the N-terminal regions of ORFs that preceded the transcriptional response. In addition, this treatment induced the synthesis of N-terminally extended proteins and elevated stop codon read-through and frameshift events. It also increased ribosome occupancy at the beginning of ORFs and potentially the duration of the elongation step. We identified proteins whose synthesis was regulated rapidly by hydrogen peroxide posttranscriptionally; however, for the majority of genes increased protein synthesis followed transcriptional regulation. These data define the landscape of genome-wide regulation of translation in response to hydrogen peroxide and suggest that potentiation (coregulation of the transcript level and translation) is a feature of oxidative stress.
Paternal social enrichment effects on maternal behavior and offspring growth
Authors: Mashoodh Rahia , Franks Becca , Curley James P. , Champagne Frances A.
Published: October 2012

Paternal environmental experiences are significant predictors of developmental outcomes in offspring and can occur even in the absence of paternal care. Although there has been a recent focus on the role of environmentally induced changes in the male germline in producing these effects, the potential mediating role of mothers has not been investigated. A role for mothers in the transmission of paternal effects has been well acknowledged in behavioral ecology, which predicts that females will dynamically adjust their reproductive investment in response to the qualities of their mate. In the present study, we show that a lifetime of socially enriched compared with impoverished housing conditions shifts anxiety-like behavior and gene expression of male mice. Females that mate with enriched-reared males exhibit increased levels of pup nursing and licking toward their offspring, which are associated with changes in gene expression within the maternal hypothalamus. Significantly, these changes in maternal behavior are correlated with the general levels of anxiety exhibited by their male mates. Further, we show that paternal environmental enrichment results in increased growth of their offspring. These results suggest that maternal–paternal interactions at mating may guide offspring development, with significant implications for the transgenerational transmission of paternal environmental experiences.
Socioeconomic gradients in child development in very young children: Evidence from India, Indonesia, Peru, and Senegal
Authors: Fernald Lia C. H. , Kariger Patricia , Hidrobo Melissa , Gertler Paul J.
Published: October 2012

Gradients across socio-economic position exist for many measures of children's health and development in higher-income countries. These associations may not be consistent, however, among the millions of children living in lower- and middle-income countries. Our objective was to examine child development and growth in young children across socio-economic position in four developing countries. We used cross-sectional surveys, child development assessments, measures of length (LAZ), and home stimulation (Family Care Index) of children in India, Indonesia, Peru, and Senegal. The Extended Ages and Stages Questionnaire (EASQ) was administered to parents of all children ages 3–23 mo in the household (
n
=8,727), and length measurements were taken for all children 0–23 mo (
n
= 11,102). Household wealth and maternal education contributed significantly and independently to the variance in EASQ and LAZ scores in all countries, while controlling for child's age and sex, mother's age and marital status, and household size. Being in the fifth wealth quintile in comparison with the first quintile was associated with significantly higher EASQ scores (0.27 to 0.48 of a standardized score) and higher LAZ scores (0.37 to 0.65 of a standardized score) in each country, while controlling for maternal education and covariates. Wealth and education gradients increased over the first two years in most countries for both EASQ and LAZ scores, with larger gradients seen in 16–23-mo-olds than in 0–7mo-olds. Mediation analyses revealed that parental home stimulation activities and LAZ were significant mediating variables and explained up to 50% of the wealth effects on the EASQ.
Effects of early intervention and the moderating effects of brain activity on institutionalized children's social skills at age 8
Authors: Almas Alisa N. , Degnan Kathryn A. , Radulescu Anca , Nelson Charles A. , Zeanah Charles H. , Fox Nathan A.
Published: October 2012

The present study examined the social skills of previously institutionalized, 8-y-old Romanian children from the Bucharest Early Intervention Project and the influence of attachment security and brain electrical activity (alpha power) on these skills. Participants included children randomized to an intervention involving foster care [Foster Care Group (FCG)], children randomized to remain in institutions [Care As Usual Group (CAUG)], and never-institutionalized children living with their families in the Bucharest community [Never-Institutionalized Group (NIG)]. A continuous rating of children’s attachment security to their primary caregiver was assessed at 42 mo of age. When children were 8 y old, teachers rated their social skills, and the children’s resting electroencephalogram alpha power was recorded. Teachers rated social skills of FCG children who were placed into foster care before 20 mo of age as no different from NIG children, and both of these groups were higher than CAUG children and FCG children placed
after
20 mo. Electroencephalogram alpha power at age 8 significantly moderated the relations between attachment security and social skills. These findings characterize institutionalized children’s social skills in middle childhood within the context of a randomized intervention while highlighting the roles of both relational and biological factors in these developmental trajectories.
Achievements and challenges in the biology of environmental effects
Authors: Rutter Michael
Published: October 2012

The starting point for the study of adverse experiences is that some have enduring consequences that continue after the period of exposure to the adversity. That raises four basic issues: whether social adversities can be considered homogeneous, whether the crucial effect lies in the “objective” or subjectively perceived “effective” environment, whether the effects are environmentally mediated, and whether the form of biological embedding involves psychological or health consequences. The findings in the literature are discussed in relation to the biological effects of supposedly positive or normal experiences, the use of natural experiments to determine the causal effects of early experience, the heterogeneity of social adversity, the possible mediators of the biological embedding, gene–environment interdependence, and remaining challenges.
Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus
Authors: Suderman Matthew , McGowan Patrick O. , Sasaki Aya , Huang Tony C. T. , Hallett Michael T. , Meaney Michael J. , Turecki Gustavo , Szyf Moshe
Published: October 2012

Early life experience is associated with long-term effects on behavior and epigenetic programming of the
NR3C1
(
GLUCOCORTICOID RECEPTOR
) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the
NR3C1
gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.
Preventing abusive head trauma resulting from a failure of normal interaction between infants and their caregivers
Authors: Barr Ronald G.
Published: October 2012

Head trauma from abuse, including shaken baby syndrome, is a devastating and potentially lethal form of infant physical abuse first recognized in the early 1970s. What has been less recognized is the role of the early increase in crying in otherwise normal infants in the first few months of life as a trigger for the abuse. In part, this is because infant crying, especially prolonged unsoothable crying, has been interpreted clinically as something wrong with the infant, the infant’s caregiver, or the interactions between them. Here, we review an alternative developmental interpretation, namely, that the early increase in crying is a typical behavioral development in normal infants and usually does not reflect anything wrong or abnormal. We also review evidence indicating that this normal crying pattern is the most common trigger for abusive head trauma (AHT). Together, these findings point to a conceptualization of AHT as the consequence of a failure in an otherwise common, iterative, and developmentally normal infant–caregiver interaction. They also imply that there is a window of opportunity for prevention of AHT, and potentially other forms of infant abuse, through a public health primary universal prevention strategy aimed at changing knowledge and behaviors of caregivers and society in general concerning normal development of infants and the significance of early increased infant crying. If effective, there may be important implications for prevention of infant abuse nationally and internationally.
Rigor, vigor, and the study of health disparities
Authors: Adler Nancy , Bush Nicole R. , Pantell Matthew S.
Published: October 2012

Health disparities research spans multiple fields and methods and documents strong links between social disadvantage and poor health. Associations between socioeconomic status (SES) and health are often taken as evidence for the causal impact of SES on health, but alternative explanations, including the impact of health on SES, are plausible. Studies showing the influence of parents’ SES on their children’s health provide evidence for a causal pathway from SES to health, but have limitations. Health disparities researchers face tradeoffs between “rigor” and “vigor” in designing studies that demonstrate how social disadvantage becomes biologically embedded and results in poorer health. Rigorous designs aim to maximize precision in the measurement of SES and health outcomes through methods that provide the greatest control over temporal ordering and causal direction. To achieve precision, many studies use a single SES predictor and single disease. However, doing so oversimplifies the multifaceted, entwined nature of social disadvantage and may overestimate the impact of that one variable and underestimate the true impact of social disadvantage on health. In addition, SES effects on overall health and functioning are likely to be greater than effects on any one disease. Vigorous designs aim to capture this complexity and maximize ecological validity through more complete assessment of social disadvantage and health status, but may provide less-compelling evidence of causality. Newer approaches to both measurement and analysis may enable enhanced vigor as well as rigor. Incorporating both rigor and vigor into studies will provide a fuller understanding of the causes of health disparities.
Critical period for acoustic preference in mice
Authors: Yang Eun-Jin , Lin Eric W. , Hensch Takao K.
Published: October 2012

Preference behaviors are often established during early life, but the underlying neural circuit mechanisms remain unknown. Adapting a unique nesting behavior assay, we confirmed a “critical period” for developing music preference in C57BL/6 mice. Early music exposure between postnatal days 15 and 24 reversed their innate bias for silent shelter, which typically could not be altered in adulthood. Instead, exposing adult mice treated acutely with valproic acid or carrying a targeted deletion of the Nogo receptor (NgR−/−) unmasked a strong plasticity of preference consistent with a reopening of the critical period as seen in other systems. Imaging of cFos expression revealed a prominent neuronal activation in response to the exposed music in the prelimbic and infralimbic medial prefrontal cortex only under conditions of open plasticity. Neither behavioral changes nor selective medial prefrontal cortex activation was observed in response to pure tone exposure, indicating a music-specific effect. Open-field center crossings were increased concomitant with shifts in music preference, suggesting a potential anxiolytic effect. Thus, music may offer both a unique window into the emotional state of mice and a potentially efficient assay for molecular “brakes” on critical period plasticity common to sensory and higher order brain areas.
Social stratification, classroom climate, and the behavioral adaptation of kindergarten children
Authors: Boyce W. Thomas , Obradović Jelena , Bush Nicole R. , Stamperdahl Juliet , Kim Young Shin , Adler Nancy
Published: October 2012

Socioeconomic status (SES) is the single most potent determinant of health within human populations, from infancy through old age. Although the social stratification of health is nearly universal, there is persistent uncertainty regarding the dimensions of SES that effect such inequalities and thus little clarity about the principles of intervention by which inequalities might be abated. Guided by animal models of hierarchical organization and the health correlates of subordination, this prospective study examined the partitioning of children's adaptive behavioral development by their positions within kindergarten classroom hierarchies. A sample of 338 5-y-old children was recruited from 29 Berkeley, California public school classrooms. A naturalistic observational measure of social position, parent-reported family SES, and child-reported classroom climate were used in estimating multilevel, random-effects models of children's adaptive behavior at the end of the kindergarten year. Children occupying subordinate positions had significantly more maladaptive behavioral outcomes than their dominant peers. Further, interaction terms revealed that low family SES and female sex magnified, and teachers’ child-centered pedagogical practices diminished, the adverse influences of social subordination. Taken together, results suggest that, even within early childhood groups, social stratification is associated with a partitioning of adaptive behavioral outcomes and that the character of larger societal and school structures in which such groups are nested can moderate rank–behavior associations.
Pharmacological chaperones for human α-
N
-acetylgalactosaminidase
Authors: Clark Nathaniel E. , Metcalf Matthew C. , Best Daniel , Fleet George W. J. , Garman Scott C.
Published: October 2012

Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-
N
-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.
Increased vulnerability to cocaine in mice lacking dopamine D3receptors
Authors: Song Rui , Zhang Hai-Ying , Li Xia , Bi Guo-Hua , Gardner Eliot L. , Xi Zheng-Xiong
Published: October 2012

Neuroimaging studies using positron emission tomography suggest that reduced dopamine D2receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D3receptors (D3Rs) in the neurobiology of addiction remains unclear, however. Here we report that D3R KO (D3−/−) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D3−/−mice. In addition, D3−/−mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D3R deletion increases vulnerability to cocaine, and that reduced D3R availability in the brain may constitute a risk factor for the development of cocaine addiction.
PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells
Authors: Hunzicker-Dunn Mary E. , Lopez-Biladeau Blanca , Law Nathan C. , Fiedler Sarah E. , Carr Daniel W. , Maizels Evelyn T.
Published: October 2012

Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and protein hormones, and induce ligand receptors and signaling intermediates. The phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway is a pivotal signaling corridor necessary for transducing the FSH signal. We report that protein kinase A (PKA) mediates the actions of FSH by signaling through multiple targets to activate PI3K/AKT. PKA uses a route that promotes phosphorylation of insulin receptor substrate-1 (IRS-1) on Tyr
989
, a canonical binding site for the 85-kDa regulatory subunit of PI3K that allosterically activates the catalytic subunit. PI3K activation leads to activation of AKT through phosphorylation of AKT on Thr
308
and Ser
473
. The adaptor growth factor receptor bound protein 2-associated binding protein 2 (GAB2) is present in a preformed complex with PI3K heterodimer and IRS-1, it is an A-kinase anchoring protein that binds the type I regulatory subunit of PKA, and it is phosphorylated by PKA on Ser
159
. Overexpression of GAB2 enhances FSH-stimulated AKT phosphorylation. GAB2, thus, seems to coordinate signals from the FSH-stimulated rise in cAMP that leads to activation of PI3K/AKT. The ability of PKA to commandeer IRS-1 and GAB2, adaptors that normally integrate receptor/nonreceptor tyrosine kinase signaling into PI3K/AKT, reveals a previously unrecognized route for PKA to activate a pathway that promotes proliferation, inhibits apoptosis, enhances translation, and initiates differentiation of granulosa cells.
Cellular complexity captured in durable silica biocomposites
Authors: Kaehr Bryan , Townson Jason L. , Kalinich Robin M. , Awad Yasmine H. , Swartzentruber B. S. , Dunphy Darren R. , Brinker C. Jeffrey
Published: October 2012

Tissue-derived cultured cells exhibit a remarkable range of morphological features in vitro, depending on phenotypic expression and environmental interactions. Translation of these cellular architectures into inorganic materials would provide routes to generate hierarchical nanomaterials with stabilized structures and functions. Here, we describe the fabrication of cell/silica composites (CSCs) and their conversion to silica replicas using mammalian cells as scaffolds to direct complex structure formation. Under mildly acidic solution conditions, silica deposition is restricted to the molecularly crowded cellular template. Inter- and intracellular heterogeneity from the nano- to macroscale is captured and dimensionally preserved in CSCs following drying and subjection to extreme temperatures allowing, for instance, size and shape preserving pyrolysis of cellular architectures to form conductive carbon replicas. The structural and behavioral malleability of the starting material (cultured cells) provides opportunities to develop robust and economical biocomposites with programmed structures and functions.
Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encoding genetic information
Authors: Li Changying , Buckwalter Matthew R. , Basu Sreyashi , Garg Manish , Chang Jiwu , Srivastava Pramod K.
Published: October 2012

Studies with a number of viral systems have shown, on the basis of the ability of a host to prime naïve T cells, that viral antigens persist in the infected host well beyond complete clearance of the infection and even when viral antigen is undetectable by the most sensitive methods. This has led to a reasonable assumption that the antigen persists through persistence of antigen-encoding genetic information (DNA or RNA) that resides in the host at a subdetectable level. Here, we demonstrate that epitopes, or epitope precursors, of a model antigen (ovalbumin) persist in a host for prolonged periods (weeks), well beyond the time at which the intact antigen has disappeared, and in the complete absence of genetic information encoding it. Dendritic cells are shown to be the site of this epitope sequestration in vivo, as well as in cultures in vitro. For sequestration to occur, the uptaken antigen must be significantly large, that is, the epitope and its 18-mer precursor are not sequestered. Dendritic cells are shown to create an hsp90-dependent intracellular pool of epitopes or epitope precursors that continues to release epitopes for presentation on the major histocompatibility complex I molecules for prolonged periods. Demonstration of such long-term sequestration of antigenic epitopes inside dendritic cells presents new opportunities for stimulation of immune response against cancers and viruses.
Solar absorption by elemental and brown carbon determined from spectral observations
Authors: Bahadur Ranjit , Praveen Puppala S. , Xu Yangyang , Ramanathan V.
Published: October 2012

Black carbon (BC) is functionally defined as the absorbing component of atmospheric total carbonaceous aerosols (TC) and is typically dominated by soot-like elemental carbon (EC). However, organic carbon (OC) has also been shown to absorb strongly at visible to UV wavelengths and the absorbing organics are referred to as brown carbon (BrC), which is typically not represented in climate models. We propose an observationally based analytical method for rigorously partitioning measured absorption aerosol optical depths (AAOD) and single scattering albedo (SSA) among EC and BrC, using multiwavelength measurements of total (EC, OC, and dust) absorption. EC is found to be strongly absorbing (SSA of 0.38) whereas the BrC SSA varies globally between 0.77 and 0.85. The method is applied to the California region. We find TC (EC + BrC) contributes 81% of the total absorption at 675 nm and 84% at 440 nm. The BrC absorption at 440 nm is about 40% of the EC, whereas at 675 nm it is less than 10% of EC. We find an enhanced absorption due to OC in the summer months and in southern California (related to forest fires and secondary OC). The fractions and trends are broadly consistent with aerosol chemical-transport models as well as with regional emission inventories, implying that we have obtained a representative estimate for BrC absorption. The results demonstrate that current climate models that treat OC as nonabsorbing are underestimating the total warming effect of carbonaceous aerosols by neglecting part of the atmospheric heating, particularly over biomass-burning regions that emit BrC.
Development of white matter and reading skills
Authors: Yeatman Jason D. , Dougherty Robert F. , Ben-Shachar Michal , Wandell Brian A.
Published: October 2012

White matter tissue properties are highly correlated with reading proficiency; we would like to have a model that relates the dynamics of an individual’s white matter development to their acquisition of skilled reading. The development of cerebral white matter involves multiple biological processes, and the balance between these processes differs between individuals. Cross-sectional measures of white matter mask the interplay between these processes and their connection to an individual’s cognitive development. Hence, we performed a longitudinal study to measure white-matter development (diffusion-weighted imaging) and reading development (behavioral testing) in individual children (age 7–15 y). The pattern of white-matter development differed significantly among children. In the left arcuate and left inferior longitudinal fasciculus, children with above-average reading skills initially had low fractional anisotropy (FA) that increased over the 3-y period, whereas children with below-average reading skills had higher initial FA that declined over time. We describe a dual-process model of white matter development comprising biological processes with opposing effects on FA, such as axonal myelination and pruning, to explain the pattern of results.
Genome sequence of the button mushroomAgaricus bisporusreveals mechanisms governing adaptation to a humic-rich ecological niche
Authors: Morin Emmanuelle , Kohler Annegret , Baker Adam R. , Foulongne-Oriol Marie , Lombard Vincent , Nagye Laszlo G. , Ohm Robin A. , Patyshakuliyeva Aleksandrina , Brun Annick , Aerts Andrea L. , Bailey Andrew M. , Billette Christophe , Coutinho Pedro M. , Deakin Greg , Doddapaneni Harshavardhan , Floudas Dimitrios , Grimwood Jane , Hildén Kristiina , Kües Ursula , LaButti Kurt M. , Lapidus Alla , Lindquist Erika A. , Lucas Susan M. , Murat Claude , Riley Robert W. , Salamov Asaf A. , Schmutz Jeremy , Subramanian Venkataramanan , Wösten Han A. B. , Xu Jianping , Eastwood Daniel C. , Foster Gary D. , Sonnenberg Anton S. M. , Cullen Dan , de Vries Ronald P. , Lundell Taina , Hibbett David S. , Henrissat Bernard , Burton Kerry S. , Kerrigan Richard W. , Challen Michael P. , Grigoriev Igor V. , Martin Francis
Published: October 2012

Agaricus bisporusis the model fungus for the adaptation, persistence, and growth in the humic-rich leaf-litter environment. Aside from its ecological role,A. bisporushas been an important component of the human diet for over 200 y and worldwide cultivation of the “button mushroom” forms a multibillion dollar industry. We present twoA. bisporusgenomes, their gene repertoires and transcript profiles on compost and during mushroom formation. The genomes encode a full repertoire of polysaccharide-degrading enzymes similar to that of wood-decayers. Comparative transcriptomics of mycelium grown on defined medium, casing-soil, and compost revealed genes encoding enzymes involved in xylan, cellulose, pectin, and protein degradation are more highly expressed in compost. The striking expansion of heme-thiolate peroxidases and β-etherases is distinctive from Agaricomycotina wood-decayers and suggests a broad attack on decaying lignin and related metabolites found in humic acid-rich environment. Similarly, up-regulation of these genes together with a lignolytic manganese peroxidase, multiple copper radical oxidases, and cytochrome P450s is consistent with challenges posed by complex humic-rich substrates. The gene repertoire and expression of hydrolytic enzymes inA. bisporusis substantially different from the taxonomically related ectomycorrhizal symbiontLaccaria bicolor. A common promoter motif was also identified in genes very highly expressed in humic-rich substrates. These observations reveal genetic and enzymatic mechanisms governing adaptation to the humic-rich ecological niche formed during plant degradation, further defining the critical role such fungi contribute to soil structure and carbon sequestration in terrestrial ecosystems. Genome sequence will expedite mushroom breeding for improved agronomic characteristics.
Structure of the enzyme-acyl carrier protein (ACP) substrate gatekeeper complex required for biotin synthesis
Authors: Agarwal Vinayak , Lin Steven , Lukk Tiit , Nair Satish K. , Cronan John E.
Published: October 2012

Although the pimeloyl moiety was long known to be a biotin precursor, the mechanism of assembly of this C7 α,ω-dicarboxylic acid was only recently elucidated. In
Escherichia coli
, pimelate is made by bypassing the strict specificity of the fatty acid synthetic pathway. BioC methylates the free carboxyl of a malonyl thioester, which replaces the usual acetyl thioester primer. This atypical primer is transformed to pimeloyl-acyl carrier protein (ACP) methyl ester by two cycles of fatty acid synthesis. The question is, what stops this product from undergoing further elongation? Although BioH readily cleaves this product in vitro, the enzyme is nonspecific, which made assignment of its physiological substrate problematical, especially because another enzyme, BioF, could also perform this gatekeeping function. We report the 2.05-Å resolution cocrystal structure of a complex of BioH with pimeloyl-ACP methyl ester and use the structure to demonstrate that BioH is the gatekeeper and its physiological substrate is pimeloyl-ACP methyl ester.
Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation
Authors: Kim Sang Bum , Pandita Raj K. , Eskiocak Ugur , Ly Peter , Kaisani Aadil , Kumar Rakesh , Cornelius Crystal , Wright Woodring E. , Pandita Tej K. , Shay Jerry W.
Published: October 2012

Nuclear factor-erythroid 2–related factor 2 (Nrf2) is a key transcriptional regulator for antioxidant and anti-inflammation enzymes that binds to its endogenous inhibitor protein, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1, in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses, such as ionizing radiation (IR), can disrupt the Nrf2–Kelch-like ECH-associated protein 1 complex. This allows Nrf2 to translocate from the cytoplasm into the nucleus to induce transcription of heme oxygenase-1 and other cytoprotective enzymes through binding to antioxidant responsive elements. However, how Nrf2 protects cells from IR-induced damage remains unclear. Here, we report that Nrf2 activation by the synthetic triterpenoids, bardoxolone methyl (BARD) and 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid–ethyl amide, protects colonic epithelial cells against IR-induced damage, in part, by enhancing signaling of the DNA damage response. Pretreatment with BARD reduced the frequency of both G1 and S/G2 chromosome aberrations and enhanced the disappearance of repairosomes (C-terminal binding protein interacting protein, Rad51, and p53 binding protein-1 foci) after IR. BARD protected cells from IR toxicity in a Nrf2-dependent manner. The p53 binding protein-1 promoter contains three antioxidant responsive elements in which Nrf2 directly binds following BARD treatment. In addition, 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid–ethyl amide provided before exposure to a lethal dose of whole-body irradiation protected WT mice from DNA damage and acute gastrointestinal toxicity, which resulted in improved overall survival. These results demonstrate that Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute IR in vitro and in vivo.
Energetic costs of cellular computation
Authors: Mehta Pankaj , Schwab David J.
Published: October 2012

Cells often perform computations in order to respond to environmental cues. A simple example is the classic problem, first considered by Berg and Purcell, of determining the concentration of a chemical ligand in the surrounding media. On general theoretical grounds, it is expected that such computations require cells to consume energy. In particular, Landauer’s principle states that energy must be consumed in order to erase the memory of past observations. Here, we explicitly calculate the energetic cost of steady-state computation of ligand concentration for a simple two-component cellular network that implements a noisy version of the Berg–Purcell strategy. We show that learning about external concentrations necessitates the breaking of detailed balance and consumption of energy, with greater learning requiring more energy. Our calculations suggest that the energetic costs of cellular computation may be an important constraint on networks designed to function in resource poor environments, such as the spore germination networks of bacteria.
Structural basis for functional cooperation between tandem helicase cassettes in Brr2-mediated remodeling of the spliceosome
Authors: Santos Karine F. , Jovin Sina Mozaffari , Weber Gert , Pena Vladimir , Lührmann Reinhard , Wahl Markus C.
Published: October 2012

Assembly of a spliceosome, catalyzing precursor–messenger RNA splicing, involves multiple RNA–protein remodeling steps, driven by eight conserved DEXD/H-box RNA helicases. The 250-kDa Brr2 enzyme, which is essential for U4/U6 di-small nuclear ribonucleoprotein disruption during spliceosome catalytic activation and for spliceosome disassembly, is the only member of this group that is permanently associated with the spliceosome, thus requiring its faithful regulation. At the same time, Brr2 represents a unique subclass of superfamily 2 nucleic acid helicases, containing tandem helicase cassettes. Presently, the mechanistic and regulatory consequences of this unconventional architecture are unknown. Here we show that in human Brr2, two ring-like helicase cassettes intimately interact and functionally cooperate and how retinitis pigmentosa-linked Brr2 mutations interfere with the enzyme’s function. Only the N-terminal cassette harbors ATPase and helicase activities in isolation. Comparison with other helicases and mutational analyses show how it threads single-stranded RNA, and structural features suggest how it can load onto an internal region of U4/U6 di-snRNA. Although the C-terminal cassette does not seem to engage RNA in the same fashion, it binds ATP and strongly stimulates the N-terminal helicase. Mutations at the cassette interface, in an intercassette linker or in the C-terminal ATP pocket, affect this cross-talk in diverse ways. Together, our results reveal the structural and functional interplay between two helicase cassettes in a tandem superfamily 2 enzyme and point to several sites through which Brr2 activity may be regulated.