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Using data from the 2003—2007 American Time Use Surveys (ATUS), we compare mothers' (N = 6,640) time spent in four parenting activities across maternal education and child age subgroups. We test the hypothesis that highly educated mothers not only spend more time in active child care than less-educated mothers but also alter the composition of that time to suit children's developmental needs more than less-educated mothers. Results support this hypothesis: not only do highly educated mothers invest more time in basic care and play when youngest children are infants or toddlers than when children are older, but differences across education groups in basic care and play time are largest among mothers with infants or toddlers; by contrast, highly educated mothers invest more time in management activities when children are 6 to 13 years old than when children are younger, and differences across education groups in management are largest among mothers with school-aged children. These patterns indicate that the education gradient in mothers' time with children is characterized by a \"developmental gradient.\"

Our current understanding of the basal ganglia (BG) has facilitated the creation of computational models that have contributed novel theories, explored new functional anatomy and demonstrated results complementing physiological experiments. However, the utility of these models extends beyond these applications. Particularly in neuromorphic engineering, where the basal ganglia's role in computation is important for applications such as power efficient autonomous agents and model-based control strategies. The neurons used in existing computational models of the BG, however, are not amenable for many low-power hardware implementations. Motivated by a need for more hardware accessible networks, we replicate four published models of the BG, spanning single neuron and small networks, replacing the more computationally expensive neuron models with an Izhikevich hybrid neuron. This begins with a network modeling action-selection, where the basal activity levels and the ability to appropriately select the most salient input is reproduced. A Parkinson's disease model is then explored under normal conditions, Parkinsonian conditions and during subthalamic nucleus deep brain stimulation (DBS). The resulting network is capable of replicating the loss of thalamic relay capabilities in the Parkinsonian state and its return under DBS. This is also demonstrated using a network capable of action-selection. Finally, a study of correlation transfer under different patterns of Parkinsonian activity is presented. These networks successfully captured the significant results of the originals studies. This not only creates a foundation for neuromorphic hardware implementations but may also support the development of large-scale biophysical models. The former potentially providing a way of improving the efficacy of DBS and the latter allowing for the efficient simulation of larger more comprehensive networks.

The aim of this study was to examine the relationship between patient education level and 5-year mortality after major lower extremity amputation. The records of all patients who underwent above-knee or below-knee amputation at the Nashville Veterans Affairs Medical Center by the vascular surgery service between January 2000 and August 2006 were retrospectively reviewed. Formal levels of education of the study patients were recorded. Outcomes were compared between those patients who had completed high school and those who had not. Bivariate analysis using χ2 and Student's t tests and multivariate logistic regression were performed. Five-year mortality for patients who had completed high school was lower than for those who had not completed high school (62.6% vs 84.3%, P = .001), even after adjusting for important clinical factors (odds ratio for death, .377; 95% confidence interval, .164–.868; P = .022). Patients with less education have increased long-term mortality after lower extremity amputation.

The additional capabilities provided by high-performance neural simulation environments and modern computing hardware has allowed for the modeling of increasingly larger spiking neural networks. This is important for exploring more anatomically detailed networks but the corresponding accumulation in data can make analyzing the results of these simulations difficult. This is further compounded by the fact that many existing analysis packages were not developed with large spiking data sets in mind. Presented here is a software suite developed to not only process the increased amount of spike-train data in a reasonable amount of time, but also provide a user friendly Python interface. We describe the design considerations, implementation and features of the HRLAnalysis(™) suite. In addition, performance benchmarks demonstrating the speedup of this design compared to a published Python implementation are also presented. The result is a high-performance analysis toolkit that is not only usable and readily extensible, but also straightforward to interface with existing Python modules.

This book highlights the applications of coupled bioluminescence assay techniques to real-world problems in drug discovery, environmental and chemical analysis, and biodefense. It separates theoretical aspects from the applied sections in a clear and readable way. Coupled Bioluminescent Assays, explains the uses of CB technologies across drug discovery to analyze toxicity, drug receptors, and enzymes. It covers applications in environmental analysis and biodefense, including cytotoxicity, fertilizer and explosives analysis, and nerve agent and pesticide detection. This is the premier reference on coupled bioluminescent assays for chemists, biochemists, and molecular biologists.

Background: The BTA TRAK™ and BTA stat™ tests for bladder cancer use monoclonal antibodies (mAbs) X13.2 and X52.1 to detect factor H (FH)-related material in urine. The exact ligands remain unknown. Methods: Western blot analyses of purified FH, recombinant factor H-related protein 1 (FHR-1), and serum and urine samples were used to identify the ligands of X13.2 and X52.1. Recombinant FH constructs were used to identify the target sites of X13.2 and X52.1. To analyze whether natural ligands of FH could compete with its recognition by the capture mAb X52.1, we used surface plasmon resonance analysis. The role of the ligands of X52.1 in the BTA TRAK assay was tested with use of purified proteins and FH-depleted samples. Results: X13.2 bound to domain 3 of FH and FH-like protein 1, whereas X52.1 bound to domain 18 of FH and to FHR-1. Using specific FH depletion from a bladder cancer patient’s urine and purified FH, we demonstrated that FH is the ligand recognized by the BTA TRAK test. By contrast, FHR-1 in urine reduced the FH-dependent test signal. Conclusions: FH is a tumor marker for bladder cancer. To reveal the presence of bladder cancer, the BTA TRAK assay detects FH, whereas FHR-1 is able to partly inhibit this detection. This indicates a special mechanism for a diagnostic immunoassay based on the combined effect of simultaneous positive and negative signals in a single sample.

Efficiently passing spiking messages in a neural model is an important aspect of high-performance simulation. As the scale of networks has increased so has the size of the computing systems required to simulate them. In addition, the information exchange of these resources has become more of an impediment to performance. In this paper we explore spike message passing using different mechanisms provided by the Message Passing Interface (MPI). A specific implementation, MVAPICH, designed for high-performance clusters with Infiniband hardware is employed. The focus is on providing information about these mechanisms for users of commodity high-performance spiking simulators. In addition, a novel hybrid method for spike exchange was implemented and benchmarked.

Semantic fluency tasks involve recalling items from a given category (e.g., animals). It is well documented that these tasks produce heavy-tailed distributions of interresponse times (IRTs). Heavy-tailed distributions have been observed in a variety of contexts promoting efficient search. The current work investigates the role of categorical transitions within a single semantic category, multiple semantic categories, and non-semantic categories (e.g., letter categories). Counterintuitively, findings suggest the longer IRTs requisite for producing heavy-tails did not occur at the categorical transitions. Rather, the longest IRTs occurred immediately after switching categories. This work highlights similarities in foraging patterns across different domains from the physical and spatial to the cognitive and abstract.

This paper provides a methodology for generating forest management plans, which explicitly maximize carbon (C) sequestration at the forest-landscape level. This paper takes advantage of concepts first presented in a paper by Meng et al. (2003; Mitigation Adaptation Strategies Global Change 8:371-403) by integrating C-sequestration objective functions in existing wood supply models. Carbon-stock calculations performed in WoodstockTM (RemSoft Inc.) are based on C yields generated from volume table data obtained from local Forest Development Survey plots and a series of wood volume-to-C content conversion factors specified in von Mirbach (2000). The approach is used to investigate the impact of three demonstration forest-management scenarios on the C budget in a 110,000 ha forest in south-central New Brunswick, Canada. Explicit demonstration scenarios addressed include (1) maximizing timber extraction either by clearcut or selection harvesting for greatest revenue generation, (2) maximizing total C storage in the forest landscape and in wood products generated from harvesting, and (3) maximizing C storage together with revenue generation. The level of clearcut harvesting was greatest for scenario 1 (>=15 x 10⁴ m³ of wood and >=943 ha of land per harvesting period), and least for scenario 2 (=0 m³ per harvesting period) where selection harvesting dominated. Because softwood saw logs were worth more than pulpwood ($60 m-³ vs. $40 m-³) and were strategic to the long-term storage of C, the production of softwood saw logs exceeded the production of pulpwood in all scenarios. Selection harvesting was generally the preferred harvesting method across scenarios. Only in scenario 1 did levels of clearcut harvesting occasionally exceed those of selection harvesting, mainly in the removal of old, dilapidated stands early in the simulation (i.e., during periods 1 through 3). Scenario 2 provided the greatest total C-storage increase over 80 years (i.e., 14 x 10⁶ Mg C, or roughly 264 Mg ha-¹) at a cost of $111 per Mg C due to lost revenues. Scenarios 3 and 1 produced reduced storage rates of roughly 9 x 10⁶ Mg C and 3 x 10⁶ Mg C, respectively; about 64% and 22% of the total, 80-year C storage calculated in scenario 2. The bulk of the C in scenario 2 was stored in the forest, amounting to about 76% of the total C sequestered.

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and generate blood cells for the entire lifespan of an animal. HSCs are mostly quiescent, but can self-renew and generate all lineages of the hematopoietic system. Their clinical significance lies in their potential to engraft after transplantation and reconstitute the blood and immune system in patients with hematological malignancies, immune deficiencies or hemoglobin abnormalities. Despite significant progress in our understanding of mechanisms involved in self-renewal, differentiation and quiescence, a coherent picture of how these mechanisms act in concert to regulate steady-state function and homeostatic responses of HSCs has not emerged yet. Importantly, reliable renewal or even maintenance of HSCs in vitro remains challenging. The identification of dozens of cytokines and of more than 200 genes affecting HSC function in knockout studies, as well as multiple publications on genome-wide expression and epigenetic signatures, still leaves significant gaps in our understanding. From a clinical-translational perspective, it is essential to bridge these gaps in our knowledge to devise strategies to maintain HSCs in vitro. This would have enormous implications for the current practice of allogeneic and autologous bone marrow transplantation, as well as gene therapy and genome editing targeting HSCs. Our lab has previously shown that culture in the presence of reduced calcium concentrations allowed striking maintenance of HSC function over at least two weeks. Furthermore, calcium controlled expression of the master hematopoietic tumor suppressor, TET2, while TET2 expression affected the response of HSCs to extracellular calcium. Despite this progress, quantitative expansion of functional HSCs was not achieved through low-calcium culture, suggesting other barriers to self-renewal exist in vitro. The goal of this thesis is to gain a deeper understanding in the barriers to self-renewal of HSCs, both in vitro and in vivo.During fetal life, HSC develop in the fetal liver (FL), where they expand, and home to the BM around birth. As FL HSCs exhibit more self-renewal than adult HSCs, we examined the response of these cells to calcium and to deletion of Tet2 in hopes of identifying barriers to self-renewal in the adult. Surprisingly, we observed that FL HSCs have very distinct calcium physiology compared to adult HSCs and could not be maintained in vitro in any calcium concentration. Only in the presence of low-calcium and after deletion of Tet2 could maintenance of functional FL HSCs be achieved in vitro. This is in sharp contrast to adult HSCs, which were maintained in low-calcium conditions, and in which deletion of Tet2 attenuated maintenance in these conditions. These data indicate more profound differences in the biology of fetal versus adult HSCs than previously appreciated, and suggest that recapitulating the extensive renewal capacity of FL HSCs in adult HSCs may not possible with identical culture conditions. Further studies into mechanisms involved in HSC maintenance in low-calcium conditions revealed that these conditions attenuated the propensity of HSCs to differentiate into megakaryocytes (Mk), hyperploid cells that generate platelets essential to hemostasis. Whereas most hematopoietic lineages arise through successive, increasingly lineage-committed progenitors, Mks can derive rapidly and directly from HSCs. Direct megakaryopoiesis from HSCs occurs in particular in response to inflammatory stimuli, such as interferon signaling. We therefore tested the hypothesis that direct Mk specification is a barrier to HSC self-renewal that is alleviated at least in part by culture in low-calcium conditions. Interferon signaling has been reported to induce direct megakaryopoiesis and also rapidly recruits HSCs into cell cycle. HSCs are also known to be susceptible to replication stress and ensuing DNA damage. We therefore examined the connection between DNA damage responses (DDR) and direct megakaryopoiesis. We discovered that interferon signaling induced DNA damage through replication stress in vivo, whereas irradiation rapidly induced Mk commitment in HSCs. These findings established a connection between a DDR and direct megakaryopoiesis. Furthermore, quiescent HSCs are subject to a physiological DDR caused by hypertranscription, while in vitro culture induced replication stress. Inflicting additional DNA damage in HSCs in vitro or in vivo rapidly induced expression of Mk markers. Even in the absence of additional DNA damage, pharmacological blockade of the G2 phase of the cell cycle induced MK differentiation and hyperploidy in HSCs, but apoptosis in progenitors. Part of the underlying mechanisms are post-transcriptional. Increased protein expression of the Mk lineage transcription factor GATA1 was induced by both DNA damage and G2 arrest, and preceded upregulation of Gata1 mRNA and other Mk genes. Expression of GATA1 protein is at least in part mediated by the integrated stress response (ISR), which modulates translation. Together these findings show that direct megakaryopoiesis from HSCs can be stimulated by DNA damage-induced G2 arrest and is at least partially post-transcriptionally regulated. As our findings suggested that direct megakaryopoiesis, among others induced by a DDR, limits HSC maintenance, we initiated studies to identify the mechanism underlying the DDR in cycling HSCs. We discovered that cycling HSCs are particularly prone to misincorporation of uracil into DNA in vivo and in vitro. Supplementation with thymidine in vitro decreased uracil incorporation, attenuated the DDR, and strikingly increased the maintenance of multipotential HSCs in vitro. Thymidine supplementation also lowered expression of CD41, a marker of Mk-committed HSCs. These data establish a profound role of a uracil-induced DDR in HSCs and indicate that direct commitment to the Mk lineage is inversely correlated with functional HSC maintenance. The DDR, however, was not affected by low-calcium conditions, indicating other pathways in addition to DDR signaling can likely lead to direct Mk specification from HSCs. Collectively, our work establishes that preventing direct Mk commitment in HSCs, either by preventing uracil incorporation or by culture in low-calcium conditions, enhances HSC maintenance, thereby establishing that the propensity to directly engage the Mk pathway is a barrier to HSC maintenance. These findings will have important implications for future efforts at manipulating HSCs in vitro and at in vivo hematopoietic recovery after insults such as irradiation, chemotherapy, and inflammation. Furthermore, two arguments support the notion that this work may have uncovered an important tumor suppressor mechanism. First, the folate cycle, which provides thymidine and prevents uracil misincorporation, is upregulated in most cancers and targeted by several drugs, while folate deficiency is not oncogenic. This suggests that limiting the supply of thymidine in HSCs prevents inadvertent expansion and malignant transformation. Second, our findings indicate that DNA-damaged HSCs, in part through uracil misincorporation, rapidly generate a lineage essential to immediate organismal survival, thus removing potentially mutated cells from the HSC pool to avoid malignant transformation. Finally, we also attempted to study the in vivo relevance of calcium regulation of HSCs. HSCs reside in the BM, and as bone is the main calcium buffering in the body. We therefore initiated studies to investigate whether changes in bone turnover, potentially mediated by changes in microenvironmental calcium concentration, affect HSCs function. Although difficult to directly correlated with calcium conditions in vitro, our findings indicate that both increased and decreased bone turnover do affect HSC function in vivo. Interestingly, bone turnover differentially affects HSCs with mutation in Tet2. These observations may have clinical significance as recent studies revealed that premature menopause, which is associated with increased bone turnover, accelerates the development of clonal hematopoiesis, a condition caused among others by mutation in Tet2.