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DNA methylation is a well-characterized epigenetic modification involved in numerous molecular and cellular functions. Methylation patterns have also been associated with aging mechanisms. However, how DNA methylation patterns change within key brain regions involved in memory formation in an age- and sex-specific manner remains unclear. Here, we performed reduced representation bisulfite sequencing (RRBS) from mouse dorsal hippocampus - which is necessary for the formation and consolidation of specific types of memories - in young and aging mice of both sexes. Overall, our findings demonstrate that methylation levels within the dorsal hippocampus are divergent between sexes during aging in genomic features correlating to mRNA functionality, transcription factor binding sites, and gene regulatory elements. These results define age-related changes in the methylome across genomic features and build a foundation for investigating potential target genes regulated by DNA methylation in an age- and sex-specific manner.

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor.

A multi-omics approach was applied to investigate the differences and correlations between characteristic volatile flavor substances and non-volatile metabolites in sausages fermented by Pediococcus pentosaceus (P. pentosaceus) and Staphylococcus carnosus (S. carnosus) alone and in a mixture. Twenty-seven volatile metabolites were identified by headspace solid-phase microextraction/gas chromatography-mass. According to orthogonal projections to latent structures-differential analysis, 17 characteristic volatile metabolites were detected in the sausages of different treatments. Utilizing ultra-high-performance liquid chromatography coupled with a mass spectrometer to analyze metabolite profiles, 42.03% of the non-volatile metabolites were classified as lipids and lipid-like molecules, 25.00% of organic acids and derivatives, and others. Seventeen characteristic flavor substances were significantly correlated with twenty differential non-volatile metabolites, and the non-volatile metabolites changed significantly. Differences in the characteristics and combinations of microorganisms themselves have a decisive role in the development of flavor substances and non-volatile metabolites in sausages.

Herein, we have developed a method for ultra–thinning MnO2 nanosheets by H2O swelling followed by a cetyltrimethylammonium bromide (CTAB)–intercalation exfoliation strategy. The thickness of the obtained U–MnO2 nanosheets was about 1–2 layers. As–prepared U–MnO2 exhibited higher turnover frequency (TOF) value of H2 production from alkaline formaldehyde solution at room temperature as compared to that of pristine MnO2 (TOF per surface Mn atom: 2.7 vs. 1.1 h–1). With the ultra–thinning process, abundant surface oxygen vacancies (VO) on U–MnO2 were demonstrated by X–ray photoelectron spectroscopy and extended X–ray absorption fine structure analysis, which could couple molecular O2 and benefit for the breaking of C H bonds from formaldehyde with the generation of OOH radical. Detailed reaction–pathway calculations showed that the O2 assisted dehydrogenation of alkaline HCHO solution were thermodynamically favored on U–MnO2 with lower energy barrier of 0.32 eV as compared to that of 1.25 eV on pristine MnO2. This work not only provides an applicable method for synthesizing ultrathin MnO2 nanosheets but also gives an evidence towards more essential understanding of hydrogen evolution reaction from alkaline formaldehyde solution at atomic level.

Performant numerical solving of differential equations is required for large-scale scientific modeling. In this manuscript we focus on two questions: (1) how can researchers empirically verify theoretical advances and consistently compare methods in production software settings and (2) how can users (scientific domain experts) keep up with the state-of-the-art methods to select those which are most appropriate? Here we describe how the confederated modular API of DifferentialEquations.jl addresses these concerns. We detail the package-free API which allows numerical methods researchers to readily utilize and benchmark any compatible method directly in full-scale scientific applications. In addition, we describe how the complexity of the method choices is abstracted via a polyalgorithm. We show how scientific tooling built on top of DifferentialEquations.jl, such as packages for dynamical systems quantification and quantum optics simulation, both benefit from this structure and provide themselves as convenient benchmarking tools.

The yellow catfish (Pelteobagrus fulvidraco) is an economically important species in eastern Asia, but its aquaculture faces bottlenecks due to the influence of environmental factors. The present study evaluated the effects of dietary carotenoid supplementation on high-temperature stress and disease resistance in yellow catfish. Fish were randomly assigned to one of six treatments: five groups were fed basal diets supplemented with 50, 100, 150, 200 or 250 mg·kg−1 carotenoids, and a control group was fed a basal diet. The feeding experiment lasted 60 d, after which the fish were exposed to acute heat shock for 1 d and then infected with Proteus mirabilis. The results showed that the specific growth rate (SGR) and weight gain (WG) were significantly increased and the feed conversion ratio (FCR) was significantly decreased in the groups supplemented with 100, 150, 200 and 250 mg·kg−1 carotenoids (P

Delayed and often impaired wound healing in the elderly presents major medical and socioeconomic challenges. A comprehensive understanding of the cellular/molecular changes that shape complex cell-cell communications in aged skin wounds is lacking. Here, we use single-cell RNA sequencing to define the epithelial, fibroblast, immune cell types, and encompassing heterogeneities in young and aged skin during homeostasis and identify major changes in cell compositions, kinetics, and molecular profiles during wound healing. Our comparative study uncovers a more pronounced inflammatory phenotype in aged skin wounds, featuring neutrophil persistence and higher abundance of an inflammatory/glycolytic Arg1Hi macrophage subset that is more likely to signal to fibroblasts via interleukin (IL)-1 than in young counterparts. We predict systems-level differences in the number, strength, route, and signaling mediators of putative cell-cell communications in young and aged skin wounds. Our study exposes numerous cellular/molecular targets for functional interrogation and provides a hypothesis-generating resource for future wound healing studies.

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5a

In vivo calcium imaging enables simultaneous recording of large neuronal ensembles engaged in complex operations. Many experiments require monitoring and identification of cell populations across multiple sessions. Population cell tracking across multiple sessions is complicated by non-rigid transformations induced by cell movement and imaging field shifts. We introduce SCOUT (Single-Cell SpatiOtemporal LongitUdinal Tracking), a fast, robust cell tracking method utilizing multiple cell-cell similarity metrics, probabilistic inference, and an adaptive clustering methodology to perform cell identification across multiple sessions. By comparing SCOUT with current popular cell tracking algorithms on simulated, 1-photon and 2-photon recordings, we empirically show this approach improves cell tracking quality, particularly when recordings exhibit spatial footprint movement between sessions or poor neural extraction quality.

Diet can impact gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown how ISC niche responds to diet and influences ISC function. Here, we demonstrated that Lepr+ mesenchymal cells (MCs) surround intestinal crypts where ISCs and transit-amplifying (TA) cells localize. The abundance of these cells increased upon administration of a high-fat diet (HFD) but dramatically decreased upon fasting. Depletion of Lepr+ MCs resulted in fewer ISCs, compromised architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, IGF1 derived from Lepr+ MCs was found to be an important effector that promotes proliferation of ISCs. Overall, Lepr+ MCs sense diet alteration and function as a novel niche for ISCs via the stromal Igf1 - epithelial Igf1r axis. These findings revealed that Lepr+ MCs are an important mediator that links systemic diet changes to local ISC function and might provide a novel therapeutic target for gut diseases.

Summary The production of germ cells in vitro would open important new avenues for stem biology and human medicine, but the mechanisms of germ cell differentiation are not well understood. The chicken, as a great model for embryology and development, was used in this study to help us explore its regulatory mechanisms. In this study, we reported a comprehensive genome-wide DNA methylation landscape in chicken germ cells, and transcriptomic dynamics was also presented. By uncovering DNA methylation patterns on individual genes, some genes accurately modulated by DNA methylation were found to be associated with cancers and virus infection, e.g., AKT1 and CTNNB1. Chicken-unique markers were also discovered for identifying male germ cells. Importantly, integrated epigenetic mechanisms were explored during male germ cell differentiation, which provides deep insight into the epigenetic processes associated with male germ cell differentiation and possibly improves treatment options to male infertility in animals and humans., Graphical Abstract, Highlights • The mechanisms of stem cell differentiation were explored using the chick embryo model • The orchestrated stem cell differentiation involves multiple epigenetic events • The unique markers in chick embryo were discovered for identifying male germ cells, In this article, Song, Li, and their colleagues reported a comprehensive genome-wide DNA methylation landscape in chicken germ cells. The integrated epigenetic mechanisms were explored, specifically, germ cell differentiation experiences through a highly orchestrated process that involves multiple epigenetic events, which would give a clue for curing male infertility in animals and humans.

To determine the effects of dietary lipid levels on growth performance, body composition and antioxidant parameters of clamworm (Perinereis aibuhitensis), 1050 clamworms were fed diets with seven lipid levels (2.37%, 4.35%, 6.29%, 8.41%, 10.31%, 12.29% and 14.33%, named L2.37, L4.35, L6.29, L8.41, L10.31, L12.29 and L14.33, respectively) for 10 weeks. Each diet was randomly assigned to triplicate groups of 50 clamworms. The results showed that the growth performance and protein efficiency ratio were significantly affected by the lipid levels. Clamworms fed L8.41 diet exhibited higher growth performance than others and the maximum specific growth rate can be possibly obtained when the diets were supplemented with 7.54% lipid level. The dietary lipid levels had significant influences on the whole body crude protein, crude lipid, moisture contents and ash profile of P. aibuhitensis. The eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were also enhanced with increasing dietary lipid levels in whole body analyses. The contents of malonaldehyde (MDA) and lipid peroxidation (LPO) in clamworms increased significantly with increasing dietary lipid levels. Meanwhile, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and total autioxidative capacity (T-AOC) tended to strengthen with dietary lipid levels increasing from 2.37% to 10.31% (except the GPX with 12.29% dietary lipid levels), and weaken with dietary lipid levels increasing from 10.31% to 14.33%. These results demonstrated that a proper dietary lipid level of 7.54%–10.31% could maintain solid growth performance and antioxidant capacity of juvenile P. aibuhitensis. Keywords: Perinereis aibuhitensis, Lipid, Growth, Body composition, Antioxidant

SUMMARYOur knowledge of transcriptional heterogeneities in epithelial stem/progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem/progenitor potential, but a non-biased dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA-sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell transcriptional states in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses produce a quasi-linear differentiation hierarchy where basal cells progress fromCol17a1high/Trp63highstate to early response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal states. Our study provides a systematic view of epidermal cellular dynamics supporting a revised “hierarchical-lineage” model of homeostasis.

The aim of this study was to investigate the phenotypic and genotypic antimicrobial resistance, integrons, and transferability of resistance markers in 243 aerobic bacteria recovered from pork at slaughter in the People's Republic of China. The organisms belonged to 22 genera of gram-negative bacteria (92.2%) and gram-positive bacteria (7.8%). High levels of resistance were detected to tetracycline, trimethoprim-sulfamethoxazole, and ampicillin (36.2 to 54.3%), and lower levels were detected to nitrofurantoin, cefotaxime, gentamicin, ciprofloxacin, and chloramphenicol (7.8 to 29.2%). Across species, genes conferring antimicrobial resistance were observed with the following frequencies: blaTEM, 40.7%; blaCMY-2, 15.2%; blaCTX-M, 11.5%; sul2, 27.2%; sul1, 14.4%; tet(A), 5.4%; tet(L), 5.4%; tet(M), 5.0%; tet(E), 3.7%; tet(C), 3.3%; tet(S), 2.5%; and tet(K), 0.8%. Various antimicrobial resistance genes were found in new carriers: blaTEM in Lactococcus garvieae, Myroides odoratimimus, Aeromonas hydrophila, Staphylococcus sciuri, Raoultella terrigena, Macrococcus caseolyticus, Acinetobacter ursingii, Sphingobacterium sp., and Oceanobacillus sp.; blaCMY-2 in Lactococcus lactis, Klebsiella oxytoca, Serratia marcescens, Acinetobacter baumannii, and Myroides phaeus; tet(L) in M. caseolyticus; sul1 in Vibrio cincinnatiensis; sul2 in Acinetobacter bereziniae, Acinetobacter johnsonii, and V. cincinnatiensis; and the class 1 integron and gene cassette aadA2 in V. cincinnatiensis. Approximately 6.6% of isolates contained class 1 integrons, and one isolate harbored class 2 integrons. Plasmid associated intI1 and androgen receptor- encoding genes were transferred into Escherichia coli J53 and E. coli DH5α by conjugation and transformation experiments, respectively. Our study highlights the importance of aerobic bacteria from pork as reservoirs for antimicrobial resistance genes and mobile genetic elements that can readily be transferred intra- and interspecies.

Highlights • Our results emphasize the importance of using phylogenetic and phylodynamic analyses to provide insights into the roles of various interventions to limit the spread of SARS-CoV-2 in China and beyond. • Understanding epidemic dynamics of SARS-CoV-2 in real time is increasingly important for guiding prevention efforts., To investigate the evolutionary and epidemiological dynamics of the current COVID-19 outbreak, a total of 112 genomes of SARS-CoV-2 strains sampled from China and 12 other countries with sampling dates between 24 December 2019 and 9 February 2020 were analyzed. We performed phylogenetic, split network, likelihood-mapping, model comparison, and phylodynamic analyses of the genomes. Based on Bayesian time-scaled phylogenetic analysis with the best-fitting combination models, we estimated the time to the most recent common ancestor (TMRCA) and evolutionary rate of SARS-CoV-2 to be 12 November 2019 (95% BCI: 11 October 2019 and 09 December 2019) and 9.90 × 10-4 substitutions per site per year (95% BCI: 6.29 × 10-4–1.35 × 10-3), respectively. Notably, the very low Re estimates of SARS-CoV-2 during the recent sampling period may be the result of the successful control of the pandemic in China due to extreme societal lockdown efforts. Our results emphasize the importance of using phylodynamic analyses to provide insights into the roles of various interventions to limit the spread of SARS-CoV-2 in China and beyond.

The fusion of digits or toes, syndactyly, can be part of complex syndromes, including Van der Woude syndrome. A subset of Van der Woude cases is caused by dominant negative mutations in the epithelial transcription factor Grainyhead like-3 (GRHL3) and Grhl3(−/−) mice have soft tissue syndactyly. Although impaired interdigital cell death of mesenchymal cells causes syndactyly in multiple genetic mutants, Grhl3(−/−) embryos had normal interdigital cell death, suggesting alternative mechanisms for syndactyly. We found that in digit separation, the overlying epidermis forms a migrating interdigital epithelial tongue (IET) as the epithelium invaginates to separate the digits. Normally, the non-adhesive surface periderm allows the IET to bifurcate as the digits separate. In contrast, in Grhl3(−/−) embryos, the IET moves normally between the digits but fails to bifurcate because of abnormal adhesion of the periderm. Our study identifies epidermal developmental processes required for digit separation.

Designing and developing integrated energy conversion system that can effectively harvest and transform various type of energy shows great prospect. Here, we synthesize ultrathin ZnO/Al2O3 composite by calcination from its Zn–Al layered double hydroxide (Zn–Al LDH) precursor, whereas the ultrathin ZnO acts as active species that can directly utilize mechanical energy to drive chemical reaction. The thickness of the obtained ultrathin ZnO/Al2O3 composite is about 4.5 nm and its piezo–catalytic activity is assessed under ultrasonication. As−prepared ultrathin ZnO/Al2O3 composite exhibits higher piezo−catalytic reaction rate (k) over methyl orange dye (MO) degradation as compared to that of ZnO/Al2O3 with the thickness about 14 nm (k: 1.19 vs. 0.23 h−1). The experimental and simulated results indicate U–ZnO/Al2O3 exhibits easy bending deformation, which can result in higher piezoelectric potential (1.42 vs. 1.23 V at 105 Pa of balanced side pressure and unbalanced top pressure). Furthermore, with the ultrathining process, abundant surface oxygen vacancies (VO) appear. As a result, the content of surface free charges is enhanced due to the presence of VO, which can be driven by piezoelectric potential and then involved in the generation of radical species during the piezo–catalytic reactions. The generated hydroxyl radical (∙OH) is the active species and it mainly comes from transformation of superoxide radicals (·O2−). This work not only gives clear understanding of piezo–catalytic process but also sheds light a promising strategy for constructing piezo–catalytic materials with optimized geometric or electronic properties.

© 2015 Elsevier Inc. Numerical methods for partial differential equations in high-dimensional spaces are often limited by the curse of dimensionality. Though the sparse grid technique, based on a one-dimensional hierarchical basis through tensor products, is popular for handling challenges such as those associated with spatial discretization, the stability conditions on time step size due to temporal discretization, such as those associated with high-order derivatives in space and stiff reactions, remain. Here, we incorporate the sparse grids with the implicit integration factor method (IIF) that is advantageous in terms of stability conditions for systems containing stiff reactions and diffusions. We combine IIF, in which the reaction is treated implicitly and the diffusion is treated explicitly and exactly, with various sparse grid techniques based on the finite element and finite difference methods and a multi-level combination approach. The overall method is found to be efficient in terms of both storage and computational time for solving a wide range of PDEs in high dimensions. In particular, the IIF with the sparse grid combination technique is flexible and effective in solving systems that may include cross-derivatives and non-constant diffusion coefficients. Extensive numerical simulations in both linear and nonlinear systems in high dimensions, along with applications of diffusive logistic equations and Fokker-Planck equations, demonstrate the accuracy, efficiency, and robustness of the new methods, indicating potential broad applications of the sparse grid-based integration factor method.

Summary During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such a mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here, we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/Ovol2 -deficient epidermal cells fail to undertake α-catenin-driven actin cytoskeletal reorganization and adhesive maturation and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations and defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-α-catenin sequential repression and highlight Ovol1 and Ovol2 as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity.

Conventional methods toward addressing the bearing capacity of strip footings on sand overlying clay may yield unreliable solutions. In this technical note, the bearing capacity of footings on sand overlying clay is evaluated using discontinuity layout optimization (DLO). A set of design charts that can be directly applied to the classical bearing capacity formulation is developed. Subsequently, a simplified regression-based approach, relevant to a wide range of geometric and strength parameters, is proposed. The model uncertainty for the proposed method is characterized. Validations are performed with the results of centrifuge tests and previously proposed analytical solutions.

Existing strength criteria are mostly formulated to describe the mechanical properties of reconstituted soils. However, the engineering characteristics of structured soils are different from those of reconstituted soils in many aspects, especially in their strength properties. Thus, the influence of soil structure (bonding and fabric) on the mechanical properties of structured soils cannot be correctly described. By analyzing the breakage mechanism of natural soils, the structured soils can be conceptualized as binary medium materials consisting of bonded blocks and weakened bands. On this basis, a new strength criterion is proposed for structured soils. The expressions of the strength criterion on both meridian and deviator planes are given to describe the strength properties of structured soils on these planes. The proposed strength criterion is compared with available test data under conventional and true triaxial stress conditions in the literature. It is observed that the proposed strength criterion agrees well with the test data.

The spatial organization of stem cells into a niche is a key factor for growth and continual tissue renewal during development, sustenance, and regeneration. Stratified epithelia serve as a great context to study the spatial aspects of the stem cell niche and cell lineages by organizing into layers of different cell types. Several types of stratified epithelia develop morphologies with advantageous, protruding structures where stem cells reside, such as rete pegs and palisades of Vogt. Here, multistage, spatial cell lineage models for epithelial stratification are used to study how the stem cell niche influences epithelial morphologies. When the stem cell niche forms along a rigid basal lamina, relatively regular morphologies are maintained. In contrast, stem cell niche formation along a free-moving basal lamina may prompt distorted epithelial morphologies with stem cells accumulating at the tips of fingerlike structures that form. The correspondence between our simulated morphologies and developmental stages of the human epidermis is also explored. Overall, our work provides an understanding of how stratified epithelia may attain distorted morphologies and sheds light on the importance of the spatial aspects of the stem cell niche.

Retinoic acid (RA) regulates many cellular behaviors during embryonic development and adult homeostasis. Like other morphogens, RA forms gradients through the use of localized sources and sinks, feedback, and interactions with other signals; this has been particularly well studied in the context of hindbrain segmentation in vertebrate embryos. Yet, as a small lipophilic molecule derived from a dietary source. -. vitamin A. -. RA differs markedly from better-studied polypeptide morphogens in its mechanisms of transport, signaling, and removal. Computational models suggest that the distinctive features of RA gradients make them particularly robust to large perturbations. Such features include combined positive and negative feedback effects via intracellular fatty acid binding proteins and RA-degrading enzymes. Here, we discuss how these features, together with feedback interactions among RA target genes, help enable RA to specify multiple, accurate pattern elements in the developing hindbrain, despite operating in an environment of high cellular and biochemical uncertainty and noise. © 2012 .

An inhomogeneous steady state pattern of nonlinear reaction-diffusion equations with no-flux boundary conditions is usually computed by solving the corresponding time-dependent reaction-diffusion equations using temporal schemes. Nonlinear solvers (e.g., Newton's method) take less CPU time in direct computation for the steady state; however, their convergence is sensitive to the initial guess, often leading to divergence or convergence to spatially homogeneous solution. Systematically numerical exploration of spatial patterns of reaction-diffusion equations under different parameter regimes requires that the numerical method be efficient and robust to initial condition or initial guess, with better likelihood of convergence to an inhomogeneous pattern. Here, a new approach that combines the advantages of temporal schemes in robustness and Newton's method in fast convergence in solving steady states of reaction-diffusion equations is proposed. In particular, an adaptive implicit Euler with inexact solver (AIIE) method is found to be much more efficient than temporal schemes and more robust in convergence than typical nonlinear solvers (e.g., Newton's method) in finding the inhomogeneous pattern. Application of this new approach to two reaction-diffusion equations in one, two, and three spatial dimensions, along with direct comparisons to several other existing methods, demonstrates that AIIE is a more desirable method for searching inhomogeneous spatial patterns of reaction-diffusion equations in a large parameter space.

Objective We explored the clinical values of 11 C-choline ( 11 C-CHO) PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas. Methods Sixteen patients with the pathological confirmation of the diagnosis of gliomas prior to receiving radiotherapy (postoperative) were included, and on whom both MRI and CHO PET scans were performed at the same position for comparison of residual tumors with the two techniques. 11 C-CHO was used as the tracer in the PET scan. A plain T1-weighted, T2-weighted and contrast-enhanced T1-weighted imaging scans were performed in the MRI scan sequence. The gliomas' residual tumor volume was defined as the area with CHO-PET high-affinity uptake and metabolism ( V CHO ) and one with MRI T1-weighted imaging high signal intensity ( V Gd ), and was determined by a group of experienced professionals and clinicians. Results (1) In CHO-PET images, the tumor target volume, i.e., the highly metabolic area with a high concentration of isotopes (SUV 1.016–4.21) and the corresponding contralateral normal brain tissues (SUV0.1–0.62), was well contrasted, and the boundary between lesions and surrounding normal brain tissues was better defined compared with MRI and 18 F-FDG PET images. (2) For patients with brain gliomas of WHO Grade II, the SUV was 1.016–2.5; for those with WHO Grades III and IV, SUVs were >26–4.2. (3) Both CHO PET and MRI were positive for 10 patients and negative for 2 patients. The residual tumor consistency between these two studies was 75%. Four of the 10 CHO-PET-positive patients were negative on MRI scans. The maximum distance between V Gd and V CHO margins was 1.8 cm. (4) The gross tumor volumes (GTVs) and the ensuing treatment regimens were changed for 31.3% (5/16) of patients based on the CHO-PET high-affinity uptake and metabolism, in which the change rate was 80% (4/5), 14.3 % (1/7) and 0% (0/4) for patients with WHO Grade II III, and IV gliomas, respectively. Conclusion Our data demonstrate that difference exists between CHO PET and MRI by which to judge and identify residual tumor for patients with brain gliomas. CHO PET is considered to be a supplementary diagnostic approach for MRI. Biological tumor target volume (BTV) displayed in the CHO PET images is useful in determining or delineating the radiotherapy target volume and making decisions in selecting treatment regimens. Tumor target volume may be defined more accurately and rationally when the CHO PET is combined with MRI.

Background: How morphogen gradients form has long been a subject of controversy. The strongest support for the view that morphogens do not simply spread by free diffusion has come from a variety of studies of the Decapentaplegic (Dpp) gradient of the Drosophila larval wing disc. Results: In the present study, we initially show how the failure, in such studies, to consider the coupling of transport to receptor-mediated uptake and degradation has led to estimates of transport rates that are orders of magnitude too low, lending unwarranted support to a variety of hypothetical mechanisms, such as "planar transcytosis" and "restricted extracellular diffusion." Using several independent dynamic methods, we obtain data that are inconsistent with such models and show directly that Dpp transport occurs by simple, rapid diffusion in the extracellular space. We discuss the implications of these findings for other morphogen systems in which complex transport mechanisms have been proposed. Conclusions: We believe that these findings resolve a major, longstanding question about morphogen gradient formation and provide a solid framework for interpreting experimental observations of morphogen gradient dynamics. © 2012 Elsevier Ltd. All rights reserved.

Summary Objectives Despite extensive childhood immunization, pertussis remains one of the world's leading causes of vaccine-preventable deaths. Incidence of pertussis in adolescents and adults has increased in many countries despite high vaccination coverage. In China, booster vaccinations against diphtheria, tetanus and pertussis are not used in adults, and little is known about pertussis incidence in the age group. The aim of this study was to determine seroprevalence of IgG antibodies to pertussis toxin (PT) and diphtheria among adults in China. Methods Blood samples were obtained from 210 healthy adults aged 18–50 years in Weifang city, China during the period of May and June 2010. Serum IgG antibodies against PT (anti-PT IgG) and diphtheria were determined by the commercial ELISA kits, respectively. According to the kit, concentration of anti-PT IgG higher than 30 IU/mL was considered positive. An antibody concentration of ≥0.1 IU/mL was defined as evidence of seroprotection against diphtheria. Results The mean concentration of anti-PT IgG antibodies was 9.95 IU/mL (95% confidence interval (CI) 8.45–11.44). Eleven (5.24%) of the studied subjects were proved to be seropositive to pertussis. Of the 210 subjects, 161 (76.6%) had anti-diphtheria antibody concentration ≥0.1 IU/mL and 49 (23.3%) had the antibody concentration between 0.01 and 0.099 IU/mL. Conclusions Our study indicated that about 5% of adults aged 18–50 years had positive anti-PT IgG antibodies, suggesting that adult pertussis is not uncommon in China. Although a high proportion of studied subjects had a protective level of immunity against diphtheria, the antibody level decreased with the increasing age of adults. Booster vaccinations against pertussis should be considered in adults in China.

For reaction-diffusion-advection equations, the stiffness from the reaction and diffusion terms often requires very restricted time step size, while the nonlinear advection term may lead to a sharp gradient in localized spatial regions. It is challenging to design numerical methods that can efficiently handle both difficulties. For reaction-diffusion systems with both stiff reaction and diffusion terms, implicit integration factor (IIF) method and its higher dimensional analog compact IIF (cIIF) serve as an efficient class of time-stepping methods, and their second order version is linearly unconditionally stable. For nonlinear hyperbolic equations, weighted essentially non-oscillatory (WENO) methods are a class of schemes with a uniformly high-order of accuracy in smooth regions of the solution, which can also resolve the sharp gradient in an accurate and essentially non-oscillatory fashion. In this paper, we couple IIF/cIIF with WENO methods using the operator splitting approach to solve reaction-diffusion-advection equations. In particular, we apply the IIF/cIIF method to the stiff reaction and diffusion terms and the WENO method to the advection term in two different splitting sequences. Calculation of local truncation error and direct numerical simulations for both splitting approaches show the second order accuracy of the splitting method, and linear stability analysis and direct comparison with other approaches reveals excellent efficiency and stability properties. Applications of the splitting approach to two biological systems demonstrate that the overall method is accurate and efficient, and the splitting sequence consisting of two reaction-diffusion steps is more desirable than the one consisting of two advection steps, because CWC exhibits better accuracy and stability.

Implicit integration factor (IIF) method, a class of efficient semi-implicit temporal scheme, was introduced recently for stiff reaction-diffusion equations. To reduce cost of IIF, compact implicit integration factor (cIIF) method was later developed for efficient storage and calculation of exponential matrices associated with the diffusion operators in two and three spatial dimensions for Cartesian coordinates with regular meshes. Unlike IIF, cIIF cannot be directly extended to other curvilinear coordinates, such as polar and spherical coordinates, due to the compact representation for the diffusion terms in cIIF. In this paper, we present a method to generalize cIIF for other curvilinear coordinates through examples of polar and spherical coordinates. The new cIIF method in polar and spherical coordinates has similar computational efficiency and stability properties as the cIIF in Cartesian coordinate. In addition, we present a method for integrating cIIF with adaptive mesh refinement (AMR) to take advantage of the excellent stability condition for cIIF. Because the second order cIIF is unconditionally stable, it allows large time steps for AMR, unlike a typical explicit temporal scheme whose time step is severely restricted by the smallest mesh size in the entire spatial domain. Finally, we apply those methods to simulating a cell signaling system described by a system of stiff reaction-diffusion equations in both two and three spatial dimensions using AMR, curvilinear and Cartesian coordinates. Excellent performance of the new methods is observed.

Scaffold proteins play an important role in the promotion of signal transmission and specificity during cell signaling. In cells, signaling proteins that make up a pathway are often physically orgnaized into complexes by scaffold proteins [1]. Previous work [2] has shown that spatial localization of scaffold can enhance signaling locally while simultaneously suppressing signaling at a distance, and the membrane confinement of scaffold proteins may result in a precipitous spatial gradient of the active product protein, high close to the membrane and low within the cell. However, cell-fate decisions critically depend on the temporal pattern of product protein close to the nucleus. In this paper, when phosphorylation signals cannot be transfered by diffusion only, two mechanisms have been proposed for long-range signaling within cells: multiple locations of scaffold proteins and dynamical movement of scaffold proteins. Thus, here we have unveiled how the spatial propagation of the phosphorylated product protein within a cell depends on the spatially and temporal localized scaffold proteins. A class of novel and fast numerical methods for solving stiff reaction diffusion equations with complex domains is briefly introduced.

Ovol2 belongs to the Ovo family of evolutionarily conserved zinc finger transcription factors that act downstream of key developmental signaling pathways including Wg/Wnt and BMP/TGF-beta. We previously reported Ovol2 expression in the basal layer of epidermis, where epidermal stem/progenitor cells reside. In this work, we use HaCaT human keratinocytes to investigate the cellular and molecular functions of Ovol2. We show that depletion of Ovol2 leads to transient cell expansion but a loss of cells with long term proliferation potential. Mathematical modeling and experimental findings suggest that both faster cycling and precocious withdrawal from the cell cycle underlie this phenotype. Ovol2 depletion also accelerates extracellular signal-induced terminal differentiation in two- and three-dimensional culture models. By chromatin immunoprecipitation, luciferase reporter, and functional rescue assays, we demonstrate that Ovol2 directly represses two critical downstream targets, c-Myc and Notch1, thereby suppressing keratinocyte transient proliferation and terminal differentiation, respectively. These findings shed light on how an epidermal cell maintains a proliferation-competent and differentiation-resistant state.

The aims of this study are to describe tumor characteristics and treatment patterns of elder breast cancer patients and to determine the factors influencing local and systemic treatments. This retrospective cohort included 866 patients (>or=60 years) referred for surgery between January 2002 and December 2006. The patients were divided into four groups according to age. Elderly women had larger tumors at diagnosis with more mucinous carcinomas, more estrogen/progesterone-positive, lower Ki-67 labeling indices and less c-erbB2 positive tumors. Comorbidities were more often recorded for older patients. They were more likely to undergo simple mastectomy or breast-conserving surgery, less likely to receive adjuvant chemotherapy and radiotherapy, compared with their younger counterparts. Multinomial and binary logistic regression showed that age was independently associated with local and systemic treatments. Our data suggest that the tumors of elderly patients are biologically more favorable, and elderly women appear to receive less aggressive treatments.

Many applications in materials involve surface diffusion of elastically stressed solids. Study of singularity formation and long-time behavior of such solid surfaces requires accurate simulations in both space and time. Here we present a high-order boundary integral method for an elastically stressed solid with axi-symmetry due to surface diffusions. In this method, the boundary integrals for isotropic elasticity in axi-symmetric geometry are approximated through modified alternating quadratures along with an extrapolation technique, leading to an arbitrarily high-order quadrature; in addition, a high-order (temporal) integration factor method, based on explicit representation of the mean curvature, is used to reduce the stability constraint on time-step. To apply this method to a periodic (in axial direction) and axi-symmetric elastically stressed cylinder, we also present a fast and accurate summation method for the periodic Green's functions of isotropic elasticity. Using the high-order boundary integral method, we demonstrate that in absence of elasticity the cylinder surface pinches in finite time at the axis of the symmetry and the universal cone angle of the pinching is found to be consistent with the previous studies based on a self-similar assumption. In the presence of elastic stress, we show that a finite time, geometrical singularity occurs well before the cylindrical solid collapses onto the axis of symmetry, and the angle of the corner singularity on the cylinder surface is also estimated.

Most nutrient solution studies on the interactions between silicon (Si) and cadmium (Cd) are short term. Here we reported a long-term experiment in which rice (Oryza sativa L.) was cultured for 105 days and harvested at four different growth stages to measure biomass accumulation and Cd uptake and distribution in shoots and roots. Exogenous Si increased shoot biomass by 61–238% and root biomass by 48–173% when the culture solution was free of Cd. When 2 μmol L−1 Cd was added, Si supply increased shoot and root biomass by 125–171% and by 100–106% compared to the zero-Si treatment. Increasing the Cd concentration to 4 μmol L−1 decreased the beneficial effects of Si on root and shoot biomass. Silicon supply decreased shoot Cd concentrations by 30–50% and Cd distribution ratio in shoot by 25.3–46%, compared to the treatment without Si supply. Additionally, lower Si supply or more serious Cd stress would lead to roots with bigger biomass and higher Si concentration. Energy-dispersive X-ray microanalysis showed that both Si and Cd accumulated synchronously in the border and middle of phytoliths of the shoots. We conclude that Si enhances plant growth and decreases Cd accumulation in shoots and thereby helps to lower the potential risks of food contamination.

Cellular signaling pathways transduce extracellular signals into appropriate responses. These pathways are typically interconnected to form networks, often with different pathways sharing similar or identical components. A consequence of this connectedness is the potential for cross talk, some of which may be undesirable. Indeed, experimental evidence indicates that cells have evolved insulating mechanisms to partially suppress “leaking” between pathways. Here we characterize mathematical models of simple signaling networks and obtain exact analytical expressions for two measures of cross talk called specificity and fidelity. The performance of several insulating mechanisms—combinatorial signaling, compartmentalization, the inhibition of one pathway by another, and the selective activation of scaffold proteins—is evaluated with respect to the trade-off between the specificity they provide and the constraints they place on the network. The effects of noise are also examined. The insights gained from this analysis are applied to understanding specificity in the yeast mating and invasive growth MAP kinase signaling network.

When explicit time discretization schemes are applied to stiff reaction-diffusion equations, the stability constraint on the time step depends on two terms: the diffusion and the reaction. The part of the stability constraint due to diffusion can be totally removed if the linear diffusions are treated exactly using integration factor (IF) or exponential time differencing (ETD) methods. For systems with severely stiff reactions, those methods are not efficient because the reaction terms in IF or ETD are still approximated with explicit schemes. In this paper, we introduce a new class of semi-implicit schemes, which treats the linear diffusions exactly and explicitly, and the nonlinear reactions implicitly. A distinctive feature of the scheme is the decoupling between the exact evaluation of the diffusion terms and implicit treatment of the nonlinear reaction terms. As a result, the size of the nonlinear system arising from the implicit treatment of the reactions is independent of the number of spatial grid points; it only depends on the number of original equations, unlike the case in which standard implicit temporal schemes are directly applied to the reaction-diffusion system. The stability region for this class of methods is much larger than existing methods using an explicit treatment of reaction terms. In particular, the one with second order accuracy is unconditionally linearly stable with respect to both diffusion and reaction. Direct numerical simulations on test equations, as well as morphogen systems from developmental biology, show the new semi-implicit schemes are efficient, robust and accurate.

The equilibrium shapes of misfitting precipitates in elastically anisotropic systems are obtained in both two and three dimensions, and the corresponding Gibbs–Thomson equation is derived as a function of the characteristic ratio between elastic and interfacial energies, L 0 . The effect of elastic inhomogeneity is investigated systematically. For soft or moderately hard particles, the stable equilibrium shape bifurcates from a fourfold symmetric shape to a twofold symmetric one in 2D and from a cubic symmetric shape to a plate-like one in 3D. For a very hard particle, the shape bifurcation is not observed in 2D for the range of L 0 investigated, but both plate-like and rod-like shapes are found in 3D. The computed Gibbs–Thomson equation is well approximated by a piecewise linear function of L 0 . Predictions are made for coarsening of many-particle systems based on an established mean-field theory. The results predict that the elastic stress has no effect on coarsening kinetics where most particles are highly symmetric (fourfold in 2D and cubic in 3D), and the exponent remains 1/3 but the rate constant increases if stress is sufficient to induce symmetry-breaking bifurcation on most particles.

Many patterns of cell and tissue organization are specified during development by gradients of morphogens, substances that assign different cell fates at different concentrations. Gradients form by morphogen transport from a localized site, but whether this occurs by simple diffusion or by more elaborate mechanisms is unclear. We attempt to resolve this controversy by analyzing recent data in ways that appropriately capture the complexity of systems in which transport, receptor interaction, endo- and exocytosis, and degradation occur together. We find that diffusive mechanisms of morphogen transport are much more plausible—and nondiffusive mechanisms much less plausible—than has generally been argued. Moreover, we show that a class of experiments, endocytic blockade, thought to effectively distinguish between diffusive and nondiffusive transport models actually fails to draw useful distinctions.