Fold Variation Research Articles

Assessment of genetic variability for grain nutrients from diverse regions: potential for wheat improvement.

Background A total of 150 bread wheat genotypes representing 121 Indian and 29 Turkish origin were screened for nutrient concentrations and grain protein content. Elemental and grain protein composition were studied by Inductively Coupled Plasma-Atomic Emission Spectrophotometer and LECO analyser, respectively. The study was performed to determine the variability in nutrient concentrations present in the collected wheat genetic material from two countries.ResultsSeveral fold variations among genotypes existed for almost all the elements. Three major components of principal component analysis (PCA) revealed 60.8% variation among the genotypes. Nutrient variables segregated into two groups, one group containing all the macroelements except sulphur; and another cluster containing proteins and all the microelements except Zn and Mn. Pearson correlation analysis and heat-map were in accordance with each other determining strong positive association between P–K, Mn–Zn, Mg–S and Cu–protein content. Also, PCA and hierarchical grouping divided all the Indian and Turkish genotypes in two main clusters.ConclusionsNutritional profile differentiated the genotypes from two countries into separate groups. However, some of the varieties were closely associated and indicated the success of global wheat exchange programs. While most of the correlations were in agreement with the previous studies, non-association of zinc with grain protein content directed towards its control by some other genetic factors. Some of the experimental wheat varieties with promising nutrient content have been suggested for future wheat advancement programs. Results obtained will be supportive for breeders involved in wheat biofortification programs, food industries and people relying on whole grain wheat products.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-3586-2) contains supplementary material, which is available to authorized users.

Genetic variation in physiological responses of mungbeans (Vigna radiata (L.) Wilczek) to drought

Mungbean is a relatively drought tolerant leguminous crop with a short life cycle. Using leaf water loss (LWL) as a screen for drought tolerance, two mungbean genotypes exhibiting more than two–fold variation in leaf water loss were explored for the genetic variation in their physiological and molecular responses to drought. Efficient stomatal regulation together with better photosynthetic capacity constituted an important trait combination for drought adaptation in water saving low LWL genotype. The stomatal closure under drought was accompanied with a concomitant down-regulation of farnesyl transferase gene. However, cooler canopy temperature, a well branched root system coupled with a relatively higher proline accumulation in water spending high LWL genotype constituted another set of adaptive traits operating when exposed to deficit soil moisture conditions. We report drought induced down-regulation of proline dehydrogenase and the presence of 118 base pair intron in this gene. The high seed yield of low LWL genotype despite a hotter canopy might be attributed to higher net assimilation and quantum yield recorded under drought in this genotype. Thus, these interlinked features contribute to adaptive mechanisms of mungbeans which is widely grown in harsh environments exposed to drought and high temperatures.

The effect of vocal fold vertical stiffness variation on voice production

A parametric study was conducted using the numerical technique that coupled a three-dimensional continuum vocal fold model with a one-dimensional Bernoulli flow model to investigate the effect of vocal fold vertical stiffness variation on voice production. Vertical stiffness gradient was defined as the ratio of the inferior-superior stiffness difference to the mean stiffness and was introduced in the cover layer. The results showed that increasing the vertical stiffness gradient would increase the peak flow rate and sound intensity and decrease the open quotient and threshold pressure. The effect was found to be more prominent at low subglottal pressures. The underlying mechanism might be that the reduced stiffness at the superior aspect of the vocal fold would allow a larger lateral displacement and result in a larger vibration. Increasing the vertical stiffness gradient was also found to increase the vertical phase difference and glottal divergent angle during the vocal fold vibration. Meanwhile, increasing the vertical stiffness variation only slightly increased the mean flow rate, which is important to maintaining the speech time between breaths.

Estimating Maximal In Vitro Skin Permeation Flux from Studies Using Non-sink Receptor Phase Conditions.

This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data. Simulated diffusion model and experimental IVPT data were generated for ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in ethyl salicylate solubility. Both simulated and experimental IVPT - time profiles were markedly affected by receptor phase solubility and receptor sampling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect. Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.

Herbaceous diversity and composition in mixed Juniperus Pinchotii-Prosopis Glandulosa communities in Southern mixed-grass prairie

ABSTRACTHerbaceous biomass and composition were measured across a continuum of increasing cover of mixed Prosopis glandulosa and Juniperus pinchotii woody plant from 1996 to 2003. The study site in northwest Texas had no history of woody plants treatment and comprised trees up to 6 m tall with cover averaging 65%. A strong, negative, linear relationship between woody plant cover and herbaceous biomass was measured (p = 0.0001). Precipitation differences resulted in 2.7 fold variation in herbaceous biomass between years (p = 0.003) and affected the slope of the decline of herbaceous biomass associated with increasing woody plant cover (p = 0.034). Within any year the slope of decline of herb biomass was parallel for Prosopis and Juniperus cover (p = 0.843). Relative to zero woody cover, 100% Prosopis cover reduced herbaceous biomass by 56% (p = 0.0001) while 100% Juniperus cover reduced herbaceous biomass 73% (p = 0.0001). At 100% cover Prosopis had twice the herbaceous biomass compared to Juniperus (p = 0.0021) but both species reduced herbaceous biomass by ± 1300 kg ha−1. Warm season herb biomass decreased with increasing Prosopis or Juniperus cover while cool season herbaceous biomass was minimally influenced by increases of either species. Multivariate analysis indicated vegetation associations differed between tree species. Vegetation differed (p = 0.001) between low (<25%) and high (>75%) Prosopis cover (dissimilarity R = 0.98), between low and high Juniperus cover (R = 0.81). Ten herbaceous species consistently decreased and 2 consistently increased with increasing woody plant cover.

Spatial differences in growth of lesser sandeel in the North Sea

Lesser sandeel, Ammodytes marinus, is a key prey to a variety of North Sea predators, including species such as single load seabirds which are highly sensitive to prey size and condition. Whilst differences in weight at age across the North Sea have been investigated previously, the scale and cause of this variation as well as the potential link to spatial differences in predator performance remains unknown. This study presents an analysis of spatial patterns in length and condition of the lesser sandeel in the North Sea and the relationship of these with physical and biological factors. Both mean length at age and condition was higher on warmer, deeper and central/north eastern fishing grounds. Sandeel in the water column exhibited large changes in condition over the season, having an initially low condition following spring emergence rising to a pronounced peak by June. Weight at age varied considerably both spatially and temporally, resulting in 4 fold and 1.9 fold variations in the number of sandeels required to obtain a specific weight, respectively. Hence, the value of sandeel as prey to single load predators varies considerably with values in central and northeastern North Sea being substantially higher than in northwestern and southern areas.

On Cancer Risk and the Hierarchical Architecture of Tissues

Tomasetti and Vogelstein (Science, 2 Jan. 2015, p. 78) demonstrated that cancer risk in different tissues is correlated with the total number of stem cell divisions, and concluded that the majority of cancer risk is attributable to “bad luck”. Here we show that their interpretation of the observed correlation is fundamentally flawed, and a thousand fold variation in risk remains after accounting for differences in the total number of stem cell divisions. We also explore possible explanations for the observed slower than linear increase of cancer risk with the total number of stem cell divisions and argue that this is the result of “Peto's paradox among somatic tissues”.During each division cells are subject to mutations, thus constantly renewing tissues inevitably accumulate mutations over time, which can potentially lead to the development of cancer. Here we show that the theoretical minimum of the number of cell divisions during tissue maintenance over a lifetime can be closely approached with a hierarchical tissue architecture. Thus, one of the main reasons of the existence of such hierarchical architecture in multicellular organisms is to minimize somatic evolution and prevent cancer. Such a hierarchical architecture is also vital in the germline (e.g. in spermatogenesis) to minimize the number of mutations passed on to the next generation.

Characterization of Intrinsic Properties of Promoters.

Accurate characterization of promoter behavior is essential for the rational design of functional synthetic transcription networks such as logic gates and oscillators. However, transcription rates observed from promoters can vary significantly depending on the growth rate of host cells and the experimental and genetic contexts of the measurement. Furthermore, in vivo measurement methods must accommodate variation in translation, protein folding, and maturation rates of reporter proteins, as well as metabolic load. The external factors affecting transcription activity may be considered to be extrinsic, and the goal of characterization should be to obtain quantitative measures of the intrinsic characteristics of promoters. We have developed a promoter characterization method that is based on a mathematical model for cell growth and reporter gene expression and exploits multiple in vivo measurements to compensate for variation due to extrinsic factors. First, we used optical density and fluorescent reporter gene measurements to account for the effect of differing cell growth rates. Second, we compared the output of reporter genes to that of a control promoter using concurrent dual-channel fluorescence measurements. This allowed us to derive a quantitative promoter characteristic (ρ) that provides a robust measure of the intrinsic properties of a promoter, relative to the control. We imposed different extrinsic factors on growing cells, altering carbon source and adding bacteriostatic agents, and demonstrated that the use of ρ values reduced the fraction of variance due to extrinsic factors from 78% to less than 4%. This is a simple and reliable method to quantitatively describe promoter properties.

Abstract A28: Bioenergetic analysis of primary human mammary epithelial cells (hMECs)

Abstract We have demonstrated reversible suppression of the tumor suppressor protein p53 by respiratory chain deficiency. Further, a recent study from a different group also suggests genetic inactivation of p53 by the impairments of oxidative metabolism, and mutations in mtDNA and TP53 gene coexist in cancers. Therefore, we predict that variation in oxidative metabolism can result in differences in p53 response among individuals. Conditions that suppress oxidative metabolism can impair p53, and thereby promote cancer development. Toward testing this hypothesis, our approach is to quantify the variation in respiratory activity of normal human mammary epithelial cells (hMECs), and then determine the correlation between respiratory activity and p53 response. Thus, we have performed in situ respirometry using 24-well Seahorse Bioscience's Extracellular Flux (XF) Analyzer on hMECs (at passage 2) isolated from breast cancer patients (n=23). The hMECs were isolated from cancer affected (AB) and non-affected (NAB) breasts and differences in parameters affecting mitochondrial bioenergetics under normal and treated (IGF1, TNFα;) conditions were assessed. Our data show 6-9 fold variation in hMECs basal respiratory activity (n=23). Further, 48%, 30% and 22% of patients showed either no difference in mitochondrial respiratory capacity upon addition of pyruvate (-2±5%), or showed at least 10% increase (26±18%) or decrease (-15±3%), respectively. Treatments with selected cytokines such as IGF1 and TNFα; for 24 hours altered the mitochondrial bioenergetics of hMECs. Overall they reduced respiratory activity in cells; and altered response to pyruvate addition in some individuals. Interestingly, matched normal hMECs from affected (AB) and not affected (NAB) breasts showed differences in the respiratory activity even at passage 2 suggesting that local environments play a critical role in the bioenergetics of normal cells and these changes do not revert ex vivo immediately when cells are removed from their environment. Acknowledgements: This work was supported by funds from Rays of Hope and Incubator grants from the Baystate Health Foundation, CEAR at the PVLSI supported by an award (A00000000004448) from Massachusetts Technology Collaborative as administrator of the John Adams Innovation Institute. Citation Format: Elizabeth M. Henchey, Sallie S. Schneider, D. Joseph Jerry, Nagendra Yadava. Bioenergetic analysis of primary human mammary epithelial cells (hMECs). [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A28.

Population Pharmacokinetics of Fludarabine and Treosulfan in Patients with Thalassemia Undergoing Hematopoietic Stem Cell Transplantation

A toxicity reduced conditioning regimen containing Treosulfan (Treo), fludarabine (Flu), thiotepa for high risk Thal Major (TM) has been used since 2009 at our centre that has significantly improved transplant outcomes of these patients compared to the historical cohort of patients receiving busulfan/ cyclophosphamide based myeloablative regimen (Mathews et al, 2013). Limited knowledge is available on the pharmacokinetics (PK), pharmacogenetics (PG) and pharmacodynamics of fludarabine and treosulfan, especially in non-malignant hematological disorders like TM. We describe here the PK of Flu and Treo in patients with TM undergoing HSCT, the factors influencing the inter-individual variability in PK and the role of these factors on HSCT outcome.Seventy one patients diagnosed with TM undergoing HSCT with Flu/Treo based conditioning regimen between January 2012 and January 2015 were included (Table: Patient demographics). Selected functional polymorphisms in the NT5E, DCK, hENT1 and GST genes that are involved in fludarabine or treosulfan metabolism were screened. All patients received Flu 40mg/m2/day x 4 days as an 1hr infusion on days 1 and 4 and Treo as 14g/m2/day x 3 days at the rate 5g/hr. Plasma was separated from the peripheral blood collected at predetermined time points after the infusion of Flu and Treo PK analysis. Plasma Flu was analyzed using a LC-MS/MS method and the concentration was expressed as mMole/ml while Treo was analyzed using a HPLC-RI method and concentration was expressed as mg/L. Flu and Treo PK was estimated using nonlinear mixed effects modeling via Monolix 4.3.3. The covariates tested for both PK were: age, sex, body weight, BSA, ferritin, and polymorphisms in NT5E, hENT1, dCK and GST genes. The PK parameters AUC, CL, V and k were estimated on day 1 for Treo and on day 1 and day 4 for Flu (Table). The influence of Flu and Treo PK and PG on graft rejection, early transplant related mortality (TRM) & chimerism status was estimated using logistic regression analysis.Wide inter-individual variation in Flu and Treo PK was noted (7 and 9 fold Vs 5 and 8 fold respectively for Day 1 & 4 Flu AUC & Cl; 33 & 31 fold variation in Treo AUC and Cl) (Table). Flu CL was significantly higher on day 4 compared to day1 (Figure A). The variation in Flu PK was explained by genetic variants in NT5E and dCK. Patients having variant genotype for the SNPs in NT5E (rs2295890) and dCK (rs11544786) showed significantly lower plasma Flu clearance compared to those with wild type genotype (p=0.006 & p=0.05 respectively) (Figure B). This is consistent with our previous report in patients with aplastic anemia undergoing HSCT (Mohanan et al. 2014; Blood: 124 (21)). None of the genetic variants in the GST genes explained the variation in Treo PK.Day21 mortality was seen in 6/71 patients (8.5%) and graft rejection in 3/66 evaluable patients (4.5%). Analysis of the influence of PK and PG variables on transplant outcome showed significantly high first dose Flu AUC to be associated with D21 mortality upon Univariate analysis (median 42.5, range 32.1-63.7 compared to 31.8, range 15.2-111 mMole*h/mL, in those with and without TRM respectively; p=0.043); none of these parameters were significantly associated with graft rejection or mixed chimerism. There was no association between Treo PK parameters and graft rejection or TRM. The influence of Flu and Treo PK on regimen related toxicity is yet to be evaluated. The lack of the influence of PK on transplant outcome could be due to lower incidence of rejection and TRM in this cohort. Further analysis in a larger cohort of patients will be done once we enroll more patients for PK analysis.Our results demonstrate that Flu PK is influenced by genetic variants in NT5E and dCK, the enzymes involved in Flu biotransformation. The relationship between high-plasma Flu exposure and TRM and given the fact that multiple factors influence TRM, we can extrapolate that the plasma Flu AUC may be a surrogate marker of overall preparative regimen intensity as reported previously (Long-Boyle et al, Bone Marrow Transplant, 2011). The lack of association of genetic variants in GST genes in explaining the inter-patient variability in treosulfan exposure suggests the involvement of other drug metabolizing genes on treosulfan PK. We are currently evaluating the role of genetic variants in a large panel of drug metabolizing genes on explaining this inter-individual variability in Treo PK. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PDB30 - Cost Analysis Study of Anti-Diabetic Fixed Dose Combination Drugs: An Indian Scenario

To compute the annual cost of FDC drugs used in the treatment of Type2 Diabetes Mellitus (T2DM) and study the variation in the costs. Indian Council of Medical Research (ICMR) and International Diabetes Federation (IDF) guidelines were used to understand the treatment of T2DM. Current Index of Medical Specialities (CIMS) Oct- Jan 2015 issue and Indian Drug Review (IDR) issue 1, Jan 2015 were used to capture the prices of medicines available in the Indian market. The annual cost of treatment and variation in the annual cost of drugs was studied. Recommended first line FDC according to International Diabetes Federation is metformin + sulfonylurea. If we initiated the treatment with metformin + glimepiride (500mg + 1mg) OD, then annual cost of treatment was found to be Rs.438-2744. A maximum variation of 533% was noted in the least-highest cost of treatment. A minimum of 1% variation was observed for metformin + glipizide (2.5mg + 400mg) OD, among combination therapy in its least-highest cost of treatment. Likewise, if the treatment is initiated with other combination therapy, say metformin + pioglitazone (500mg +15mg) BD, then annual cost of treatment was found to be Rs.1387-6935. This showed a maximum variation of 665% in its least-highest cost of treatment. On the other hand metformin + voglibose (500 + 0.3mg) combination showed a minimum price variation of 86% only. It was concluded that a maximum of 6 fold variation was observed in the least-highest costs of treatment with metformin + voglibose (500mg + 0.3mg). A wide variation exist in the minimum and maximum price of anti-diabetic FDC manufactured across the different brands available in the Indian market.

Control over overall shape and size in de novo designed proteins

We recently described general principles for designing ideal protein structures stabilized by completely consistent local and nonlocal interactions. The principles relate secondary structure patterns to tertiary packing motifs and enable design of different protein topologies. To achieve fine control over protein shape and size within a particular topology, we have extended the design rules by systematically analyzing the codependencies between the lengths and packing geometry of successive secondary structure elements and the backbone torsion angles of the loop linking them. We demonstrate the control afforded by the resulting extended rule set by designing a series of proteins with the same fold but considerable variation in secondary structure length, loop geometry, β-strand registry, and overall shape. Solution NMR structures of four designed proteins for two different folds show that protein shape and size can be precisely controlled within a given protein fold. These extended design principles provide the foundation for custom design of protein structures performing desired functions.

Piezoelectric-driven droplet impact printing with an interchangeable microfluidic cartridge

Microfluidic impact printing has been recently introduced, utilizing its nature of simple device architecture, low cost, non-contamination, and scalable multiplexability and high throughput. In this paper, we have introduced an impact-based droplet printing platform utilizing a simple plug-and-play microfluidic cartridge driven by piezoelectric actuators. Such a customizable printing system allows for ultrafine control of droplet volume from picoliters (∼23 pl) to nanoliters (∼10 nl), a 500 fold variation. The high flexibility of droplet generation can be simply achieved by controlling the magnitude of actuation (e.g., driving voltage) and the waveform shape of actuation pulses, in addition to nozzle size restrictions. Detailed printing characterizations on these parameters have been conducted consecutively. A multiplexed impact printing system has been prototyped and demonstrated to provide the functions of single-droplet jetting and droplet multiplexing as well as concentration gradient generation. Moreover, a generic biological assay has also been tested and validated on this printing platform. Therefore, the microfluidic droplet printing system could be of potential value to establish multiplexed micro reactors for high-throughput life science applications.

Risk Factors and Epidemiology of Gastric Cancer in Pakistan.

Gastric cancer is the 2nd most common cause of death among all cancers and is the 4th most common cancer in the world. The number of deaths due to gastric cancer is about 800,000 annually. Gastric cancer is more common in men as compared to women and is 3rd most common cancer after colorectal and breast cancers in women. A progressive rise in the incidence rate has been observed in females over the last 5 years. The highest incidence of stomach cancer is in China, South America and Eastern Europe. The incidence of gastric cancer has 20 fold variation worldwide. Global variation is linked by two factors which play important role in developing gastric cancer. One is infection with Helicobacter pylori and the 2nd is diet. South Asia is a region with low risk, despite a high prevalence of H.pylori. Gastric carcinoma is common in southern region of India. Gastric cancer is more readily treated if diagnosed early. This study aims to provide awareness about gastric cancer as well as an updated knowledge about risk factors and epidemiology of gastric cancer in Pakistan.

Bacterial growth efficiency in a partly eutrophicated bay of South China Sea: Implication for anthropogenic impacts and potential hypoxia events.

Bacterial metabolism plays a dual role [bacterial production (BP) and bacterial respiration (BR)] in the aquatic ecosystem and potentially leads to hypoxia in the coastal eutrophic area. Bacterial growth efficiency (BGE) is an important index showing the contribution of bacterial metabolism to marine biological production and carbon budget in the pelagic ecosystem. In this study, the spatial and seasonal variety as well as diurnal variation dynamics of BGE and associated ecological characteristics were investigated in a partly eutrophicated subtropical bay (the Daya Bay) located in the northern South China Sea. Furthermore, the relationship between bacterial metabolism and potential hypoxia event was analyzed. The average BGE was 0.14 and 0.22 in summer and winter, respectively, which was lower than the mean value ever reported in other coastal and estuarine waters. The diurnal variations of BGE and BP were widely fluctuated in the Daya Bay, with approximately 3-8 fold variation of BP and 2-3 fold variation of BR in different seasons, suggesting the importance of short-term ecological dynamics on evaluating the long-term ecological processes in the coastal waters. BR was the predominant contributor to the bacterial carbon demand; however, the variation of BGE was controlled by BP in both seasons. BGE was always high in the near-shore waters with higher eutrophic level and more active BP and BR. The bacterial metabolism could deplete dissolved oxygen (DO) in the Daya bay within about 9 days when the water body was enclosed and photosynthesis was prohibited. Therefore, low DO concentration and potential hypoxia was more likely to be found in the near-shore waters of the Daya Bay in summer, since the water was stratified and enclosed with poor water exchange capacity in this area. While in winter, hypoxia seldom occurred due to vertical mixing throughout the water column. Further biological-physical coupling research is recommended to find out the detailed formation mechanism of hypoxia in the bay, and to predict the potential hypoxia events and their environmental impacts in the future.

Quantitative Study for the Surface Dehydration of Vocal Folds Based on High-Speed Imaging

From the perspective of the glottal area and mucosal wave, quantitatively estimate the differences of vocal fold on laryngeal activity during phonation at three different dehydration levels. Controlled three sets of tests. A dehydration experiment for 10 excised canine larynges was conducted at 16cm H2O. According to the dehydration cycle time (H), dehydration levels were divided into three degrees (0% H, 50% H, 75% H). The glottal area and mucosal wave under three dehydration levels were extracted from high-speed images and digital videokymography (DKG) image sequences. Direct and non-direct amplitude components were derived from glottal areas. The amplitude and frequency of mucosal wave were calculated from DKG image sequences. These parameters in condition of three dehydration levels were compared for statistical analysis. The results showed a significant difference in direct (P = 0.001; P = 0.005) and non-direct (P = 0.005; P = 0.016) components of glottal areas between every two different dehydration levels. Considering the right-upper, right-lower, left-upper, and left-lower of vocal fold, the amplitudes of mucosal waves consistently decreased with increasing of dehydration levels. But, there was no significant difference in frequency. Surface dehydration could give rise to complex variation of vocal fold on tissues and vibratory mechanism, which should need analyzing from multiple perspectives. The results suggested that the combination of glottal area and mucosal wave could be better to research the change of vocal fold at different dehydrations. It would become a better crucial research tool for the clinical treatment of dehydration-induced laryngeal pathologies.

Cortical Folding of the Primate Brain: An Interdisciplinary Examination of the Genetic Architecture, Modularity, and Evolvability of a Significant Neurological Trait in Pedigreed Baboons (Genus Papio).

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ∼1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical-cortical connectivity, and gyrification's potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution.

Sequence and Misfolding in the Ancient TIM Barrel Motif

Protein folding energy landscapes have been driven by evolution to minimize the energetic and topological frustration experienced during the folding reaction. Small 2 state folders, whose folding rates correlate with their topologies, are good examples of evolution at work. However, larger proteins are often found to have partially-folded intermediates on their energy landscape, some of which can be misfolded. (βα)8 TIM barrel proteins, one of the most common motifs in biology, are one such class of proteins. Previous studies on several diverse TIM barrels have shown that the structures of their misfolded intermediates are not conserved. We hypothesize that large, local in sequence clusters of isoleucine, leucine, and valine (ILV) residues drive the formation of the misfolded intermediate in TIM barrels. These clusters are not conserved in the structures, but do correlate with strong protection against hydrogen exchange in folding intermediates. To test the generality of this hypothesis, we expanded our studies to the indole-3-glycerol phosphate synthase from S. solfataricus (sIGPS). sIGPS has two ILV clusters in different locations than those found in the E. coli α-subunit of trp synthase. The common fold but sequence variations allows a test of the importance of ILV clusters in the early misfolding events. Continuous-flow trFRET has been used to measure pair-wise distance distributions for several βα segments in the misfolded intermediate that appears after a few 10's of microseconds. To complement the pair-wise measurements, SAXS experiments provide global dimensions of the earliest folding events. The insights obtained will explore the link between sequence, ILV clusters and misfolding for the TIM barrel architecture. NIH GM23303.

Cellular processes involved in human epidermal cells exposed to extremely low frequency electric fields

We observed on different tissues and organisms a biological response after exposure to pulsed low frequency and low amplitude electric or electromagnetic fields but the precise mechanism of cell response remains unknown. The aim of this publication is to understand, using bioinformatics, the biological relevance of processes involved in the modification of gene expression. The list of genes analyzed was obtained after microarray protocol realized on cultures of human epidermal explants growing on deepidermized human skin exposed to a pulsed low frequency electric field. The directed acyclic graph on a WebGestalt Gene Ontology module shows six categories under the biological process root: “biological regulation”, “cellular process”, “cell proliferation”, “death”, “metabolic process” and “response to stimulus”. Enriched derived categories are coherent with the type of in vitro culture, the stimulation protocol or with the previous results showing a decrease of cell proliferation and an increase of differentiation. The Kegg module on WebGestalt has highlighted “cell cycle” and “p53 signaling pathway” as significantly involved. The Kegg website brings out interactions between FoxO, MAPK, JNK, p53, p38, PI3K/Akt, Wnt, mTor or NF-KappaB. Some genes expressed by the stimulation are known to have an exclusive function on these pathways. Analyses performed with Pathway Studio linked cell proliferation, cell differentiation, apoptosis, cell cycle, mitosis, cell death etc. with our microarrays results. Medline citation generated by the software and the fold change variation confirms a diminution of the proliferation, activation of the differentiation and a less well-defined role of apoptosis or wound healing. Wnt and DKK functional classes, DKK1, MACF1, ATF3, MME, TXNRD1, and BMP-2 genes proposed in previous publications after a manual analysis are also highlighted with other genes after Pathway Studio automatic procedure. Finally, an analysis conducted on a list of genes characterized by an accelerated regulation after extremely low frequency pulsed stimulation also confirms their role in the processes of cell proliferation and differentiation. Bioinformatics approach allows in-depth research, without the bias of pre-selection, on cellular processes involved in a huge gene list.

Proteomics analysis of urine reveals acute phase response proteins as candidate diagnostic biomarkers for prostate cancer.

Despite the overall success of prostate specific antigen (PSA) in screening and detection of prostate cancer (PCa), its use has been limited due to the lack of specificity. The principal driving goal currently within PCa research is to identify non-invasive biomarker(s) for early detection of aggressive tumors with greater sensitivity and specificity than PSA. In this study, we focused on identification of non-invasive biomarkers in urine with higher specificity than PSA. We tested urine samples from PCa and benign prostatic hyperplasia (BPH) patients by 2-D DIGE coupled with MS and bioinformatics analysis. Statistically significant (p < 0.05), 1.8 fold variation or more in abundance, showed 41 spots, corresponding to 23 proteins. The Ingenuity Pathway Analysis showed significant association with the Acute Phase Response Signaling pathway. Nine proteins with differential abundances were included in this pathway: AMBP, APOA1, FGA, FGG, HP, ITIH4, SERPINA1, TF and TTR. The expression pattern of 4 acute phase response proteins differed from the defined expression in the canonical pathway. The urine levels of TF, AMPB and HP were measured by immunoturbidimetry in an independent validation set. The concentration of AMPB in urine was significantly higher in PCa while levels of TF and HP were opposite (p < 0.05). The AUC for the individual proteins ranged from 0.723 to 0.754. The combination of HP and AMBP yielded the highest accuracy (AUC = 0.848), greater than PSA. The proposed biomarker set is quickly quantifiable and economical with potential to improve the sensitivity and specificity of PCa detection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12953-014-0059-9) contains supplementary material, which is available to authorized users.