Interlinked Pathways Research Articles

Problems and Solutions: A Scaled-up Electrode for Li-S Batteries

The recent rapid expansion of the Li-ion battery (LIB) market has been fueled by the rapid increase in demand for electric vehicles and energy storage systems (ESS) that are able to run and last longer. The Li-S battery (LSB), which has attracted much attention due to the very high theoretical reversible specific capacity of sulfur cathodes, 1675 mA h g−1, leading to a very high theoretical energy density of LSBs, 2600 Wh kg−1. In addition, sulfur is both inexpensive and abundant.1 However, both sulfur and Li2S (the final sulfur reduction product) have poor inherent electrical conductivity. Another inherent problem of any LSB containing a cathode with a high loading of sulfur, is the massive dissolution of the LiSn moieties formed by sulfur reduction that leads to a subsequent loss of active material.2 Once LiSn products are dissolved in the electrolyte solution, they diffuse to the Li anode and undergo continuous reduction processes, causing a phenomenon known as the shuttle mechanism during cycling, which prevents full recharge of the sulfur reduction products in LSBs. Much effort has been devoted in recent years to overcome the intrinsic problems of sulfur cathodes. We concentrate here on attempts to develop freestanding sulfur cathodes. A freestanding electrode is fabricated without binder and powdery conductive materials, thereby allowing higher percentages of active material in the cathode. In addition, because of their porous structure, freestanding electrodes can provide 3D interlinked pathways for electrons and Li+ ions, thereby improving the electrochemical response of sulfur in the cathode.3 In order to promote the practical development of LSBs, it is imperative to investigate the performance of scaled-up LSBs and solve technical problems which cannot be considered at the level of small-scale cells. For that purpose, we have developed an up-scaling methodology for Li-S batteries based on pouch cell assembly, using freestanding electrodes. The stacked pouch cells we prepared demonstrated high discharge capacity and rate capability at a high sulfur loading of 2.8 mg cm-2. However, we experienced relatively poor cycling performance of pouch cells containing metallic lithium anodes, which can be attributed to the localized mossy growth of metallic lithium deposits in the charging process. In order to resolve this problem that arises from the poor behavior of Li metal anodes in these cells, we developed long-term lithium-ion sulfur pouch cells containing prelithiated C-coated Si/SiOx anodes which do not suffer from dendritic growth of Li. In this work we did not intend to develop new materials or to develop sulfur electrodes with fully practical high loading. We concentrated in the challenge of up-scaling Li-S battery prototypes from small laboratory coin type cells to much larger pouch cells. A. Rosenman, E. Markevich, G. Salitra, D. Aurbach, A. Garsuch, F. F. Chesneau, Adv. Energy Mater. 2015, 5, 1500212H. A. Salem, G. Babu, C. V. Rao, L. M. R. Arava, J. Am. Chem. Soc. 2015,137, 11542H.-S. Kang, Y.-K. Sun, Adv. Funct. Mater. 2016, 26, 1225

Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health.

Sulfur-containing amino acids are integral to the molecular mechanisms that underlie many aspects of cellular function and homeostasis, facilitated by reversible changes in the oxidation states of sulfur atoms. Sulfur-containing amino acids are metabolically linked by interacting pathways that impact the one-carbon metabolic cycle and generation of methyl groups, the folate cycle, and maintenance of the major cellular redox buffer; glutathione. Dysregulation of these pathways is associated with diverse pathologies, notably of the cardiovascular (CV) system, which are typically characterized by inappropriate plasma levels of sulfur-containing amino acids. Recent Advances: Perhaps not surprisingly, the cellular redox state has emerged as a major regulator of many enzymatic processes within these metabolic cycles. The metabolism of cysteine can also result in the production of hydrogen sulfide (H2S), a signaling molecule whose activity is potentially linked to intracellular levels of both reactive oxygen species (ROS) and molecular oxygen. In most cases, the endogenous physiological sources of ROS that might mediate the interlinked metabolic pathways of sulfur-containing biomolecules remain unknown. However, the family of NADPH oxidases, and Nox4 in particular, is emerging as a likely candidate. This review focuses on the current knowledge of key aspects of sulfur metabolism, which are regulated by redox-based chemical reactions, and the likely intracellular oxidant sources that might mediate this regulation. This knowledge will be important to guide future targeted therapeutic interventions in diverse CV disorders.

Soil as a Basic Nexus Tool: Soils at the Center of the Food–Energy–Water Nexus

Soil is the medium for plant growth and the substrate for all biogeochemical and biogeophysical processes. Soil’s unique natural organization forms the foundation of any food–water–energy nexus system. It forms a habitat for billions of diverse micro, meso, and macrofauna and flora and is the basis of numerous ecosystem services essential to human well-being and nature conservancy. It moderates soil hydrological processes within the entire vadose zone: which is part of the earth between the soil surface and the phreatic zone. Soil structure also supports numerous ecosystem services including nutrient transformation and availability, water quality and renewability, denaturing and transport of pollutants, and groundwater table fluctuations. It also moderates the soil–water–plant-energy nexus with the replenishement of green-water supply (from precipitation) for plants and soil biota, which in turn enables the production of biomass as a source of food, feed, fiber, and biofuel feedstock. Indeed, soil is a very large reservoir for water and carbon with strong influences on local, regional, and global climate. Also, the energy factor is connected with the climate change through soil–water–food–energy nexus because of numerous interlinked pathways including gaseous emissions, energy and food production, and recycling of nutrients and water at regional, national, and global scales. Through provisioning of numerous ecosystem services, the soil–water–food–energy–climate nexus is interwoven with the ecosystem security and functioning of planet’s four ecospheres (i.e., atmosphere, hydrosphere, lithosphere, and the biosphere). Therefore, the health of soil, plants, animals, people, and ecosystems is one and indivisible. This interconnectivity is also the basis of the “4 per Thousand” initiative adopted by the COP21, the Climate Summit of 2015 in Paris, and “Adapting African Agriculture” (AAA) by COP22 in Morocco. Consequently, soil is not only a foundation for securing the natural resources: food, water and energy, but it is under desperate need to be integrated and appreciated in understanding the complex interconnectedness of any food, energy, water and soil system. Concentration and stock of soil organic carbon are the key soil properties that determine the physical, chemical, biological, and ecological properties and processes, and are major control of all nexuses described herein. This chapter presents a conceptual model and the role of soil as a naturally organized medium to protect global food, water, energy securities. Moreover, it elaborates on using soil as a basic nexus tool and proposes a paradigm shift in integrating soil and creating the food–energy–water–soil nexus.

GENOME-WIDE ASSOCIATION STUDY OF A MULTIMODAL IMAGING BIOMARKER IN THE ADNI COHORT

Genome-wide association studies (GWAS) in Alzheimer's disease (AD) using neuroimaging-based phenotypes are typically derived from a single imaging modality. However, AD is a complex disorder involving different inter-linked pathogenic pathways. To explore genetic influences on disease progression, we generated a novel disease progression score (DPS) comprising cortical β-amyloid levels and hippocampal volume, then using it as a quantitative phenotype in GWAS. Study participants were part of the AD Neuroimaging Initiative (ADNI). Hippocampal volumes were computed with FreeSurfer from T1-weighted MRI scans. Cortical Aβ42 levels were computed as standardised uptake values ratio (SUVR) from florbetapir PET scans. The AD-DPS was computed by jointly modelling the long-term time evolution of hippocampal volume and cortical SUVR for 1088 individuals, using the growth models via alternating conditional expectation (GRACE) algorithm. We used this DPS as a continuous phenotype for a GWAS in 846 subjects of Caucasian ancestry, covarying for sex, age, APOE4 status, baseline SUVR and 2 principal components of population structure. Additionally, we repeated the analysis stratified by APOE4 status. Progression curves were in good agreement with proposed models of AD biomarker evolution (Figures 1–2). A genome-wide significant association with AD-DPS was found on chromosome 4 for rs3733541 (p=9.45e-09), located 300 kbp upstream of the KIT gene (Figure 3). This association was not found when testing hippocampal volume and Aβ42 burden separately. There were no genome-wide significant SNPs in the stratified analyses. However, the standardised effect size for rs3733541 was greater in APOE4 non-carriers (β=-0.11± 0.02, p=9.5e-5) than in APOE4 carriers (β=-0.08±0.02, p=3e-3). We describe the first use of a DPS derived from multiple imaging modalities in a quantitative trait-GWAS. The KIT gene and its ligand stem cell factor (SCF) are involved in a pathway leading to migration and differentiation of neural stem cells to sites of brain injury. Significantly lower levels of SCF have been found in the plasma and CSF of patients with early AD. If validated in future studies, this novel susceptibility locus may influence the joint occurrence of hippocampal atrophy and amyloid deposition in AD. Long-term progression curves for two AD biomarkers. Left, florbetapir PET SUVR; right, bilateral hippocampal volume. Disease progression score stratified by diagnostic group (left) and by MCI progression status (right). Manhattan plots for the GWAS of hippocampal volume (top), amyloid burden (middle), disease progression score (bottom). The blue line is the threshold for suggestive associations at p = 1e-5; the red line is the threshold for genome-wide significant associations at p = 5e-8.

Radiation and Thyroid Cancer.

Radiation-induced damage is a complex network of interlinked signaling pathways, which may result in apoptosis, cell cycle arrest, DNA repair, and cancer. The development of thyroid cancer in response to radiation, from nuclear catastrophes to chemotherapy, has long been an object of study. A basic overview of the ionizing and non-ionizing radiation effects of the sensitivity of the thyroid gland on radiation and cancer development has been provided. In this review, we focus our attention on experiments in cell cultures exposed to ionizing radiation, ultraviolet light, and proton beams. Studies on the involvement of specific genes, proteins, and lipids are also reported. This review also describes how lipids are regulated in response to the radiation-induced damage and how they are involved in thyroid cancer etiology, invasion, and migration and how they can be used as both diagnostic markers and drug targets.

Modeling central metabolism and energy biosynthesis across microbial life

BackgroundAutomatically generated bacterial metabolic models, and even some curated models, lack accuracy in predicting energy yields due to poor representation of key pathways in energy biosynthesis and the electron transport chain (ETC). Further compounding the problem, complex interlinking pathways in genome-scale metabolic models, and the need for extensive gapfilling to support complex biomass reactions, often results in predicting unrealistic yields or unrealistic physiological flux profiles.ResultsTo overcome this challenge, we developed methods and tools (http://coremodels.mcs.anl.gov) to build high quality core metabolic models (CMM) representing accurate energy biosynthesis based on a well studied, phylogenetically diverse set of model organisms. We compare these models to explore the variability of core pathways across all microbial life, and by analyzing the ability of our core models to synthesize ATP and essential biomass precursors, we evaluate the extent to which the core metabolic pathways and functional ETCs are known for all microbes. 6,600 (80 %) of our models were found to have some type of aerobic ETC, whereas 5,100 (62 %) have an anaerobic ETC, and 1,279 (15 %) do not have any ETC. Using our manually curated ETC and energy biosynthesis pathways with no gapfilling at all, we predict accurate ATP yields for nearly 5586 (70 %) of the models under aerobic and anaerobic growth conditions. This study revealed gaps in our knowledge of the central pathways that result in 2,495 (30 %) CMMs being unable to produce ATP under any of the tested conditions. We then established a methodology for the systematic identification and correction of inconsistent annotations using core metabolic models coupled with phylogenetic analysis.ConclusionsWe predict accurate energy yields based on our improved annotations in energy biosynthesis pathways and the implementation of diverse ETC reactions across the microbial tree of life. We highlighted missing annotations that were essential to energy biosynthesis in our models. We examine the diversity of these pathways across all microbial life and enable the scientific community to explore the analyses generated from this large-scale analysis of over 8000 microbial genomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2887-8) contains supplementary material, which is available to authorized users.

Viral/Nonviral Chimeric Nanoparticles To Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing.

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.

Use of In Situ Proximity Ligation Assays for Systems Analysis of Signaling Pathways.

Understanding signaling pathway networks via protein-protein interactions (PPIs) at the cellular level is a significant task that has not yet been completed. Here, a systems approach that computationally infers interlinked pathways from numerous PPIs is described. The endogenous PPIs can be empirically detected using an in situ proximity ligation assay (PLA), which detects and visualizes endogenous PPIs and post-translational modifications of proteins with a high sensitivity and specificity. This unit includes two parts: (1) conversion of gene lists into PPIs for investigation and (2) large-scale detection and analysis of endogenous PPIs for elucidating pathway networks. © 2016 by John Wiley & Sons, Inc.

Noise propagation with interlinked feed-forward pathways.

Functionally similar pathways are often seen in biological systems, forming feed-forward controls. The robustness in network motifs such as feed-forward loops (FFLs) has been reported previously. In this work, we studied noise propagation in a development network that has multiple interlinked FFLs. A FFL has the potential of asymmetric noise-filtering (i.e., it works at either the “ON” or the “OFF” state in the target gene). With multiple, interlinked FFLs, we show that the propagated noises are largely filtered regardless of the states in the input genes. The noise-filtering property of an interlinked FFL can be largely derived from that of the individual FFLs, and with interlinked FFLs, it is possible to filter noises in both “ON” and “OFF” states in the output. We demonstrated the noise filtering effect in the developmental regulatory network of Caenorhabditis elegans that controls the timing of distal tip cell (DTC) migration. The roles of positive feedback loops involving blmp-1 and the degradation regulation of DRE-1 also studied. Our analyses allow for better inference from network structures to noise-filtering properties, and provide insights into the mechanisms behind the precise DTC migration controls in space and time.

NFkB pathway and inhibition: an overview

The nuclear factor kappa B (NFkB) modulates a broad range of cellular processes. NFkB pathway is stimulated by various signaling cascades and is involved in various cross-talks in the cell. NFkB controls the pro-inflammatory response by the TNFα and IL-1 signaling pathway. Inflammation is a defense mechanism of the body but when prolonged and chronic it results in various diseases, such as cancer, neurodegeneration, ageing, obesity, etc. NFkB pathway could be regulated at various levels to control chronic inflammation. As NFkB is involved in various cross-talks within the cell, a better understanding of the inter-linked pathway using computational modeling may introduce us with potential new drug targets. E3 ligases unlike other components of the pathway provide specificity, as it binds to the substrate molecule. Drugs designed to inhibit E3 ligase will ultimately choke the proteosomal degradation pathway and inhibit the NFkB pathway. This review provides the knowledge of the detailed NFkB pathway and its molecular mechanism. Also, we focused on computational modeling using deterministic and stochastic modeling methods in NFkB signaling pathway. This review also focuses on E3 ligases structure, function and inhibition by small-molecules as well as computational drug designing methods and their significance in finding new therapeutic candidates.

Combination therapy in the extended cardiovascular continuum: a focus on perindopril and amlodipine.

The progression of cardiovascular disease could be regarded as following atherosclerosis-related and age-related pathways. The starting points for these pathways are different--risk factors or aortic ageing--but they conclude in the same way: end-stage heart disease. Together these interlinked pathways form the extended cardiovascular continuum. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been shown to interrupt or slow the progression of cardiovascular disease along one pathway, the cardiovascular atherosclerotic continuum. Cardiovascular protection with RAAS inhibitors varies; different RAAS inhibitors offer different levels of protection. Similarly, calcium channel blockers (CCBs) also have clearly shown protective effect of cardiovascular system, especially as it regards cerebrovascular disease risk. The AngloScandinavian Cardiac Outcomes Trial (ASCOT) showed that a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and CCB amlodipine offered better cardiovascular protection in at-risk hypertensive patients than beta-blocker and thiazide. By attenuating the deleterious effects of cardiovascular disease at multiple stages of the extended cardiovascular continuum on top of lowering blood pressure (BP), perindopril and amlodipine could interrupt and slow the progression of cardiovascular disease. These antihypertensive agents have complementary vascular effects that enhance cardiovascular protection and reduce side-effects. Evidence from ASCOT shows that antihypertensive and vascular effects of amlodipine with and without perindopril have translated into real-life clinical benefits. A strategy using ACE inhibitors and CCBs, such as perindopril and amlodipine, to target multiple stages in both pathways of cardiovascular disease could effectively reduce cardiovascular risk and lower BP.

50 years forward: mechanisms of hyperglycaemia-driven diabetic complications

The advent of insulin treatment in 1923 meant fewer diabetes deaths from acute metabolic deterioration and sepsis and a progressive increase in the burden of disease caused by end-organ damage. These diabetic complications are the major cause of morbidity and premature mortality among diabetic subjects. Over the last 50 years it has become apparent that diabetic complications in disparate tissues may result from a combination of common pathological processes. Pathways activated by initial metabolic insults are promoted by co-factors such as renin-angiotensin-aldosterone system activation, hyperinsulinaemia, underlying genetic susceptibility, and traditional vascular risk factors, particularly hypertension and lipids. These common pathways include AGE formation, reactive oxygen species overproduction, protein kinase C activation, mitochondrial dysfunction and activation of proinflammatory and profibrotic signalling cascades. Once established, these interlinked pathways become self-perpetuating. Many drugs acting against individual downstream targets in these pathways have failed due to lack of efficacy or adverse effects. Gains in the future may be made by better control of existing risk factors, more sophisticated modulation of tissue glucose and insulin signalling, and interventions to improve mitochondrial function and reduce oxidative stress. Epigenetic and microRNA research may lead to methods to disrupt the mechanisms whereby pathological pathways are perpetuated. Expansion in capacity and expertise in biomarker measurement and analysis may allow better targeting of therapies to patients who are most likely to benefit. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

Two pathways to causal control: Use and availability of information in the environment in people with and without signs of depression

Perceiving one's causal control is important for adaptive behavior. Studying depression and other individual differences has provided insight into typical as well as pathological causal processing. We set out to study factors that have been shown to distinguish those with and without signs of depression and affect perceptions of causal control: levels of behavior, the availability of outcomes and learning about the environment or context. Two experiments were carried out in which participants, scoring low and high on the Beck Depression Inventory using established cutoffs, completed a causal control task, in which outcomes occurred with a low (.25) or high probability (.75). Behavior levels were either constrained (N1=73) or unconstrained (N2=74). Overall, findings showed that levels of behavior influenced people's experiences of the context in which events occurred. For all participants, very high behavior levels eliminated sensitivity to levels of outcomes occurring in the environment and lead to judgments that were consistent with conditional probabilities as opposed to the experimenter programmed contingency. Thus increased behavior increased perceived control via influence on context experience. This effect was also evident for those scoring high on the BDI. Overall conclusions are that behavior and context provide two important interlinked psychological pathways to perceived control. However, situations that constrain people's ability to respond freely can prevent people with signs of depression from taking control of a situation that would otherwise be uncontrollable.

Pathways to empowerment?: dynamics of women's participation in Global Value Chains

Gender plays an important role in shaping outcomes of participation within Global Value Chains (GVCs). Employment in GVCs may potentially empower women, but little is known about the dynamics by which GVCs bring about empowerment, rather studies highlight women's rights abuses and on-going gender-based discrimination. This paper considers whether and how employment within GVCs empowers women workers. By drawing from an in-depth empirical study of women workers employed in the Kenyan tea and cut-flower industries, it develops three interlinked pathways to empowerment. These pathways, ‘being’, ‘doing’ and ‘sharing’, offer some positive changes from women workers' perspectives. In so doing, we offer a more nuanced perspective on employment for women in GVCs in African agriculture, acknowledging the constraints but also noting the potential for positive outcomes.

Abstract A48: Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer

Abstract Low-grade serous ovarian carcinoma is a distinct neoplasm from high-grade serous ovarian carcinoma and is chemo-resistant, both in the first line setting as well as in subsequent lines of therapy. Serous ovarian tumors of low malignant potential and low grade serous ovarian cancer (LGSOC) appear to be dependent, in part, on the activation of the mitogen-activated protein kinase (MAPK) survival signaling pathway, and furthermore display significantly higher prevalence of KRAS or BRAF mutations in contrast to high-grade serous carcinomas. The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK (MAPK) survival pathways are interlinked survival signaling pathways, where compensatory activation of one of the pathways in response to the inhibition of the other has been observed. Given their ability to cross-talk, simultaneous inhibition of the MAPK and PI3K/PTEN signaling cascades may significantly enhance anti-tumor activity as compared with inhibition of either cascade alone. Preclinical studies have shown that the combination of MEK and PI3K inhibitors, both in vitro and in vivo, enhanced anti-tumor effects and induced apoptosis in cell lines and primary patient-derived models across a range of cancer types. In the present series of studies, we report: 1- the anti-tumor activity of the combination of two investigational drugs, a phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor, SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against patient-derived ovarian cancer xenograft models harboring KRAS mutations from low, intermediate and high grade ovarian tumors), and 2- the preliminary clinical activity of the combination in ovarian patients. In patient-derived xenografts of low and intermediate grade ovarian cancer, the combination led to significantly greater antitumor activity than that of single agent treatments. In the high grade model of ovarian cancer, no additive effects on antitumor activity were observed in the combination as compared to pimasertib as a single agent. The combination of pimasertib and SAR245409 is currently being investigated in patients with refractory solid tumors in an ongoing Phase Ib Trial (EMR200066-006; NCT01390818), where objective responses have been reported in 2 out of 4 evaluable patients with low-grade serous ovarian carcinoma. A phase 2 study (EMR200066-012, EudraCT Number 2013-000902-40) will investigate the activity of the combination pimasertib and SAR245409 in subjects with recurrent or metastatic low grade ovarian cancer, a patient population which has a high unmet medical need. Citation Format: Sukhvinder S. Sidhu, Frank Campana, Coumaran Egile, Karl Hsu, Samantha Goodstal, Ekaterine Asatiani, Lars Damstrup, Joanne Lager, Janet Ogden, Loic Vincent. Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A48.

Analysis of Protein-Protein Interactions in Cross-talk Pathways Reveals CRKL Protein as a Novel Prognostic Marker in Hepatocellular Carcinoma

Deciphering the network of signaling pathways in cancer via protein-protein interactions (PPIs) at the cellular level is a promising approach but remains incomplete. We used an in situ proximity ligation assay to identify and quantify 67 endogenous PPIs among 21 interlinked pathways in two hepatocellular carcinoma (HCC) cells, Huh7 (minimally migratory cells) and Mahlavu (highly migratory cells). We then applied a differential network biology analysis and determined that the novel interaction, CRKL-FLT1, has a high centrality ranking, and the expression of this interaction is strongly correlated with the migratory ability of HCC and other cancer cell lines. Knockdown of CRKL and FLT1 in HCC cells leads to a decrease in cell migration via ERK signaling and the epithelial-mesenchymal transition process. Our immunohistochemical analysis shows high expression levels of the CRKL and CRKL-FLT1 pair that strongly correlate with reduced disease-free and overall survival in HCC patient samples, and a multivariate analysis further established CRKL and the CRKL-FLT1 as novel prognosis markers. This study demonstrated that functional exploration of a disease network with interlinked pathways via PPIs can be used to discover novel biomarkers.

Pathways from parental AIDS to child psychological, educational and sexual risk: Developing an empirically-based interactive theoretical model

Increasing evidence demonstrates negative psychological, health, and developmental outcomes for children associated with parental HIV/AIDS illness and death. However, little is known about how parental AIDS leads to negative child outcomes. This study used a structural equation modelling approach to develop an empirically-based theoretical model of interactive relationships between parental or primary caregiver AIDS-illness, AIDS-orphanhood and predicted intervening factors associated with children's psychological distress, educational access and sexual health. Cross-sectional data were collected in 2009–2011, from 6002 children aged 10–17 years in three provinces of South Africa using stratified random sampling. Comparison groups included children orphaned by AIDS, orphaned by other causes and non-orphans, and children whose parents or primary caregivers were unwell with AIDS, unwell with other causes or healthy. Participants reported on psychological symptoms, educational access, and sexual health risks, as well as hypothesized sociodemographic and intervening factors. In order to build an interactive theoretical model of multiple child outcomes, multivariate regression and structural equation models were developed for each individual outcome, and then combined into an overall model. Neither AIDS-orphanhood nor parental AIDS-illness were directly associated with psychological distress, educational access, or sexual health. Instead, significant indirect effects of AIDS-orphanhood and parental AIDS-illness were obtained on all measured outcomes. Child psychological, educational and sexual health risks share a common set of intervening variables including parental disability, poverty, community violence, stigma, and child abuse that together comprise chain effects. In all models, parental AIDS-illness had stronger effects and more risk pathways than AIDS-orphanhood, especially via poverty and parental disability. AIDS-orphanhood and parental AIDS-illness impact child outcomes through multiple, interlinked pathways. The interactive model developed in this study suggests key areas of focus for interventions with AIDS-affected children.

Alterations in metabolic pathways and networks in Alzheimer's disease.

The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

Age-Dependent and Gender-Dependent Regulation of Hypothalamic-Adrenocorticotropic-Adrenal Axis

Tightly regulated output of glucocorticoids is critical to maintaining immune competence, the structure of neurons, muscle, and bone, blood pressure, glucose homeostasis, work capacity, and vitality in the human and experimental animal. Age, sex steroids, gender, stress, body composition, and disease govern glucocorticoid availability through incompletely understood mechanisms. According to an ensemble concept of neuroendocrine regulation, successful stress adaptations require repeated incremental signaling adjustments among hypothalamic corticotropin-releasing hormone and arginine vasopressin, pituitary adrenocorticotropic hormone, and adrenal corticosteroids. Signals are transduced via (positive) feedforward and (negative) feedback effects. Age and gonadal steroids strongly modulate stress-adaptive glucocorticoid secretion by such interlinked pathways.

Host response to intravenous injection of epsilon toxin in mouse model: A proteomic view

Epsilon toxin (ETX) is an extremely potent pore-forming toxin and a category B biological agent. ETX is a major virulence determinant of Clostridium perfringens toxinotypes B and D, and is implicated in pathogenesis of rapidly fatal economically important pulpy kidney disease in lambs caused by toxinotype D. Despite being a toxin, ETX can be utilized as a tool to target glutamatergic neurons and for drug delivery into the CNS. 2DE-MS approach was employed to elucidate the host response to ETX following intravenous injection in mouse model. In total, 136 proteins were identified either differentially expressed in brain (18) and kidney (33); showing specific interaction with ETX from lysates of brain (4), kidney (21), or from plasma (42); and urine markers (18) of intoxication. Differentially expressed proteins in kidney included those involved in calcium homeostasis and cytoskeletal organization. Proteins involved in ER and oxidative stress and energy metabolism also showed differential levels in the target tissue after ETX treatment. The known functions of the proteins differentially expressed and those interacting with ETX indicate involvement of interlinked pathways. This study provides first proteomic account of host response to ETX exposure providing clues to mechanism of toxicity and potential therapeutic targets.