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Filamin A (FLNA) is a cytoplasmic actin binding protein, recently shown to be expressed as a long and short isoform. Mutations in FLNA are associated with a wide spectrum of disorders, including an X-linked form of chronic intestinal pseudo-obstruction (CIPO). However, the role of FLNA in intestinal development and function is largely unknown. In this study, we show that FLNA is expressed in the muscle layer of the small intestine from early human fetal stages. Expression of FLNA variants associated with CIPO, blocked expression of the long flna isoform and led to an overall reduction of RNA and protein levels. As a consequence, contractility of human intestinal smooth muscle cells was affected. Lastly, our transgenic zebrafish line showed that the flna long isoform is required for intestinal elongation and peristalsis. Histological analysis revealed structural and architectural changes in the intestinal smooth muscle of homozygous fish, likely triggered by the abnormal expression of intestinal smooth muscle markers. No defect in the localization or numbers of enteric neurons was observed. Taken together, our study demonstrates that the long FLNA isoform contributes to intestinal development and function. Since loss of the long FLNA isoform does not seem to affect the enteric nervous system, it likely results in a myopathic form of CIPO, bringing new insights to disease pathogenesis.

PML and HIF1a expression

Supplementary legends

Microarray data analysis

New neuroblastoma patient cohort

Purpose: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations.Experimental Design: Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro. Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann–Whitney tests, respectively. Gene expression was assessed using chip microarrays.Results: PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas.Conclusions: Our work reveals a novel PML-I–TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398–409. ©2016 AACR.

Pathway analysis

Background Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord. Methods ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair. Results ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours. Conclusions Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.

Summary The enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1 and 7. Defects in the development and function of the ENS cause a range of enteric neuropathies, including Hirschsprung disease. Little is known about the signals that specify early ENS progenitors, limiting progress in the generation of enteric neurons from human pluripotent stem cells (hPSCs) to provide tools for disease modeling and regenerative medicine for enteric neuropathies. We describe the efficient and accelerated generation of ENS progenitors from hPSCs, revealing that retinoic acid is critical for the acquisition of vagal axial identity and early ENS progenitor specification. These ENS progenitors generate enteric neurons in vitro and, following in vivo transplantation, achieved long-term colonization of the ENS in adult mice. Thus, hPSC-derived ENS progenitors may provide the basis for cell therapy for defects in the ENS., Highlights • Retinoic acid alters the axial identity of hPSC-derived neural crest cells • ENS progenitor markers are upregulated in response to RA • ENS progenitors are capable of generating enteric neurons in vitro • hPSC ENS progenitors colonize the ENS of mice following long-term transplantation, In this article, Frith and colleagues show that retinoic acid (RA) signaling alters the axial identity of hPSC-derived neural crest cells in a time- and dose-dependent manner. They utilized this to derive enteric nervous system (ENS) progenitors from hSPCs, which can differentiate to enteric neurons in vitro and colonize the ENS of adult mice following long-term transplantation.

Purpose Enterocystoplasty is adopted for patients requiring bladder augmentation, but significant long-term complications highlight need for alternatives. We established a protocol for creating a natural-derived bladder extracellular matrix (BEM) for developing tissue-engineered bladder, and investigated its structural and functional characteristics. Methods Porcine bladders were de-cellularised with a dynamic detergent–enzymatic treatment using peristaltic infusion. Samples and fresh controls were evaluated using histological staining, ultrastructure (electron microscopy), collagen, glycosaminoglycans and DNA quantification and biomechanical testing. Compliance and angiogenic properties (Chicken chorioallantoic membrane [CAM] assay) were evaluated. T test compared stiffness and glycosaminoglycans, collagen and DNA quantity. p value of Results Histological evaluation demonstrated absence of cells with preservation of tissue matrix architecture (collagen and elastin). DNA was 0.01 μg/mg, significantly reduced compared to fresh tissue 0.13 μg/mg (p p p = 0.011). CAM assay showed significantly increased number of convergent allantoic vessels after 6 days compared to day 1 (p Conclusion Dynamic detergent–enzymatic treatment produces a BEM which retains structural characteristics, increases strength and stiffness and is more compliant than native tissue. Furthermore, BEM shows angiogenic potential. These data suggest the use of BEM for development of tissue-engineered bladder for patients requiring bladder augmentation.

Contains fulltext : 245512.pdf (Publisher’s version ) (Open Access) Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested-whole blood, dermal fibroblasts or saliva-but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to 'missing heritability' in developmental defects.

In the knowledge economy, organizational information is one of a firm's most valuable assets. However, despite significant advances in information security (InfoSec) research, problems in the field persist. This paper contends that advances in reliability and safety can help inform the future of InfoSec research. Specifically, the paper presents a framework for security organizing that is based on previous research about the organizational mindfulness characteristics of high reliability organizations (HROs). This paper considers the similarities among reliability, safety, and InfoSec, provides an initial validation of a potential construct for measuring security organizing in the workplace, and discusses opportunities for future research.

The protection of organizational information and information systems (IS) is a socio-technical issue and requires insiders take on a more proactive set of security roles. Accordingly, we contend that insiders’ abilities to enact these diverse information security roles can be explained by behavioral complexity theory. Adapted to the security context, behavioral complexity theory stipulates that insider’s ability to take appropriate precautions against organizational security threats is explained by their (1) repertoire of security roles and associated behaviors (i.e., security behavioral repertoire) and their (2) ability to switch from role to role (i.e., security behavioral differentiation). However, beyond behavioral complexity, protecting against complex security-related threats in the workplace requires significant psychological resources of insiders. Thus, to examine the influence of behavioral complexity on insiders’ protection motivation, we develop and examine an extended model of behavioral complexity including insiders’ workplace resilience—a significant work-related psychological resource Our results fully support the extended security behavioral complexity model’s role in driving an insider’s protection motivation.

Executives in many industries have fallen prey to socially engineered attacks known as spear phishing. Using highly targeted emails, social engineers trick victims into performing unintended action...

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analysed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non cell-autonomous manner. Analysis of human gut fetal tissues with aKIAA0586mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Background & Aims The enteric nervous system (ENS), which regulates many gastrointestinal functions, is derived from neural crest cells (NCCs). Defective NCC migration during embryonic development may lead to enteric neuropathies such as Hirschsprung's disease (hindgut aganglionosis). Sox10 is known to be essential for cell migration but downstream molecular events regulating early NCC migration have not been fully elucidated. This study aimed to determine how Sox10 regulates migration of sacral NCCs toward the hindgut using Dominant megacolon mice, an animal model of Hirschsprung's disease with a Sox10 mutation. Methods We used time-lapse live cell imaging to determine the migration defects of mutant sacral NCCs; genome-wide microarrays, site-directed mutagenesis and whole embryo culture to identify Sox10 targets; and liquid chromatography and tandem mass spectrometry to ascertain downstream effectors of Sox10. Results Sacral NCCs exhibited retarded migration to the distal hindgut in Sox10-null embryos with simultaneous down-regulated expression of cadherin-19 (Cdh19). Sox10 was found to bind directly to the Cdh19 promoter. Cdh19 knockdown resulted in retarded sacral NCC migration in vitro and ex vivo, whereas re-expression of Cdh19 partially rescued the retarded migration of mutant sacral NCCs in vitro. Cdh19 formed cadherin-catenin complexes, which then bound to F-actin of the cytoskeleton during cell migration. Conclusions Cdh19 is a direct target of Sox10 during early sacral NCC migration towards the hindgut and forms cadherin-catenin complexes which interact with the cytoskeleton in migrating cells. Elucidation of this novel molecular pathway helps to provide insights into the pathogenesis of ENS developmental defects.

Cyberthreats create unique risks for organizations and individuals, especially regarding breaches of personally identifiable information (PII). However, relatively little research has examined hackings distinct impact on privacy. The authors analyze cyber breaches of PII and found that they are significantly larger compared to other breaches, showing that past breaches are useful for predicting future breaches.

Spinal cord injury (SCI) causes paralysis, multisystem impairment and reduced life expectancy, as yet with no cure. Stem cell therapy can potentially replace lost neurons, promote axonal regeneration and limit scar formation, but an optimal stem cell source has yet to be found. Enteric neural stem cells (ENSC) isolated from the enteric nervous system (ENS) of the gastrointestinal (GI) tract are an attractive source. Here, we used the chick embryo to assess the potential of ENSC to integrate within the developing spinal cord. In vitro, isolated ENSC formed extensive cell connections when co‐cultured with spinal cord (SC)‐derived cells. Further, qRT‐PCR analysis revealed the presence of TuJ1(+) neurons, S100(+) glia and Sox10(+) stem cells within ENSC neurospheres, as well as expression of key neuronal subtype genes, at levels comparable to SC tissue. Following ENSC transplantation to an ablated region of chick embryo SC, donor neurons were found up to 12 days later. These neurons formed bridging connections within the SC injury zone, aligned along the anterior/posterior axis, and were immunopositive for TuJ1. These data provide early proof of principle support for the use of ENSCs for SCI, and encourage further research into their potential for repair.

Many organisations create, store, or purchase information that links individuals’ identities to other data. Termed personally identifiable information (PII), this information has become the lifeblood of many firms across the globe. As organisations accumulate their constituencies’ PII (e.g. customers’, students’, patients’, and employees’ data), individuals’ privacy will depend on the adequacy of organisations’ information privacy safeguards. Despite existing protections, many breaches still occur. For example, US organisations reported around 4,500 PII-breach events between 2005 and 2015. With such a high number of breaches, determining all threats to PII within organisations proves a burdensome task. In light of this difficulty, we utilise text-mining and cluster analysis techniques to create a taxonomy of various organisational PII breaches, which will help drive targeted research towards organisational PII protection. From an organisational systematics perspective, our classification system provides a foundation to explain the diversity among the myriad of threats. We identify eight major PII-breach types and provide initial literature reviews for each type of breach. We detail how US organisations differ regarding their exposure to these breaches, as well as how the level of severity (i.e. number of records affected) differs among these PII breaches. Finally, we offer several paths for future research.

Most of the enteric nervous system derives from the "vagal" neural crest, lying at the level of somites 1-7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the "vagal crest" subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3-7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.

Practitioners and researchers alike recognize the positive influence insiders' behavior can have on information systems (IS) security. This awareness has resulted in a research stream focused on the performance of protective behaviors. We contribute to this research stream by extending an oft-cited theory in the information security literatureprotection motivation theory (PMT)to include the relationship of insiders' psychological capital (PsyCap) with the mechanisms of PMT.PsyCap is a construct of role-breadth psychological capacities and resources embodying important work-related motivational resources. Therefore, given the varied facets central to PMT, determining the relationship of PsyCap with each distinct PMT mechanism is an important contribution. Furthermore, prior research has established that individuals can develop their PsyCap. Consequently, considering the relationship of role-breadth PsyCap with the PMT mechanisms provides an important and malleable, motivational antecedent that complements PMT and is absent from most assessments of the contemporary PMT model. We find support for PsyCap's relationship with the mechanisms of PMT and suggest opportunities to develop PsyCap in conjunction with other organizational security efforts. We present our findings, discuss their implications for research and practice, and highlight several opportunities for future research. Extended PMT model is proposed that includes the relationship of insiders' PsyCap.PsyCap uniquely relates to each threat and coping appraisal mechanism of PMT.Via the facets of PMT, PsyCap indirectly relates to protection motivation and PMBs.Higher levels of PsyCap are related to more PMBs and higher protection motivation.Opportunities exist to build insiders' PsyCap and improve information security.

BACKGROUND & AIMS: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multigenerational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide. METHODS: We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3; however, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons. RESULTS: Within the linkage region, we identified 1 putative splice variant in the lipopolysaccharide responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on messenger RNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the Indian hedgehog gene (IHH) and its mediator, the transcription factor GLI family zinc finger 3 (GLI3). When expressed in cells, the RET-P399L variant disrupted protein glycosylation and had altered phosphorylation following activation by GDNF. The deletion in GDNF prevented secretion of its gene product, reducing RET activation, and the IHH-Q51K variant reduced expression of the transcription factor GLI1. Injection of morpholinos that target ihh reduced the number of enteric neurons to 13% +/- 1.4% of control zebrafish. CONCLUSIONS: In a study of a large family with history of HSCR, we identified variants in LRBA, RET, the gene encoding the RET ligand (GDNF), IHH, and a gene encoding a mediator of IHH signaling (GLI3). These variants altered functions of the gene products when expressed in cells and knockout of ihh reduced the number of enteric neurons in the zebrafish gut.

Protecting organizational information is a top priority for most firms. This reality, coupled with the fact that organizational insiders control much of their organizations’ valuable information, has led both researchers and practitioners to acknowledge the importance of insiders’ behavior for information security (InfoSec). Until recently, researchers have employed only a few theories to understand these influences, and this has generated calls for a broadened theoretical repertoire. Given this opportunity, we incorporate the framework of emotions developed in the information systems (IS) discipline by Beaudry and Pinsonneault (2010) and add the broaden-and-build theory (BBT) to understand the influence of discrete positive and negative emotions on insiders’ precaution-taking activities. Our findings demonstrate that the relationship between both positive and negative emotions and precaution taking is mediated by insiders’ (1) psychological capital (PsyCap), a higher-order, work-related construct of positive psychological resource capabilities, and (2) psychological distancing, a coping mechanism characterized by insiders’ attempts to detach themselves psychologically from a situation. By considering these factors, our model explains 32 percent of the variance in insiders’ precaution taking in organizations. Researchers and practitioners can use these findings to develop effective insider InfoSec training, including emotional appeals that increase insiders’ precaution taking. Accepted version Source info: Information Systems Research (ISR), Forthcoming

Neural tube defects (NTDs), including spina bifida and anencephaly, are among the most common birth defects worldwide, but their underlying genetic and cellular causes are not well understood. Some NTDs are preventable by supplemental folic acid. However, despite widespread use of folic acid supplements and implementation of food fortification in many countries, the protective mechanism is unclear. Pax3 mutant (splotch; Sp2H) mice provide a model in which NTDs are preventable by folic acid and exacerbated by maternal folate deficiency. Here, we found that cell proliferation was diminished in the dorsal neuroepithelium of mutant embryos, corresponding to the region of abolished Pax3 function. This was accompanied by premature neuronal differentiation in the prospective midbrain. Contrary to previous reports, we did not find evidence that increased apoptosis could underlie failed neural tube closure in Pax3 mutant embryos, nor that inhibition of apoptosis could prevent NTDs. These findings suggest that Pax3 functions to maintain the neuroepithelium in a proliferative, undifferentiated state, allowing neurulation to proceed. NTDs in Pax3 mutants were not associated with abnormal abundance of specific folates and were not prevented by formate, a one-carbon donor to folate metabolism. Supplemental folic acid restored proliferation in the cranial neuroepithelium. This effect was mediated by enhanced progression of the cell cycle from S to G2 phase, specifically in the Pax3 mutant dorsal neuroepithelium. We propose that the cell-cycle-promoting effect of folic acid compensates for the loss of Pax3 and thereby prevents cranial NTDs., Summary: Neural tube defects in a folic-acid-responsive, folate-sensitive mouse model are associated with a localised proliferation defect in the neuroepithelium. Supplemental folic acid stimulates progression through S phase to correct this abnormality.

SummaryThe enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1-7. Defects in the development and function of the ENS give rise to a range of disorders, termed enteric neuropathies and include conditions such as Hirschsprung’s disease. Little is known about the signalling that specifies early ENS progenitors. This has, thus far, limited progress in the generation of enteric neurons from human Pluripotent Stem Cells (hPSCs) that could provide a useful tool for disease modelling and regenerative medicine. We describe the efficient and accelerated generation of ENS progenitors from hPSCs, revealing that retinoic acid is critical for the acquisition of both vagal axial identity and early ENS progenitor specification. These ENS progenitors generate enteric neuronsin vitroand followingin vivotransplantation, achieving long-term colonisation of the ENS in adult mice. Thus, hPSC-derived ENS progenitors may provide the basis for cell therapy for defects in the ENS.

Enteric neuropathies, such as Hirschsprung disease (HSCR), comprise a number of severe diseases of the enteric nervous system (ENS) of the gastrointestinal (GI) tract with, as yet, no cures. The replacement of absent or diseased enteric neurons via stem cell transplantation directly into diseased gut represents a novel, curative therapy. This idea is supported by over two decades of preclinical research, carried out mainly in mice, demonstrating that neural crest-derived stem cells can be isolated from the gut, expanded in culture, and transplanted into gut in vivo where they migrate, proliferate, differentiate, and become functionally active. Here, we review some of the learnings from these studies, outlining the diseases potentially amenable to stem cell replacement therapy, the animals used to model disease, the different types of stem cells that could be used for therapy, the methodologies developed to prepare and deliver stem cells to the gut, and cell safety considerations. With the significant progress that has already been made by the field, the aim of developing a curative stem cell therapy for devastating diseases of the enteric nervous system is rapidly approaching reality.

With the implantation of software-driven devices comes unique privacy and security threats to the human body.

The enteric nervous system (ENS) is required for peristalsis of the gut and is derived from Enteric Neural Crest Cells (ENCCs). During ENS development, the RET receptor tyrosine kinase plays a critical role in the proliferation and survival of ENCCs, their migration along the developing gut, and differentiation into enteric neurons. Mutations in RET and its ligand GDNF cause Hirschsprung disease (HSCR), a complex genetic disorder in which ENCCs fail to colonize variable lengths of the distal bowel. To identify key regulators of ENCCs and the pathways underlying RET signaling, gene expression profiles of untreated and GDNF-treated ENCCs from E14.5 mouse embryos were generated. ENCCs express genes that are involved in both early and late neuronal development, whereas GDNF treatment induced neuronal maturation. Predicted regulators of gene expression in ENCCs include the known HSCR genes Ret and Sox10, as well as Bdnf, App and Mapk10. The regulatory overlap and functional interactions between these genes were used to construct a regulatory network that is underlying ENS development and connects to known HSCR genes. In addition, the adenosine receptor Ala (Adora2a) and neuropeptide Y receptor Y2 (Npy2r) were identified as possible regulators of terminal neuronal differentiation in GDNF-treated ENCCs. The human orthologue of Npy2r maps to the HSCR susceptibility locus 4q31.3-q32.3, suggesting a role for NPY2R both in ENS development and in HSCR. (C) 2016 Elsevier Inc. All rights reserved.

Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.

Current methods to replace damaged upper airway epithelium with exogenous cells are limited. Existing strategies use grafts that lack mucociliary function, leading to infection and the retention of secretions and keratin debris. Strategies that regenerate airway epithelium with mucociliary function are clearly desirable and would enable new treatments for complex airway disease. Here, we investigated the influence of the extracellular matrix (ECM) on airway epithelial cell adherence, proliferation and mucociliary function in the context of bioengineered mucosal grafts. In vitro, primary human bronchial epithelial cells (HBECs) adhered most readily to collagen IV. Biological, biomimetic and synthetic scaffolds were compared in terms of their ECM protein content and airway epithelial cell adherence. Collagen IV and laminin were preserved on the surface of decellularised dermis and epithelial cell attachment to decellularised dermis was greater than to the biomimetic or synthetic alternatives tested. Blocking epithelial integrin α2 led to decreased adherence to collagen IV and to decellularised dermis scaffolds. At air–liquid interface (ALI), bronchial epithelial cells cultured on decellularised dermis scaffolds formed a differentiated respiratory epithelium with mucociliary function. Using in vivo chick chorioallantoic membrane (CAM), rabbit airway and immunocompromised mouse models, we showed short-term preservation of the cell layer following transplantation. Our results demonstrate the feasibility of generating HBEC grafts on clinically applicable decellularised dermis scaffolds and identify matrix proteins and integrins important for this process. The long-term survivability of pre-differentiated epithelia and the relative merits of this approach against transplanting basal cells should be assessed further in pre-clinical airway transplantation models., Collagen IV- and laminin-rich decellularised dermis scaffolds support a mucociliary airway epithelial graft but in vivo transplantation in pre-clinical models is challenging http://bit.ly/2IdQp5d

Three-dimensional (3D) cancer models are overlooking the scientific landscape with the primary goal of bridging the gaps between two-dimensional (2D) cell lines, animal models and clinical research. Here, we describe an innovative tissue engineering approach applied to colorectal cancer (CRC) starting from decellularized human biopsies in order to generate an organotypic 3D-bioactive model. This in vitro 3D system recapitulates the ultrastructural environment of native tissue as demonstrated by histology, immunohistochemistry, immunofluorescence and scanning electron microscopy analyses. Mass spectrometry of proteome and secretome confirmed a different stromal composition between decellularized healthy mucosa and CRC in terms of structural and secreted proteins. Importantly, we proved that our 3D acellular matrices retained their biological properties: using CAM assay, we observed a decreased angiogenic potential in decellularized CRC compared with healthy tissue, caused by direct effect of DEFA3. We demonstrated that following a 5 days of recellularization with HT-29 cell line, the 3D tumor matrices induced an over-expression of IL-8, a DEFA3-mediated pathway and a mandatory chemokine in cancer growth and proliferation. Given the biological activity maintained by the scaffolds after decellularization, we believe this approach is a powerful tool for future pre-clinical research and screenings.

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.

The management of information security can be conceptualized as a complex adaptive system because the actions of both insiders and outsiders co-evolve with the organizational environment, thereby leading to the emergence of overall security of informational assets within an organization. Thus, the interactions among individuals and their environments at the micro-level form the overall security posture at the macro-level. Additionally, in this complex environment, security threats evolve constantly, leaving organizations little choice but to evolve alongside those threats or risk losing everything. In order to protect organizational information systems and associated informational assets, managers are forced to adapt to security threats by training employees and by keeping systems and security procedures updated. This research explains how organizational information security can perhaps best be managed as a complex adaptive system (CAS) and models the complexity of IS security risks and organizational responses using agent-based modeling (ABM). We present agent-based models that illustrate simple probabilistic phishing problems as well as models that simulate the organizational security outcomes of complex theoretical security approaches based on general deterrence theory (GDT) and protection motivation theory (PMT).

Many healthcare providers in the US are seeking increased efficiency and effectiveness by rapidly adopting information technology (IT) solutions such as electronic medical record (EMR) systems. Legislation such as the Health Information Technology for Economic and Clinical Health Act (HITECH), which codified the adoption and “meaningful use” of electronic records in the US, has further spurred the industry-wide adoption of EMR. However, despite what are often large investments in EMR, studies indicate that the healthcare industry maintains a culture of system workarounds. Though perhaps not uncommon, the creation of informal workflows among healthcare workers is problematic for assuring information security and patient privacy, particularly when involving decisions of information management (e.g., information storage, retrieval, and/or transmission). Drawing on the framework of contextual integrity, we assert that one can often explain workarounds involving information transmissions in terms of trade-offs informed by context-specific informational norms. We surveyed healthcare workers and analyzed their willingness to engage in a series of EMR workaround scenarios. Our results indicate that contextual integrity provides a useful framework for understanding information transmission and workaround decisions in the health sector. Armed with these findings, managers and system designers should be better able to anticipate healthcare workers’ information transmission principles (e.g., privacy norms) and workaround patterns (e.g., usage norms). We present our findings and discuss their significance for research and practice.

Healthcare in the digital age is undergoing an IT revolution. In the US, spurred by legislation such as the Health Information Technology and Economics Clinical Health (HITECH) Act, electronic health records (EHR) adoption has dramatically increased. Meanwhile, enabled by mobile devices and ubiquitous networks, patients and physicians interact with health information in novel ways. Given health information's sensitive nature, however, a cautious approach to IT integration is warranted to ensure that patients' sensitive information is protected. Although health information security is of great interest in both academia and practice, relatively little scholarship has examined the security implications of the behavior of those who actually use IT in the healthcare sector. To stimulate this important discussion, the authors briefly describe the changing landscape of an IT-enabled healthcare ecosystem and discuss the emerging issues of mobility and security. This article is part of a special issue on IT security.