Functions of lipid raft membrane microdomains at the blood-brain barrier

The blood-brain barrier (BBB) is a highly specialized structural and functional component of the central nervous system that separates the circulating blood from the brain and spinal cord parenchyma. Brain endothelial cells (BECs) that primarily constitute the BBB are tightly interconnected by multiprotein complexes, the adherens junctions and the tight junctions, thereby creating a highly restrictive cellular barrier. Lipid-enriched membrane microdomain compartmentalization is an inherent property of BECs and allows for the apicobasal polarity of brain endothelium, temporal and spatial coordination of cell signaling events, and actin remodeling. In this manuscript, we review the role of membrane microdomains, in particular lipid rafts, in the BBB under physiological conditions and during leukocyte transmigration/diapedesis. Furthermore, we propose a classification of endothelial membrane microdomains based on their function, or at least on the function ascribed to the molecules included in such heterogeneous rafts: (1) rafts associated with interendothelial junctions and adhesion of BECs to basal lamina (scaffolding rafts); (2) rafts involved in immune cell adhesion and migration across brain endothelium (adhesion rafts); (3) rafts associated with transendothelial transport of nutrients and ions (transporter rafts).

The etiology of cleft palate formation in BMP7-deficient mice

Palatogenesis is a complex process implying growth, elevation and fusion of the two lateral palatal shelves during embryogenesis. This process is tightly controlled by genetic and mechanistic cues that also coordinate the growth of other orofacial structures. Failure at any of these steps can result in cleft palate, which is a frequent craniofacial malformation in humans. To understand the etiology of cleft palate linked to the BMP signaling pathway, we studied palatogenesis in Bmp7-deficient mouse embryos. Bmp7 expression was found in several orofacial structures including the edges of the palatal shelves prior and during their fusion. Bmp7 deletion resulted in a general alteration of oral cavity morphology, unpaired palatal shelf elevation, delayed shelf approximation, and subsequent lack of fusion. Cell proliferation and expression of specific genes involved in palatogenesis were not altered in Bmp7-deficient embryos. Conditional ablation of Bmp7 with Keratin14-Cre or Wnt1-Cre revealed that neither epithelial nor neural crest-specific loss of Bmp7 alone could recapitulate the cleft palate phenotype. Palatal shelves from mutant embryos were able to fuse when cultured in vitro as isolated shelves in proximity, but not when cultured as whole upper jaw explants. Thus, deformations in the oral cavity of Bmp7-deficient embryos such as the shorter and wider mandible were not solely responsible for cleft palate formation. These findings indicate a requirement for Bmp7 for the coordination of both developmental and mechanistic aspects of palatogenesis.

Spatial cognition, body representation and affective processes: the role of vestibular information beyond ocular reflexes and control of posture

A growing number of studies in humans demonstrate the involvement of vestibular information in tasks that are seemingly remote from well-known functions such as space constancy or postural control. In this review article we point out three emerging streams of research highlighting the importance of vestibular input: (1) Spatial Cognition: Modulation of vestibular signals can induce specific changes in spatial cognitive tasks like mental imagery and the processing of numbers. This has been shown in studies manipulating body orientation (changing the input from the otoliths), body rotation (changing the input from the semicircular canals), in clinical findings with vestibular patients, and in studies carried out in microgravity. There is also an effect in the reverse direction; top-down processes can affect perception of vestibular stimuli. (2) Body Representation: Numerous studies demonstrate that vestibular stimulation changes the representation of body parts, and sensitivity to tactile input or pain. Thus, the vestibular system plays an integral role in multisensory coordination of body representation. (3) Affective Processes and Disorders: Studies in psychiatric patients and patients with a vestibular disorder report a high comorbidity of vestibular dysfunctions and psychiatric symptoms. Recent studies investigated the beneficial effect of vestibular stimulation on psychiatric disorders, and how vestibular input can change mood and affect. These three emerging streams of research in vestibular science are—at least in part—associated with different neuronal core mechanisms. Spatial transformations draw on parietal areas, body representation is associated with somatosensory areas, and affective processes involve insular and cingulate cortices, all of which receive vestibular input. Even though a wide range of different vestibular cortical projection areas has been ascertained, their functionality still is scarcely understood.

A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer

XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients.

Syntheses, characterization and crystal structures of a new functionalised TTF derivative and its Ni(II) complex

The new ligand 4,5-bis (2-pyridylmethylsulfanyl)-4',5'-bis(cyanoethylthio)tetrathiafulvalene (BPM-BCET-TTF) and its nickel(II) complex have been prepared and crystallographically characterized. The Ni(II) complex shows octahedral geometry around the metal ion with the coordination site occupied by the pyridyl nitrogen atoms, the thioether sulfur atoms of the ligand and cis coordination of the halide ions.

Structural Studies of Transition Metal Complexes with 4,5-Bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene: Probing Their Potential for the Construction of Multifunctional Molecular Assemblies

Three divalent transition metal complexes of 4,5-bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene have been prepared and crystallographically characterized. The isostructural Co(II) and the Ni(II) complexes show octahedral geometries around the metal ions with the coordination sites occupied by the pyridyl nitrogen atoms and the thioether sulfur atoms of the ligand and cis coordination of the halide ions. Cyclic voltammetry reveals that the complexation leads to a small anodic shift in the first oxidation potential of the TTF system.

Coordinating Platform-Based Multi-Sourcing: Introducing the Theory of Convention

Spurred by the consumer market, companies increasingly deploy smartphones or tablet computers in their operations. However, unlike private users, companies typically struggle to cover their needs with existing applications, and therefore expand mobile software platforms through customized applications from multiple software vendors. Companies thereby combine the concepts of multi-sourcing and software platform ecosystems in a novel platform-based multi-sourcing setting. This implies, however, the clash of two different approaches towards the coordination of the underlying one-to-many inter-organizational relationships. So far, however, little is known about impacts of merging coordination approaches. Relying on convention theory, we addresses this gap by analyzing a platform-based multi-sourcing project between a client and six software vendors, that develop twenty-three custom-made applications on a common platform (Android). In doing so, we aim to understand how unequal coordination approaches merge, and whether and for what reason particular coordination mechanisms, design decisions, or practices disappear, while new ones emerge.

Content-Aware Delivery of Scalable Video in Network Coding Enabled Named Data Networks

In this work, we propose a novel network coding enabled NDN architecture for the delivery of scalable video. Our scheme utilizes network coding in order to address the problem that arises in the original NDN protocol, where optimal use of the bandwidth and caching resources necessitates the coordination of the forwarding decisions. To optimize the performance of the proposed network coding based NDN protocol and render it appropriate for transmission of scalable video, we devise a novel rate allocation algorithm that decides on the optimal rates of Interest messages sent by clients and intermediate nodes. This algorithm guarantees that the achieved flow of Data objects will maximize the average quality of the video delivered to the client population. To support the handling of Interest messages and Data objects when intermediate nodes perform network coding, we modify the standard NDN protocol and introduce the use of Bloom filters, which store efficiently additional information about the Interest messages and Data objects. The proposed architecture is evaluated for transmission of scalable video over PlanetLab topologies. The evaluation shows that the proposed scheme performs very close to the optimal performance

The temporal evolution of nonverbal synchrony in outpatient psychotherapy: An aggregation of single-case studies

Objective: The authors quantified nonverbal synchrony—the coordination of patient's and therapist's movement—in a random sample of same-sex psychotherapy dyads. The authors contrasted nonverbal synchrony in these dyads with a control condition and assessed its association with session-level and overall psychotherapy outcome. Method: Using an automated objective video analysis algorithm (Motion Energy Analysis; MEA), the authors calculated nonverbal synchrony in (n = 104) videotaped psychotherapy sessions from 70 Caucasian patients (37 women, 33 men, mean age = 36.5 years, SD = 10.2) treated at an outpatient psychotherapy clinic. The sample was randomly drawn from an archive (N = 301) of routinely videotaped psychotherapies. Patients and their therapists assessed session impact with self-report postsession questionnaires. A battery of pre- and postsymptomatology questionnaires measured therapy effectiveness. Results: The authors found that nonverbal synchrony is higher in genuine interactions contrasted with pseudointeractions (a control condition generated by a specifically designed shuffling procedure). Furthermore, nonverbal synchrony is associated with session-level process as well as therapy outcome: It is increased in sessions rated by patients as manifesting high relationship quality and in patients experiencing high self-efficacy. Higher nonverbal synchrony characterized psychotherapies with higher symptom reduction. Conclusions: The results suggest that nonverbal synchrony embodies the patients' self-reported quality of the relationship and further variables of therapy process. This hitherto overlooked facet of therapeutic relationships might prove useful as an indicator of therapy progress and outcome. (PsycINFO Database Record (c) 2015 APA, all rights reserved)

Taxonomy, phylogeny and molecular epidemiology of Echinococcus multilocularis: From fundamental knowledge to health ecology.

Alveolar echinococcosis, caused by the tapeworm Echinococcus multilocularis, is one of the most severe parasitic diseases in humans and represents one of the 17 neglected diseases prioritised by the World Health Organisation (WHO) in 2012. Considering the major medical and veterinary importance of this parasite, the phylogeny of the genus Echinococcus is of considerable importance; yet, despite numerous efforts with both mitochondrial and nuclear data, it has remained unresolved. The genus is clearly complex, and this is one of the reasons for the incomplete understanding of its taxonomy. Although taxonomic studies have recognised E. multilocularis as a separate entity from the Echinococcus granulosus complex and other members of the genus, it would be premature to draw firm conclusions about the taxonomy of the genus before the phylogeny of the whole genus is fully resolved. The recent sequencing of E. multilocularis and E. granulosus genomes opens new possibilities for performing in-depth phylogenetic analyses. In addition, whole genome data provide the possibility of inferring phylogenies based on a large number of functional genes, i.e. genes that trace the evolutionary history of adaptation in E. multilocularis and other members of the genus. Moreover, genomic data open new avenues for studying the molecular epidemiology of E. multilocularis: genotyping studies with larger panels of genetic markers allow the genetic diversity and spatial dynamics of parasites to be evaluated with greater precision. There is an urgent need for international coordination of genotyping of E. multilocularis isolates from animals and human patients. This could be fundamental for a better understanding of the transmission of alveolar echinococcosis and for designing efficient healthcare strategies.

Domain Globalization: Using Languages to Support Technical and Social Coordination

When a project is realized in a globalized environment, multiple stakeholders from different organizations work on the same system. Depending on the stakeholders and their organizations, various (possibly overlapping) concerns are raised in the development of the system. In this context a Domain Specific Language (DSL) supports the work of a group of stakeholders who are responsible for addressing a specific set of concerns. This chapter identifies the open challenges arising from the coordination of globalized domain-specific languages. We identify two types of coordination: technical coordination and social coordination. After presenting an overview of the current state of the art, we discuss first the open challenges arising from the composition of multiple DSLs, and then the open challenges associated to the collaboration in a globalized environment.

Reading strategies in Stargardt's disease with foveal sparing

ABSTRACT: BACKGROUND: Subjects with a ring scotoma can use two retinal loci, a foveal and a peripheral, for reading. Our aim was to investigate the relative use of both retinal loci as a function of the spared foveal area size and the spatial resolution at both retinal loci. FINDINGS: Two patients with Stargardt's disease and ring scotomas read through a scanning laser ophthalmoscope a series of letters and words at various character sizes. The number of fixations made using each retinal locus was quantified. The relative use of each retinal locus depended on character size of the stimulus. Both patients used exclusively the eccentric retinal locus to read words of large character sizes. At small character sizes, the central retinal locus was predominantly used. For reading letters or words, once foveal fixation was used, patients did not shift back to the eccentric retinal locus. When spatial resolution allowed deciphering at both the eccentric and the central areas, patients consistently fixated with the eccentric retinal locus. CONCLUSIONS: Spatial resolution at the eccentric locus appears as a determinant factor to select the retinal area for reading. Reading strategies in patients with Stargardt's disease and a ring scotoma demonstrate a pattern of coordination of both eccentric and central retinal loci, reflecting a high degree of adaptation.

The Mountain Research Initiative Reaches Outward and Clombs Upward

Mountain regions provide a multitude of goods and services for much of humanity (Price and Butt 2000; Becker and Bugmann 2001), especially in the realms of water supply, biodiversity, and other ecosystem services (Schimel et al 2002; Körner et al 2005; Viviroli et al 2007; Viviroli et al 2011). However, the future ability of mountain regions to provide goods and services to both highland and lowland residents is seriously threatened by climatic changes, environmental pollution, unsustainable management of natural resources, and serious gaps in understanding of mountain systems (Huber et al 2005). Disciplinary, interdisciplinary, and transdisciplinary research is required to maintain these goods and services in the face of these forces. The global mountain research community, however, has historically operated at a suboptimal level because of insufficient communication across geographic and linguistic barriers, less than desirable coordination of research frameworks, and a lack of funding.

α-Ketoglutarate regulates acid-base balance through an intrarenal paracrine mechanism

Paracrine communication between different parts of the renal tubule is increasingly recognized as an important determinant of renal function. Previous studies have shown that changes in dietary acid-base load can reverse the direction of apical α-ketoglutarate (αKG) transport in the proximal tubule and Henle's loop from reabsorption (acid load) to secretion (base load). Here we show that the resulting changes in the luminal concentrations of αKG are sensed by the αKG receptor OXGR1 expressed in the type B and non-A-non-B intercalated cells of the connecting tubule (CNT) and the cortical collecting duct (CCD). The addition of 1 mM αKG to the tubular lumen strongly stimulated Cl--dependent HCO3- secretion and electroneutral transepithelial NaCl reabsorption in microperfused CCDs of wild-type mice but not Oxgr1-/- mice. Analysis of alkali-loaded mice revealed a significantly reduced ability of Oxgr1-/- mice to maintain acid-base balance. Collectively, these results demonstrate that OXGR1 is involved in the adaptive regulation of HCO3- secretion and NaCl reabsorption in the CNT/CCD under acid-base stress and establish αKG as a paracrine mediator involved in the functional coordination of the proximal and the distal parts of the renal tubule.

Family satisfaction in the intensive care unit: what makes the difference?

PURPOSE: To assess family satisfaction in the ICU and to identify parameters for improvement. METHODS: Multicenter study in Swiss ICUs. Families were given a questionnaire covering overall satisfaction, satisfaction with care and satisfaction with information/decision-making. Demographic, medical and institutional data were gathered from patients, visitors and ICUs. RESULTS: A total of 996 questionnaires from family members were analyzed. Individual questions were assessed, and summary measures (range 0-100) were calculated, with higher scores indicating greater satisfaction. Summary score was 78 +/- 14 (mean +/- SD) for overall satisfaction, 79 +/- 14 for care and 77 +/- 15 for information/decision-making. In multivariable multilevel linear regression analyses, higher severity of illness was associated with higher satisfaction, while a higher patient:nurse ratio and written admission/discharge criteria were associated with lower overall satisfaction. Using performance-importance plots, items with high impact on overall satisfaction but low satisfaction were identified. They included: emotional support, providing understandable, complete, consistent information and coordination of care. CONCLUSIONS: Overall, proxies were satisfied with care and with information/decision-making. Still, several factors, such as emotional support, coordination of care and communication, are associated with poor satisfaction, suggesting the need for improvement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-009-1611-4) contains supplementary material, which is available to authorized users.