Statistical mechanics of multi-edge networks

Statistical properties of binary complex networks are well understood and recently many attempts have been made to extend this knowledge to weighted ones. There are, however, subtle yet important considerations to be made regarding the nature of the weights used in this generalization. Weights can be either continuous or discrete magnitudes, and in the latter case, they can additionally have undistinguishable or distinguishable nature. This fact has not been addressed in the literature insofar and has deep implications on the network statistics. In this work we face this problem introducing multiedge networks as graphs where multiple (distinguishable) connections between nodes are considered. We develop a statistical mechanics framework where it is possible to get information about the most relevant observables given a large spectrum of linear and nonlinear constraints including those depending both on the number of multiedges per link and their binary projection. The latter case is particularly interesting as we show that binary projections can be understood from multiedge processes. The implications of these results are important as many real-agent-based problems mapped onto graphs require this treatment for a proper characterization of their collective behavior.

Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

Synaptic depression and slow oscillatory activity in a biophysical network model of the cerebral cortex

Short-term synaptic depression (STD) is a form of synaptic plasticity that has a large impact on network computations. Experimental results suggest that STD is modulated by cortical activity, decreasing with activity in the network and increasing during silent states. Here, we explored different activity-modulation protocols in a biophysical network model for which the model displayed less STD when the network was active than when it was silent, in agreement with experimental results. Furthermore, we studied how trains of synaptic potentials had lesser decay during periods of activity (UP states) than during silent periods (DOWN states), providing new experimental predictions. We next tackled the inverse question of what is the impact of modifying STD parameters on the emergent activity of the network, a question difficult to answer experimentally. We found that synaptic depression of cortical connections had a critical role to determine the regime of rhythmic cortical activity. While low STD resulted in an emergent rhythmic activity with short UP states and long DOWN states, increasing STD resulted in longer and more frequent UP states interleaved with short silent periods. A still higher synaptic depression set the network into a non-oscillatory firing regime where DOWN states no longer occurred. The speed of propagation of UP states along the network was not found to be modulated by STD during the oscillatory regime; it remained relatively stable over a range of values of STD. Overall, we found that the mutual interactions between synaptic depression and ongoing network activity are critical to determine the mechanisms that modulate cortical emergent patterns.

Developmental expression of the oligodendrocyte myelin glycoprotein in the mouse telencephalon

The oligodendrocyte myelin glycoprotein is a glycosylphosphatidylinositol-anchored protein expressed by neurons and oligodendrocytes in the CNS. Attempts have been made to identify the functions of the myelin-associated inhibitory proteins (MAIPs) after axonal lesion or in neurodegeneration. However, the developmental roles of some of these proteins and their receptors remain elusive. Recent studies indicate that NgR1 and the recently discovered receptor PirB restrict cortical synaptic plasticity. However, the putative factors that trigger these effects are unknown. Since Nogo-A is mostly associated with the endoplasmic reticulum and MAG appears late during development, the putative participation of OMgp should be considered. Here we examine the pattern of development of OMgp immunoreactive elements during mouse telencephalic development. OMgp immunoreactivity in the developing cortex follows the establishment of the thalamo-cortical barrel-field. At cellular level, we located OMgp neuronal membranes in dendrites and axons as well as in brain synaptosome fractions and axon varicosities. Lastly, the analysis of the barrel-field in OMgp-deficient mice revealed that although thalamo-cortical connections were formed, their targeting in layer IV was altered and numerous axons ectopically invaded layer II-III. Our data support the idea that early-expressed MAIPs play an active role during development and point to OMgp participating in thalamo-cortical connections.

Generative models of the human connectome.

The human connectome represents a network map of the brain's wiring diagram and the pattern into which its connections are organized is thought to play an important role in cognitive function. The generative rules that shape the topology of the human connectome remain incompletely understood. Earlier work in model organisms has suggested that wiring rules based on geometric relationships (distance) can account for many but likely not all topological features. Here we systematically explore a family of generative models of the human connectome that yield synthetic networks designed according to different wiring rules combining geometric and a broad range of topological factors. We find that a combination of geometric constraints with a homophilic attachment mechanism can create synthetic networks that closely match many topological characteristics of individual human connectomes, including features that were not included in the optimization of the generative model itself. We use these models to investigate a lifespan dataset and show that, with age, the model parameters undergo progressive changes, suggesting a rebalancing of the generative factors underlying the connectome across the lifespan.

Tietoliikenneanalysaattorin testausohjelmiston suunnittelu ja toteutus ICONIX-prosessin avulla

Matkapuhelinverkot kehittyvät jatkuvasti tarjoten asiakkailleen uusia palveluja ja nopeampia datayhteyksiä. Verkkojen eri protokollien testaamisessa käytetään apuna tietoliikenneanalysaattoreita, joiden avulla matkapuhelinverkkojen eri rajapinnoissa liikkuvaa informaatiota voidaan tutkia yksityiskohtaisesti. Tämän työn tarkoituksena oli suunnitella ja toteuttaa etämonitorointianalysaattorin testauksessa käytettävä testausohjelmisto ICONIX-prosessin avulla. Suunnitteluun katsottiin kuuluvan prosessiin mukaiset vaatimusmäärittelyn, analyysin ja alustavan suunnittelun sekä yksityiskohtaisen suunnittelun vaiheet. Toteutus muodostui vastaavasti ohjelmointityöstä ja yksikkötestauksesta. Työn tuloksena saatiin suunnittelun ja toteutuksen aikana syntyneet erilaiset kaaviot ja ohjelmakoodi. Lisäksi testausohjelmistoa käytettiin etämonitorointianalysaattorin toiminnallisuus- ja suorituskykytesteissä, joiden perusteella arvioitiin toteutetun testausohjelmiston toimivuutta. Testausohjelmiston todettiin sopivan etämonitorointianalysaattorin testaukseen, sillä niin toiminnallisuustestit kuin kuormitustestitkin saatiin suoritettua onnistuneesti toteutetun testausohjelmiston avulla. ICONIX-prosessin todettiin sopivan testausohjelmiston suunnitteluun, vaikka testausohjelmisto onkin toimintaperiaatteeltaan erilainen, kuin prosessia esittelevissä lähteissä esimerkkeinä käytetyt ohjelmistot. Eri suunnitteluvaiheisiin kului prosessiin tottumattomalta aikaa, mutta toisaalta laadittuja suunnitelmia ei tarvinnut enää toteutusvaiheen aikana muuttaa ja ohjelmointityö oli hyvin suoraviivaista.

Operational Reliability Analysis of a Three-Tiered Thin-Client ERP-system in an International Corporate Environment

Internationalization and the following rapid growth have created the need to concentrate the IT systems of many small-to-medium-sized production companies. Enterprise Resource Planning systems are a common solution for such companies. Deployment of these ERP systems consists of many steps, one of which is the implementation of the same shared system at all international subsidiaries. This is also one of the most important steps in the internationalization strategy of the company from the IT point of view. The mechanical process of creating the required connections for the off-shore sites is the easiest and most well-documented step along the way, but the actual value of the system, once operational, is perceived in its operational reliability. The operational reliability of an ERP system is a combination of many factors. These factors vary from hardware- and connectivity-related issues to administrative tasks and communication between decentralized administrative units and sites. To accurately analyze the operational reliability of such system, one must take into consideration the full functionality of the system. This includes not only the mechanical and systematic processes but also the users and their administration. All operational reliability in an international environment relies heavily on hardware and telecommunication adequacy so it is imperative to have resources dimensioned with regard to planned usage. Still with poorly maintained communication/administration schemes no amount of bandwidth or memory will be enough to maintain a productive level of reliability. This thesis work analyzes the implementation of a shared ERP system to an international subsidiary of a Finnish production company. The system is Microsoft Dynamics Ax, currently being introduced to a Slovakian facility, a subsidiary of Peikko Finland Oy. The primary task is to create a feasible base of analysis against which the operational reliability of the system can be evaluated precisely. With a solid analysis the aim is to give recommendations on how future implementations are to be managed.

Networks of noisy oscillators with correlated degree and frequency dispersion

We investigate how correlations between the diversity of the connectivity of networks and the dynamics at their nodes affect the macroscopic behavior. In particular, we study the synchronization transition of coupled stochastic phase oscillators that represent the node dynamics. Crucially in our work, the variability in the number of connections of the nodes is correlated with the width of the frequency distribution of the oscillators. By numerical simulations on Erdös-Rényi networks, where the frequencies of the oscillators are Gaussian distributed, we make the counterintuitive observation that an increase in the strength of the correlation is accompanied by an increase in the critical coupling strength for the onset of synchronization. We further observe that the critical coupling can solely depend on the average number of connections or even completely lose its dependence on the network connectivity. Only beyond this state, a weighted mean-field approximation breaks down. If noise is present, the correlations have to be stronger to yield similar observations.

Striatal pre- and postsynaptic profile of adenosine A2A receptor antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively.

Hiljaisen tiedon siirto Etelä-Karjalan Osuuspankin Imatrankosken konttorissa

Tutkimuksen tarkoituksena on osallistua liiketaloustieteelliseen keskusteluun hiljaisen tiedon siirtämisestä sekä vahvistaa Etelä-Karjalan Osuuspankissa käytävää keskustelua hiljaisesta tiedosta. Tutkimuksen tavoitteena on ymmärtää ja kuvata, mitä hiljainen tieto tarkoittaa Etelä-Karjalan Osuuspankin Imatrankosken konttorissa, kuinka hiljaisen tiedon siirtoa siellä tehdään sekä kuinka siellä kannattaisi tehdä hiljaisen tiedon siirtoa. Tutkimus toteutettiin kahdentoista laadullisen teemahaastattelun avulla. Hiljainen tieto tarkoittaa Imatrankosken konttorissa käytännön sekä kokemuksen kautta muodostunutta tietoa ja osaamista, mitä on vaikea ilmaista sanoin, mutta sen avulla toiminnasta tulee asiakaslähtöisempää. Hiljaisen tietotaidon siirtäminen sukupolvien välisen kuilun yli nähdään tärkeänä. Hiljainen tieto siirtyy Imatrankosken konttorissa henkilöltä toiselle epävirallisissa yhteyksissä vuorovaikutuksen avulla. Ensimmäiseksi on kiinnitettävä huomiota ympäristöön, jossa hiljaista tietoa siirretään ja sitten valittaviin menetelmiin. Ratkaisut onnistuneempaan hiljaisen tiedon siirtoon liittyvät tietynlaiseen ympäristöön, vuorovaikutukseen ihmisten välillä, yhteistyöhön ja työn kautta oppimiseen, tapoihin sekä menetelmiin, kuten perehdyttäminen, mentorointi, benchmarking, palaverit ja koulutukset, työkierto sekä tekniikan hyödyntäminen.

Soins aux mineurs non accompagnés (MNA): l'expérience lausannoise [Caring for unaccompanied minors: an experience from Lausanne].

La prise en charge médicale du mineur non accompagné est complexe et nécessite la mise en place d'un réseau biopsychosocial. A Lausanne, l'Unité multidisciplinaire de santé des adolescents (UMSA) joue un rôle préventif et curatif pour cette population extrêmement vulnérable. Une prise en charge psychologique rapide est souvent nécessaire en raison des événements de vie dramatiques auxquels la plupart de ces adolescents ont été confrontés. L'absence de projet d'avenir pour la majorité de ces adolescents reste une entrave majeure à leur développement et à leur santé mentale et physique. Medical treatment of an unaccompanied minor is made more complicated firstly by its connections with the politics of immigration and secondly by the difficulty in gaining recognition of the priority of the minor's interests. Enabling healthcare teams to travel and meet these particularly vulnerable youths makes medical care more accessible to them and facilitates an optimal bio-psycho-social treatment. For most of these adolescents it is their lack of plans for the future which remains the major obstacle to their development and mental and physical health.

Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus.

The adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission. Here, we used a combination of serial-section immuno-electron microscopy, confocal microscopy, and electrophysiology to examine the formation of perisynaptic processes on adult-born neurons. We found that the afferent and efferent synapses of newborn neurons are ensheathed by astrocytic processes, irrespective of the age of the neurons or the size of their synapses. The quantification of gliogenesis and the distribution of astrocytic processes on synapses formed by adult-born neurons suggest that the majority of these processes are recruited from pre-existing astrocytes. Furthermore, the inhibition of astrocytic glutamate re-uptake significantly reduced postsynaptic currents and increased paired-pulse facilitation in adult-born neurons, suggesting that perisynaptic processes modulate synaptic transmission on these cells. Finally, some processes were found intercalated between newly formed dendritic spines and potential presynaptic partners, suggesting that they may also play a structural role in the connectivity of new spines. Together, these results indicate that pre-existing astrocytes remodel their processes to ensheathe synapses of adult-born neurons and participate to the functional and structural integration of these cells into the hippocampal network.

Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus.

The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and γ-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function.

An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a genetic disease known to lead to cerebral structural alterations, which we study using the framework of the macroscopic white-matter connectome. We create weighted connectomes of 44 patients with 22q11DS and 44 healthy controls using diffusion tensor magnetic resonance imaging, and perform a weighted graph theoretical analysis. After confirming global network integration deficits in 22q11DS (previously identified using binary connectomes), we identify the spatial distribution of regions responsible for global deficits. Next, we further characterize the dysconnectivity of the deficient regions in terms of sub-network properties, and investigate their relevance with respect to clinical profiles. We define the subset of regions with decreased nodal integration (evaluated using the closeness centrality measure) as the affected core (A-core) of the 22q11DS structural connectome. A-core regions are broadly bilaterally symmetric and consist of numerous network hubs - chiefly parietal and frontal cortical, as well as subcortical regions. Using a simulated lesion approach, we demonstrate that these core regions and their connections are particularly important to efficient network communication. Moreover, these regions are generally densely connected, but less so in 22q11DS. These specific disturbances are associated to a rerouting of shortest network paths that circumvent the A-core in 22q11DS, "de-centralizing" the network. Finally, the efficiency and mean connectivity strength of an orbito-frontal/cingulate circuit, included in the affected regions, correlate negatively with the extent of negative symptoms in 22q11DS patients, revealing the clinical relevance of present findings. The identified A-core overlaps numerous regions previously identified as affected in 22q11DS as well as in schizophrenia, which approximately 30-40% of 22q11DS patients develop.

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.