Aberrant Topology Research Articles

Application of diffusional kurtosis imaging for insights into structurally aberrant topology in Parkinson's disease.

Parkinson's disease (PD) has been regarded as a disconnection syndrome with functional and structural disturbances. However, as the anatomic determinants, the structural disconnections in PD have yet to be fully elucidated. To non-invasively construct structural networks based on microstructural complexity and to further investigate their potential topological abnormalities in PD given the technical superiority of diffusion kurtosis imaging (DKI) to the quantification of microstructure. The microstructural data of gray matter in both the PD group and the healthy control (HC) group were acquired using DKI. The structural networks were constructed at the group level by a covariation approach, followed by the calculation of topological properties based on graph theory and statistical comparisons between groups. A total of 51 patients with PD and 50 HCs were enrolled. Individuals were matched between groups with respect to demographic characteristics (P >0.05). The constructed structural networks in both the PD and HC groups featured small-world properties. In comparison with the HC group, the PD group exhibited significantly altered global properties, with higher normalized characteristic path lengths, clustering coefficients, local efficiency values, and characteristic path lengths and lower global efficiency values (P <0.05). In terms of nodal centralities, extensive nodal disruptions were observed in patients with PD (P <0.05); these disruptions were mainly distributed in the sensorimotor network, default mode network, frontal-parietal network, visual network, and subcortical network. These findings contribute to the technical application of DKI and the elucidation of disconnection syndrome in PD.

Aberrant topologies of bacterial membrane proteins revealed by high sensitivity fluorescence labelling

The cytoplasmic membrane compartmentalises the bacterial cell into cytoplasm and periplasm. Proteins located in this membrane have a defined topology that is established during their biogenesis. However, the accuracy of this fundamental biosynthetic process is unknown. We developed compartment-specific fluorescence labelling methods with up to single-molecule sensitivity. Application of these methods to the single and multi-spanning membrane proteins of the Tat protein transport system revealed rare topogenesis errors. This methodology also detected low level soluble protein mislocalization from the cytoplasm to the periplasm. This study shows that it is possible to uncover rare errors in protein localization by leveraging the high sensitivity of fluorescence methods.

Aberrant topology of white matter networks in patients with methamphetamine dependence and its application in support vector machine-based classification

Brain white matter (WM) networks have been widely studied in neuropsychiatric disorders. However, few studies have evaluated alterations in WM network topological organization in patients with methamphetamine (MA) dependence. Therefore, using machine learning classification methods to analyze WM network topological attributes may give new insights into patients with MA dependence. In the study, diffusion tensor imaging-based probabilistic tractography was used to map the weighted WM networks in 46 MA-dependent patients and 46 control subjects. Using graph-theoretical analyses, the global and regional topological attributes of WM networks for both groups were calculated and compared to determine inter-group differences using a permutation-based general linear model. In addition, the study used a support vector machine (SVM) learning approach to construct a classifier for discriminating subjects with MA dependence from control subjects. Relative to the control group, the MA-dependent group exhibited abnormal topological organization, as evidenced by decreased small-worldness and modularity, and increased nodal efficiency in the right medial superior temporal gyrus, right pallidum, and right ventromedial putamen; the MA-dependent group had the higher hubness scores in 25 regions, which were mainly located in the default mode network. An SVM trained with topological attributes achieved classification accuracy, sensitivity, specificity, and kappa values of 98.09% ± 2.59%, 98.24% ± 4.00%, 97.94% ± 4.26%, and 96.18% ± 5.19% for patients with MA dependence. Our results may suggest altered global WM structural networks in MA-dependent patients. Furthermore, the abnormal WM network topological attributes may provide promising features for the construction of high-efficacy classification models.

Smooth muscle cell specific ablation of CXCL12 downregulates endothelial CXCR7 leading to defective coronary arteries and cardiac hypertrophy

Abstract Aims The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12−/−). Methods and results SM-CXCL12−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Conclusion Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWF-Austria

Disrupted Small-world Networks are Associated with Decreased Vigilant Attention after Total Sleep Deprivation

Sleep deprivation critically affects vigilant attention. Previous neuroimaging studies have revealed altered inter-regional functional connectivity after sleep deprivation, which may disrupt topological properties of brain functional networks. However, little is known about alterations in the topology of intrinsic connectivity and its involvement in attention performance after sleep deprivation. In the current study, we investigated the topological properties of brain networks derived from resting-state functional magnetic resonance imaging of 26 healthy men in rested wakefulness (RW) state and after 36 h of total sleep deprivation (TSD). In the predefined sparsity threshold range, both global and nodal network properties were evaluated based on graph theory analysis. Vigilant attention was assessed using the psychomotor vigilance test (PVT) before and after TSD. Furthermore, Pearson’s correlation analyses were conducted to explore the association between altered network properties and changed PVT performance after TSD. At the global level, the brain functional networks in the TSD state showed a significantly lower small-world coefficient than RW, with decreased global efficiency. At the nodal level, the altered regions were selectively distributed in frontoparietal networks, sensorimotor networks, temporal regions, and salience networks. More specifically, the altered clustering coefficient in the posterior superior temporal sulcus (pSTS) and insula, and altered local efficiency in pSTS were further associated with PVT performance after TSD. Our results suggest that the topological properties of brain functional networks are disrupted, and aberrant topology of temporal networks and salience networks may act as neural signatures underlying the vigilant attention impairments after TSD.

Smooth Muscle Specific Ablation of CXCL12 in Mice Downregulates CXCR7 Associated with Defective Coronary Arteries and Cardiac Hypertrophy.

The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12−/−). SM-CXCL12−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

The ER membrane protein complex is required to ensure correct topology and stable expression of flavivirus polyproteins.

Flaviviruses translate their genomes as multi-pass transmembrane proteins at the endoplasmic reticulum (ER) membrane. Here, we show that the ER membrane protein complex (EMC) is indispensable for the expression of viral polyproteins. We demonstrated that EMC was essential for accurate folding and post-translational stability rather than translation efficiency. Specifically, we revealed degradation of NS4A-NS4B, a region rich in transmembrane domains, in absence of EMC. Orthogonally, by serial passaging of virus on EMC-deficient cells, we identified two non-synonymous point mutations in NS4A and NS4B, which rescued viral replication. Finally, we showed a physical interaction between EMC and viral NS4B and that the NS4A-4B region adopts an aberrant topology in the absence of the EMC leading to degradation. Together, our data highlight how flaviviruses hijack the EMC for transmembrane protein biogenesis to achieve optimal expression of their polyproteins, which reinforces a role for the EMC in stabilizing challenging transmembrane proteins during synthesis.

Crystal stuctures of MglB-2 (TP0684), a topologically variant d-glucose-binding protein from Treponema pallidum, reveal a ligand-induced conformational change.

Previously, we determined the crystal structure of apo-TpMglB-2, a d-glucose-binding component of a putative ABC transporter from the syphilis spirochete Treponema pallidum. The protein had an unusual topology for this class of proteins, raising the question of whether the d-glucose-binding mode would be different in TpMglB-2. Here, we present the crystal structures of a variant of TpMglB-2 with and without d-glucose bound. The structures demonstrate that, despite its aberrant topology, the protein undergoes conformational changes and binds d-glucose similarly to other Mgl-type proteins, likely facilitating d-glucose uptake in T. pallidum.

Disrupted Topology of Frontostriatal Circuits Is Linked to the Severity of Insomnia.

Insomnia is one of the most common health complaints, with a high prevalence of 30~50% in the general population. In particular, neuroimaging research has revealed that widespread dysfunctions in brain regions involved in hyperarousal are strongly correlated with insomnia. However, whether the topology of the intrinsic connectivity is aberrant in insomnia remains largely unknown. In this study, resting-state functional magnetic resonance imaging (rsfMRI) in conjunction with graph theoretical analysis, was used to construct functional connectivity matrices and to extract the attribute features of the small-world networks in insomnia. We examined the alterations in global and local small-world network properties of the distributed brain regions that are predominantly implicated in the frontostriatal network between 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without insomnia symptoms (NIS). Correlations between the small-world properties and clinical measurements were also generated to identify the differences between the two groups. Both the IS group and the NIS group exhibited a small-worldness topology. Meanwhile, the global topological properties didn't show significant difference between the two groups. By contrast, participants in the IS group showed decreased regional degree and efficiency in the left inferior frontal gyrus (IFG) compared with subjects in the NIS group. More specifically, significantly decreased nodal efficiency in the IFG was found to be negatively associated with insomnia scores, whereas the abnormal changes in nodal betweenness centrality of the right putamen were positively correlated with insomnia scores. Our findings suggested that the aberrant topology of the salience network and frontostriatal connectivity is linked to insomnia, which can serve as an important biomarker for insomnia.

Aberrant topologies and reconfiguration pattern of functional brain network in children with second language reading impairment.

Prior work has extensively studied neural deficits in children with reading impairment (RI) in their native language but has rarely examined those of RI children in their second language (L2). A recent study revealed that the function of the local brain regions was disrupted in children with RI in L2, but it is not clear whether the disruption also occurs at a large-scale brain network level. Using fMRI and graph theoretical analysis, we explored the topology of the whole-brain functional network during a phonological rhyming task and network reconfigurations across task and short resting phases in Chinese children with English reading impairment versus age-matched typically developing (TD) children. We found that, when completing the phonological task, the RI group exhibited higher local network efficiency and network modularity compared with the TD group. When switching between the phonological task and the short resting phase, the RI group showed difficulty with network reconfiguration, as reflected in fewer changes in the local efficiency and modularity properties and less rearrangement of the modular communities. These findings were reproducible after controlling for the effects of in-scanner accuracy, participant gender, and L1 reading performance. The results from the whole-brain network analyses were largely replicated in the task-activated network. These findings provide preliminary evidence supporting that RI in L2 is associated with not only abnormal functional network organization but also poor flexibility of the neural system in responding to changing cognitive demands.

Apolipoprotein e epsilon 4 allele is associated with aberrant topology of large-scale functional networks in cognitively normal elderly persons: A graph theoretical analysis

Apolipoprotein e epsilon 4 allele is associated with aberrant topology of large-scale functional networks in cognitively normal elderly persons: A graph theoretical analysis

The X-ray Structure of NccX from Cupriavidus metallidurans 31A Illustrates Potential Dangers of Detergent Solubilization When Generating and Interpreting Crystal Structures of Membrane Proteins

The x-ray structure of NccX, a type II transmembrane metal sensor, from Cupriavidus metallidurans 31A has been determined at a resolution of 3.12 Å. This was achieved after solubilization by dodecylphosphocholine and purification in the presence of the detergent. NccX crystal structure did not match the model based on the extensively characterized periplasmic domain of its closest homologue CnrX. Instead, the periplasmic domains of NccX appeared collapsed against the hydrophobic transmembrane segments, leading to an aberrant topology incompatible with membrane insertion. This was explained by a detergent-induced redistribution of the hydrophobic interactions among the transmembrane helices and a pair of hydrophobic patches keeping the periplasmic domains together in the native dimer. Molecular dynamics simulations performed with the full-length protein or with the transmembrane segments were used along with in vivo homodimerization assays (TOXCAT) to evaluate the determinants of the interactions between NccX protomers. Taken as a whole, computational and experimental results are in agreement with the structural model of CnrX where a cradle-shaped periplasmic metal sensor domain is anchored into the inner membrane by two N-terminal helices. In addition, they show that the main determinant of NccX dimerization is the periplasmic soluble domain and that the interaction between transmembrane segments is highly dynamic. The present work introduces a new crystal structure for a transmembrane protein and, in line with previous studies, substantiates the use of complementary theoretical and in vivo investigations to rationalize a three-dimensional structure obtained in non-native conditions.

Aberrant topology of striatum’s connectivity is associated with the number of episodes in depression

In major depressive disorder, depressive episodes reoccur in ∼60% of cases; however, neural mechanisms of depressive relapse are poorly understood. Depressive episodes are characterized by aberrant topology of the brain's intrinsic functional connectivity network, and the number of episodes is one of the most important predictors for depressive relapse. In this study we hypothesized that specific changes of the topology of intrinsic connectivity interact with the course of episodes in recurrent depressive disorder. To address this hypothesis, we investigated which changes of connectivity topology are associated with the number of episodes in patients, independently of current symptoms and disease duration. Fifty subjects were recruited including 25 depressive patients (two to 10 episodes) and 25 gender- and age-matched control subjects. Resting-state functional magnetic resonance imaging, Harvard-Oxford brain atlas, wavelet-transformation of atlas-shaped regional time-series, and their pairwise Pearson's correlation were used to define individual connectivity matrices. Matrices were analysed by graph-based methods, resulting in outcome measures that were used as surrogates of intrinsic network topology. Topological scores were subsequently compared across groups, and, for patients only, related with the number of depressive episodes and current symptoms by partial correlation analysis. Concerning the whole brain connectivity network of patients, small-world topology was preserved but global efficiency was reduced and global betweenness-centrality increased. Aberrant nodal efficiency and centrality of regional connectivity was found in the dorsal striatum, inferior frontal and orbitofrontal cortex as well as in the occipital and somatosensory cortex. Inferior frontal changes were associated with current symptoms, whereas aberrant right putamen network topology was associated with the number of episodes. Results were controlled for effects of total grey matter volume, medication, and total disease duration. This finding provides first evidence that in major depressive disorder aberrant topology of the right putamen's intrinsic connectivity pattern is associated with the course of depressive episodes, independently of current symptoms, medication status and disease duration. Data suggest that the reorganization of striatal connectivity may interact with the course of episodes in depression thereby contributing to depressive relapse risk.

Brain network connectivity assessed using graph theory in frontotemporal dementia

To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD). Graph theoretical analysis was applied to resting state functional MRI data from 18 patients with probable bvFTD and 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested. Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major "hub" regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction. Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients.

Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis

Brain regions are not independent. They are interconnected by white matter tracts, together forming one integrative complex network. The topology of this network is crucial for efficient information integration between brain regions. Here, we demonstrate that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network. Using graph theoretical analysis, complex structural brain networks of 40 schizophrenia patients and 40 human healthy controls were examined. Diffusion tensor imaging was used to reconstruct the white matter connections of the brain network, with the strength of the connections defined as the level of myelination of the tracts as measured through means of magnetization transfer ratio magnetic resonance imaging. Patients displayed a preserved overall small-world network organization, but focusing on specific brain regions and their capacity to communicate with other regions of the brain revealed significantly longer node-specific path lengths (higher L) of frontal and temporal regions, especially of bilateral inferior/superior frontal cortex and temporal pole regions. These findings suggest that schizophrenia impacts global network connectivity of frontal and temporal brain regions. Furthermore, frontal hubs of patients showed a significant reduction of betweenness centrality, suggesting a less central hub role of these regions in the overall network structure. Together, our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regions.

Loss of topological relationships in a Pleurocapsalean cyanobacterium (Chroococcidiopsis sp.) with partially inactivatedftsZ

When inactivation of the cell division geneftsZ was attempted in the Pleurocapsalean cyanobacteriumChroococcidiopsis CCMEE 029via homologous recombination by using a both-ends truncatedftsZ fragment cloned into the suicide mobilizable plasmid pRL271, the scored transconjugants invariably died upon restreaking. The integration of plasmid pRL271-FZ into the transconjugants genome by single crossover events, leading to the generation of two mutated copies offtsZ, characterized by whole plasmid in-between, was assessed by colony PCR. HeteroplasmicftsZ mutants occurred mostly as cell aggregations, lacking the regularity of successive division planes. Their aberrant topology was resolved by electron transmission microscopy as resulting from the irregular clustering of distinct aggregates. These results suggested that FtsZ is essential in this cyanobacterium able of binary and multiple division and that its partial inactivation results in an impaired coordination in time and space of successive divisions undertaken by single cells.

Prion Topology and Toxicity

Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. Chakrabarti and Hegde (2009) now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology.

Exploring Component Stability Using Life-Stage Concordance In Sabethine Mosquitoes (Diptera: Culicidae).

- Morphological characters from sabethine mosquitoes were coded from larvae, pupae and adults, and life-stage partitions were evaluated to determine the contribution of each to the topology of a combined cladogram. Initial tests failed to find congruence between characters partitioned by life stage. However, when components from the combined analysis were tested using reduced taxon sets, a high degree of concordance between partitions was observed. A procedure for assessing individual life-stage contribution is employed, in which exhaustive searches are used to explore all possible arrangements for each of the selected components. Seven of the 10 components examined were able to recover the combined topology with a reduced taxon set. Congruent arrangements of taxa were typically observed for two or more life stages, although partitioned data were less resolved and frequently included aberrant topologies (those not supported by other partitioned or combined reduced taxon tree sets). In addition, none of the partitioned data sets gave robust results for all tests, suggesting that studies which emphasize character data from single life stages may support misleading arrangements of taxa. One component on the combined cladogram was not supported by any of the life-stage partitions when analysed separately. These results are complementary to "total evidence" approach, and demonstrate that partitions of data are useful for examining suits of characters which may cause some components of the "total.

Exploring Component Stability Using Life-Stage Concordance In Sabethine Mosquitoes (Diptera: Culicidae)

Morphological characters from sabethine mosquitoes were coded from larvae, pupae and adults, and life-stage partitions were evaluated to determine the contribution of each to the topology of a combined cladogram. Initial tests failed to find congruence between characters partitioned by life stage. However, when components from the combined analysis were tested using reduced taxon sets, a high degree of concordance between partitions was observed. A procedure for assessing individual life-stage contribution is employed, in which exhaustive searches are used to explore all possible arrangements for each of the selected components. Seven of the 10 components examined were able to recover the combined topology with a reduced taxon set. Congruent arrangements of taxa were typically observed for two or more life stages, although partitioned data were less resolved and frequently included aberrant topologies (those not supported by other partitioned or combined reduced taxon tree sets). In addition, none of the partitioned data sets gave robust results for all tests, suggesting that studies which emphasize character data from single life stages may support misleading arrangements of taxa. One component on the combined cladogram was not supported by any of the life-stage partitions when analysed separately. These results are complementary to “total evidence” approach, and demonstrate that partitions of data are useful for examining suits of characters which may cause some components of the “total

Environmental influences on locomotor recovery following cortical lesions in rats.

Groups of rats were exposed to an enriched environment 2 hr per day for 30 days during the immediate pre- and/or postoperative period, or not at all. Animals in four of these groups sustained lesions in the bilateral sensorimotor cortex. One sham-operated control group was enriched pre- and postoperatively; a second control group was not. Animals were trained preoperatively to locomote across a narrow elevated runway. Testing on the locomotor task began 31 days after surgery and continued until preoperative performance levels were achieved. Preoperative enrichment had the most potent influence on initial deficit and recovery of locomotion. Animals that were enriched preoperatively failed to demonstrate any deficit postoperatively, and the topology of their hindlimb movement appeared to be normal. In preoperatively impoverished animals, postoperative enrichment reduced the degree of initial deficit and speeded recovery of locomotion when compared with animals not enriched at all. However, preoperatively impoverished rats demonstrated an aberrant topology of hindlimb movement even after they were "behaviorally recovered".