A quantitative model of a cooperative two-state equilibrium in DNA: experimental tests, insights, and predictions.

Quantitative parameters for a two-state cooperative transition in duplex DNAs were finally obtained during the last 5 years. After a brief discussion of observations pertaining to the existence of the two-state equilibrium per se, the lengths, torsion, and bending elastic constants of the two states involved and the cooperativity parameter of the model are simply stated. Experimental tests of model predictions for the responses of DNA to small applied stretching, twisting, and bending stresses, and changes in temperature, ionic conditions, and sequence are described. The mechanism and significance of the large cooperativity, which enables significant DNA responses to such small perturbations, are also noted. The capacity of the model to resolve a number of long-standing and sometimes interconnected puzzles in the extant literature, including the origin of the broad pre-melting transition studied by numerous workers in the 1960s and 1970s, is demonstrated. Under certain conditions, the model predicts significant long-range attractive or repulsive interactions between hypothetical proteins with strong preferences for one or the other state that are bound to well-separated sites on the same DNA. A scenario is proposed for the activation of the ilvPG promoter on a supercoiled DNA by integration host factor.

Regional GABA Concentrations Modulate Inter-network Resting-state Functional Connectivity.

Coordinated activity within and differential activity between large-scale neuronal networks such as the default mode network (DMN) and the control network (CN) is a critical feature of brain organization. The CN usually exhibits activations in response to cognitive tasks while the DMN shows deactivations; in addition, activity between the two networks is anti-correlated at rest. To address this issue, we used functional MRI to measure whole-brain BOLD signal during resting-state and task-evoked conditions, and MR spectroscopy (MRS) to quantify GABA and glutamate concentrations, in nodes within the DMN and CN (MPFC and DLPFC, respectively) in 19 healthy individuals at 3 Tesla. We found that GABA concentrations in the MPFC were significantly associated with DMN deactivation during a working memory task and with anti-correlation between DMN and CN at rest and during task performance, while GABA concentrations in the DLPFC weakly modulated DMN-CN anti-correlation in the opposite direction. Highlighting specificity, glutamate played a less significant role related to brain activity. These findings indicate that GABA in the MPFC is potentially involved in orchestrating between-network brain activity at rest and during task performance.

Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity.

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed 11 C-Pittsburgh Compound-B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta-amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large-scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30-55, median age = 43.5) and a stark lack of anti-correlation. However, in contrast to typically developing controls (n = 20, ages 30-55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB-negative Down's syndrome group (n = 19, ages 30-48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB-positive (n = 15, ages 39-55, median age = 48.0) and PiB-negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.

Co-sequencing and novel delayed anti-correlation identify function for pancreatic enriched microRNA biomarkers in a rat model of acute pancreatic injury.

BACKGROUND: Co-sequencing of messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA) across a time series (1, 3, 6, 24, and 48 h post injury) was used to identify potential miRNA-gene interactions during pancreatic injury, associate serum and tissue levels of candidate miRNA biomarkers of pancreatic injury, and functionally link these candidate miRNA biomarkers to observed histopathology. RNAs were derived from pancreatic tissues obtained in experiments characterizing the serum levels of candidate miRNA biomarkers in response to acute pancreatic injury in rats. RESULTS: No correlation was discovered between tissue and serum levels of the miRNAs. A combination of differential gene expression, novel delayed anti-correlation analysis and experimental database interrogation was used to identify messenger RNAs and miRNAs that experienced significant expression change across the time series, that were negatively correlated, that were complementary in sequence, and that had experimentally supported relationships. This approach yielded a complex signaling network for future investigation and a link for the specific candidate miRNA biomarkers, miR-216a-5p and miR-217-5p, to cellular processes that were in fact the prominent histopathology observations in the same experimental samples. RNA quality bias by treatment was observed in the study samples and a statistical correction was applied. The relevance and impact of that correction on significant results is discussed. CONCLUSION: The described approach allowed extraction of miRNA function from genomic data and defined a mechanistic anchor for these miRNAs as biomarkers. Functional and mechanistic conclusions are supported by histopathology findings.

Dissociated patterns of anti-correlations with dorsal and ventral default-mode networks at rest.

Previous studies of resting state functional connectivity have demonstrated that the default-mode network (DMN) is negatively correlated with a set of brain regions commonly activated during goal-directed tasks. However, the location and extent of anti-correlations are inconsistent across different studies, which has been posited to result largely from differences in whether or not global signal regression (GSR) was applied as a pre-processing step. Notably, coordinates of seed regions-of-interest defined within the posterior cingulate cortex (PCC)/precuneus, an area often employed to study functional connectivity of the DMN, have been inconsistent across studies. Taken together with recent observations that the DMN contains functionally heterogeneous subdivisions, it is presently unclear whether these seeds map to different DMN subnetworks, whose patterns of anti-correlation may differ. If so, then seed location may be a non-negligible factor that, in addition to differences in preprocessing steps, contributes to the inconsistencies reported among published studies regarding DMN correlations/anti-correlations. In this study, they examined anti-correlations of different subnetworks within the DMN during rest using both seed-based and point process analyses, and discovered that: (1) the ventral branch of the DMN (vDMN) yielded significantly weaker anti-correlations than that associated with the dorsal branch of the DMN (dDMN); (2) vDMN anti-correlations introduced by GSR were distinct from dDMN anti-correlations; (3) PCC/precuneus seeds employed by earlier studies mapped to different DMN subnetworks, which may explain some of the inconsistency (in addition to preprocessing steps) in the reported DMN anti-correlations. Hum Brain Mapp 38:2454-2465, 2017. © 2017 Wiley Periodicals, Inc.

Characterization of the temporo-parietal junction by combining data-driven parcellation, complementary connectivity analyses, and functional decoding.

The right temporo-parietal junction (RTPJ) is consistently implicated in two cognitive domains, attention and social cognitions. We conducted multi-modal connectivity-based parcellation to investigate potentially separate functional modules within RTPJ implementing this cognitive dualism. Both task-constrained meta-analytic coactivation mapping and task-free resting-state connectivity analysis independently identified two distinct clusters within RTPJ, subsequently characterized by network mapping and functional forward/reverse inference. Coactivation mapping and resting-state correlations revealed that the anterior cluster increased neural activity concomitantly with a midcingulate-motor-insular network, functionally associated with attention, and decreased neural activity concomitantly with a parietal network, functionally associated with social cognition and memory retrieval. The posterior cluster showed the exact opposite association pattern. Our data thus suggest that RTPJ links two antagonistic brain networks processing external versus internal information.

The amplitude of the resting-state fMRI global signal is related to EEG vigilance measures.

In resting-state functional magnetic resonance imaging (fMRI), functional connectivity measures can be influenced by the presence of a strong global component. A widely used pre-processing method for reducing the contribution of this component is global signal regression, in which a global mean time series signal is projected out of the fMRI time series data prior to the computation of connectivity measures. However, the use of global signal regression is controversial because the method can bias the correlation values to have an approximately zero mean and may in some instances create artifactual negative correlations. In addition, while many studies treat the global signal as a non-neural confound that needs to be removed, evidence from electrophysiological and fMRI measures in primates suggests that the global signal may contain significant neural correlates. In this study, we used simultaneously acquired fMRI and electroencephalographic (EEG) measures of resting-state activity to assess the relation between the fMRI global signal and EEG measures of vigilance in humans. We found that the amplitude of the global signal (defined as the standard deviation of the global signal) exhibited a significant negative correlation with EEG vigilance across subjects studied in the eyes-closed condition. In addition, increases in EEG vigilance due to the ingestion of caffeine were significantly associated with both a decrease in global signal amplitude and an increase in the average level of anti-correlation between the default mode network and the task-positive network.

Aberrant resting-state functional connectivity of the globus pallidus interna in first-episode schizophrenia.

BACKGROUND: The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS: 71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: Baseline imaging data from 63 FES patients and 55 HC met quality standards and were analyzed. FES patients exhibited less negative connectivity and increased positive connectivity between the right anterior GPi and several cortical and subcortical areas at baseline compared to HC (PFWE < 0.05). Positive functional connectivity between the right anterior GPi and several brain areas, including the right dorsal anterior cingulate gyrus, was associated with severity of positive symptoms (PFWE < 0.05) and predicted treatment response after 8 weeks (n = 28, adjusted R2 = 0.486, p < 0.001). CONCLUSIONS: Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

COMPENSATORY BRAIN CONNECTION DISCOVERY IN ALZHEIMER'S DISEASE.

Identification of the specific brain networks that are vulnerable or resilient in neurodegenerative diseases can help to better understand the disease effects and derive new connectomic imaging biomarkers. In this work, we use brain connectivity to find pairs of structural connections that are negatively correlated with each other across Alzheimer's disease (AD) and healthy populations. Such anti-correlated brain connections can be informative for identification of compensatory neuronal pathways and the mechanism of brain networks' resilience to AD. We find significantly anti-correlated connections in a public diffusion-MRI database, and then validate the results on other databases.

Disrupted Anti-correlation Between the Default and Dorsal Attention Networks During Hyperthermia Exposure: An fMRI Study.

Environmental hyperthermia is a common risk factor for occupational safety in many situations due to decreased vigilance performances. Previously, we have reported that decreased resting-state functional connectivity within the default mode network (DMN) and decreased activations in dorsal attention network (DAN) such as dorsolateral prefrontal cortex (DLPFC) were correlated with selective attention deficits during hyperthermia. However, whether the inherent functionally organized anti-correlation between the DMN and DAN would contribute to the behavioral deficits remains unclear. In this study, we collected the resting-state fMRI data of 25 participants during two simulated thermal conditions: normothermic condition (25°C for 1 h) and hyperthermic condition (50°C for 1 h). Using group independent component analysis (ICA), we investigated the functional connectivity within the DMN and DAN, as well as the anti-correlations between both networks. Paired comparisons revealed that decreased intranetwork functional connectivity in the medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC) in the DMN contributed to executive control performance during hyperthermia using multivariate linear regression analysis. Paired comparison on the DAN showed that increased one in the posterior part of the middle and inferior temporal gyrus nearby the temporal-parietal junction area contributed to preserved alerting performance. Lastly but most importantly, we found that decreased correlation between mPFC in the DMN and intraparietal sulcus (IPS) area in the DAN contributed to the executive control deficit, suggesting a weaker intrinsic anti-correlation between DMN and DAN during hyperthermia. These findings indicated that a functional reorganized architecture of DMN and DAN might provide a potential neural basis of the selective deficits for different cognitive-demand attention tasks in high-temperature environments.

Investigating Human Visual Sensitivity to Binocular Motion-in-Depth for Anti- and De-Correlated Random-Dot Stimuli.

Motion-in-depth can be detected by using two different types of binocular cues: change of disparity (CD) and inter-ocular velocity differences (IOVD). To investigate the underlying detection mechanisms, stimuli can be constructed that isolate these cues or contain both (FULL cue). Two different methods to isolate the IOVD cue can be employed: anti-correlated (aIOVD) and de-correlated (dIOVD) motion signals. While both types of stimuli have been used in studies investigating the perception of motion-in-depth, for the first time, we explore whether both stimuli isolate the same mechanism and how they differ in their relative efficacy. Here, we set out to directly compare aIOVD and dIOVD sensitivity by measuring motion coherence thresholds. In accordance with previous results by Czuba et al. (2010), we found that motion coherence thresholds were similar for aIOVD and FULL cue stimuli for most participants. Thresholds for dIOVD stimuli, however, differed consistently from thresholds for the two other cues, suggesting that aIOVD and dIOVD stimuli could be driving different visual mechanisms.

Decoupling of reaction time-related default mode network activity with cognitive demand.

Reaction Time (RT) is associated with increased amplitude of the Blood Oxygen-Level Dependent (BOLD) response in task positive regions. Few studies have focused on whether opposing RT-related suppression of task activity also occurs. The current study used two Go/No-go tasks with different cognitive demands to examine regions that showed greater BOLD suppression for longer RT trials. These RT-related suppression effects occurred within the DMN and were task-specific, localizing to separate regions for the two tasks. In the task requiring working memory, RT-related de-coupling of the DMN occurred. This was reflected by opposing RT-BOLD effects for different DMN regions, as well as by reduced positive RT-related Psycho-Physiological Interaction (PPI) connectivity within the DMN and a lack of negative RT-related PPI connectivity between DMN and task positive regions. The results suggest that RT-related DMN suppression is task-specific. RT-related de-coupling of the DMN with more complex task demands may contribute to lapses of attention and performance decrements that occur during cognitively-demanding tasks.