Disrupted stepwise functional brain organization in overweight individuals

Functional hierarchy establishes core axes of the brain, and overweight individuals show alterations in the networks anchored on these axes, particularly in those involved in sensory and cognitive control systems. However, quantitative assessments of hierarchical brain organization in overweight individuals are lacking. Capitalizing stepwise functional connectivity analysis, we assess altered functional connectivity in overweight individuals relative to healthy weight controls along the brain hierarchy. Seeding from the brain regions associated with obesity phenotypes, we conduct stepwise connectivity analysis at different step distances and compare functional degrees between the groups. We find strong functional connectivity in the somatomotor and prefrontal cortices in both groups, and both converge to transmodal systems, including frontoparietal and default-mode networks, as the number of steps increased. Conversely, compared with the healthy weight group, overweight individuals show a marked decrease in functional degree in somatosensory and attention networks across the steps, whereas visual and limbic networks show an increasing trend. Associating functional degree with eating behaviors, we observe negative associations between functional degrees in sensory networks and hunger and disinhibition-related behaviors. Our findings suggest that overweight individuals show disrupted functional network organization along the hierarchical axis of the brain and these results provide insights for behavioral associations.

Asymmetry of cortical functional hierarchy in humans and macaques suggests phylogenetic conservation and adaptation

The human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, i.e., asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a hierarchical functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization. These asymmetries were heritable and comparable between humans and macaques, suggesting (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques and variable heritability in humans. This may reflect an evolutionary adaptation allowing for experience-dependent specialization, linked to higher-order cognitive functions uniquely developed in humans.

Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that ‘classical’ and ‘basal-like’ cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, we identify distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. Cell states are connected by a differentiation hierarchy, with ‘classical’ cells concentrated at the endpoint. In an imaging-based drug screen, expression of ‘classical’ subtype genes correlates with better drug response. Our results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes, and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.

A hierarchical GBP network promotes cytosolic LPS recognition and sepsis

Bacterial lipopolysaccharide (LPS) is one of the most bioactive substances known. Trace amounts trigger robust immunity to infection but also life-threatening sepsis causing millions of deaths each year. LPS contamination of the cytosol elicits a caspase-dependent inflammasome pathway promoting cytokine release and host cell death. Here, we report an immune GTPase network controls multiple steps in this pathway by genome-engineering mice to lack 7 different guanylate-binding proteins (GBPs). Gbp2-/- and Gbp3-/- mice had severe caspase-11-driven defects that protected them from septic shock. Gbp2 recruited caspase-11 for LPS recognition whereas Gbp3 assembled and trafficked the pyroptotic pore-forming protein, gasdermin D, after caspase-11 cleavage. Together, our results identify a new functional hierarchy wherein different GBPs choreograph sequential steps in the non-canonical inflammasome pathway to control Gram-negative sepsis.

Modeling the Theory-Form: Beyond the Elements of Observational Postulation

We formalize a theory of the subject by sketching a pragmatic functional hierarchy of sapient cognition. Our expanded framework attempts to articulate a normative understanding of discursive cognition by demarcating its functional propriety within a naturalist rejoinder, seeing in the functional development of cognition from pre-discursive to discursive abilities an increase and refinement in representational competence found in non-intentional systems. We therein explain how sapient cognitive systems not only engage in patterns of material and formal inference to map intensional relations between phenomena in nature through theoretical and practical reasonings, but also engage in practices of theoretical construction and systematic integration through techniques of formalization that make the unity of nature and thought progressively intelligible. We trace the development of mind in its representational function from barren discriminatory capacities, shared with inanimate objects, to complex theory-forming systematizing conceptual abilities enabling agents to theoretically map and intervene upon the world of which they are part, and to embed the informational indexes they register from the environment that makes globally explicit the objective modal structure of the world.

Dissociable Multi-scale Patterns of Development in Personalized Brain Networks

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derived personalized functional networks across 29 scales in a large sample of youths (n=693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling systematically adhered to and strengthened a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks dissociably mediated the emergence of executive function. These results delineate maturation of multi-scale brain networks, which varies according to a functional hierarchy and impacts cognitive development.

A touch of hierarchy: population receptive fields reveal fingertip integration in Brodmann areas in human primary somatosensory cortex

Several neuroimaging studies have shown the somatotopy of body part representations in primary somatosensory cortex (S1), but the functional hierarchy of distinct subregions in human S1 has not been adequately addressed. The current study investigates the functional hierarchy of cyto-architectonically distinct regions, Brodmann areas BA3, BA1, and BA2, in human S1. During functional MRI experiments, we presented participants with vibrotactile stimulation of the fingertips at three different vibration frequencies. Using population Receptive Field (pRF) modeling of the fMRI BOLD activity, we identified the hand region in S1 and the somatotopy of the fingertips. For each voxel, the pRF center indicates the finger that most effectively drives the BOLD signal, and the pRF size measures the spatial somatic pooling of fingertips. We find a systematic relationship of pRF sizes from lower-order areas to higher-order areas. Specifically, we found that pRF sizes are smallest in BA3, increase slightly towards BA1, and are largest in BA2, paralleling the increase in visual receptive field size as one ascends the visual hierarchy. Additionally, we find that the time-to-peak of the hemodynamic response in BA3 is roughly 0.5 s earlier compared to BA1 and BA2, further supporting the notion of a functional hierarchy of subregions in S1. These results were obtained during stimulation of different mechanoreceptors, suggesting that different afferent fibers leading up to S1 feed into the same cortical hierarchy.

MR. Estimator, a toolbox to determine intrinsic timescales from subsampled spiking activity

Here we present our Python toolbox “MR. Estimator” to reliably estimate the intrinsic timescale from electrophysiologal recordings of heavily subsampled systems. Originally intended for the analysis of time series from neuronal spiking activity, our toolbox is applicable to a wide range of systems where subsampling—the difficulty to observe the whole system in full detail—limits our capability to record. Applications range from epidemic spreading to any system that can be represented by an autoregressive process. In the context of neuroscience, the intrinsic timescale can be thought of as the duration over which any perturbation reverberates within the network; it has been used as a key observable to investigate a functional hierarchy across the primate cortex and serves as a measure of working memory. It is also a proxy for the distance to criticality and quantifies a system’s dynamic working point.

Fast and adaptive protein structure representations for machine learning

The growing prevalence and popularity of protein structure data, both experimental and computationally modelled, necessitates fast tools and algorithms to enable exploratory and interpretable structure-based machine learning. Alignment-free approaches have been developed for divergent proteins, but proteins sharing functional and structural similarity are often better understood via structural alignment, which has typically been too computationally expensive for larger datasets. Here, we introduce the concept of rotation-invariant shape-mers to multiple structure alignment, creating a structure aligner that scales well with the number of proteins and allows for aligning over a thousand structures in 20 minutes. We demonstrate how alignment-free shape-mer counts and aligned structural features, when used in machine learning tasks, can adapt to different levels of functional hierarchy in protein kinases, pinpointing residues and structural fragments that play a role in catalytic activity.

Central Place Theory and the Emergence of Floating Markets in the Mekong Delta of Vietnam

This research re-examines Walter Christaller (1933)’s central place theory paradigm to explain the emergence of a network of floating markets in the Mekong River Delta’s dense network of rivers and canals. Because road transportation is underdeveloped, floating markets play an important role for local people. They provide access to transportation and opportunities to trade, especially for the region’s diverse agricultural products. Furthermore, the floating markets support inland infrastructures. This research challenges Christaller’s (1933) assumptions about population thresholds and geographical range, and Mulligan et al.’s (2012) understanding of interaction among consumer choices, company aggregation and functional hierarchy. It finds that riverine traders employ flexible transaction strategies.