Development of broad modulus profile upon polymer-polymer interface formation between immiscible glassy-rubbery domains.

Interfaces of glassy materials such as thin films, blends, and composites create strong unidirectional gradients to the local heterogeneous dynamics that can be used to elucidate the length scales and mechanisms associated with the dynamic heterogeneity of glasses. We focus on bilayer films of two different polymers with very different glass transition temperatures ([Formula: see text]) where previous work has demonstrated a long-range (∼200 nm) profile in local [Formula: see text] is established between immiscible glassy and rubbery polymer domains when the polymer-polymer interface is formed to equilibrium. Here, we demonstrate that an equally long-ranged gradient in local modulus [Formula: see text] is established when the polymer-polymer interface ([Formula: see text]5 nm) is formed between domains of glassy polystyrene (PS) and rubbery poly(butadiene) (PB), consistent with previous reports of a broad [Formula: see text] profile in this system. A continuum physics model for the shear wave propagation caused by a quartz crystal microbalance across a PB/PS bilayer film is used to measure the viscoelastic properties of the bilayer during the evolution of the PB/PS interface showing the development of a broad gradient in local modulus [Formula: see text] spanning [Formula: see text]180 nm between the glassy and rubbery domains of PS and PB. We suggest these broad profiles in [Formula: see text] and [Formula: see text] arise from a coupling of the spectrum of vibrational modes across the polymer-polymer interface as a result of acoustic impedance matching of sound waves with [Formula: see text] nm during interface broadening that can then trigger density fluctuations in the neighboring domain.

Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity.

The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM's ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.

Effects of Xylanase A double mutation on substrate specificity and structural dynamics.

While protein activity is traditionally studied with a major focus on the active site, the activity of enzymes has been hypothesized to be linked to the flexibility of adjacent regions, warranting more exploration into how the dynamics in these regions affects catalytic turnover. One such enzyme is Xylanase A (XylA), which cleaves hemicellulose xylan polymers by hydrolysis at internal ß-1,4-xylosidic linkages. It contains a "thumb" region whose flexibility has been suggested to affect the activity. The double mutation D11F/R122D was previously found to affect activity and potentially bias the thumb region to a more open conformation. We find that the D11F/R122D double mutation shows substrate-dependent effects, increasing activity on the non-native substrate ONPX2 but decreasing activity on its native xylan substrate. To characterize how the double mutant causes these kinetics changes, nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations were used to probe structural and flexibility changes. NMR chemical shift perturbations revealed structural changes in the double mutant relative to the wild-type, specifically in the thumb and fingers regions. Increased slow-timescale dynamics in the fingers region was observed as intermediate-exchange line broadening. Lipari-Szabo order parameters show negligible changes in flexibility in the thumb region in the presence of the double mutation. To help understand if there is increased energetic accessibility to the open state upon mutation, alchemical free energy simulations were employed that indicated thumb opening is more favorable in the double mutant. These studies aid in further characterizing how flexibility in adjacent regions affects the function of XylA.

How collectively integrated are ecological communities?

Beyond abiotic conditions, do population dynamics mostly depend on a species' direct predators, preys and conspecifics? Or can indirect feedback that ripples across the whole community be equally important? Determining where ecological communities sit on the spectrum between these two characterizations requires a metric able to capture the difference between them. Here we show that the spectral radius of a community's interaction matrix provides such a metric, thus a measure of ecological collectivity, which is accessible from imperfect knowledge of biotic interactions and related to observable signatures. This measure of collectivity integrates existing approaches to complexity, interaction structure and indirect interactions. Our work thus provides an original perspective on the question of to what degree communities are more than loose collections of species or simple interaction motifs and explains when pragmatic reductionist approaches ought to suffice or fail when applied to ecological communities.

C-terminal region of Rv1039c (PPE15) protein of Mycobacterium tuberculosis targets host mitochondria to induce macrophage apoptosis.

Mycobacterium tuberculosis (Mtb) genome possesses a unique family called Proline-Glutamate/Proline-Proline-Glutamate (PE/PPE) gene family, exclusive to pathogenic mycobacterium. Some of these proteins are known to play role in virulence and immune response modulation, but many are still uncharacterized. This study investigated the role of C-terminal region of Rv1039c (PPE15) in inducing mitochondrial perturbations and macrophage apoptosis. Our in-silico studies revealed the disordered, coiled, and hydrophobic C-terminal region in Rv1039c has similarity with C-terminal of mitochondria-targeting pro-apoptotic host proteins. Wild type Rv1039c and C-terminal deleted Rv1039c (Rv1039c-/-Cterm) recombinant proteins were purified and their M. smegmatis knock-in strains were constructed which were used for in-vitro experiments. Confocal microscopy showed localization of Rv1039c to mitochondria of PMA-differentiated THP1 macrophages; and reduced mitochondrial membrane depolarization and production of mitochondrial superoxides were observed in response to Rv1039c-/-Cterm in comparison to full-length Rv1039c. The C-terminal region of Rv1039c was found to activate caspases 3, 7 and 9 along with upregulated expression of pro-apoptotic genes like Bax and Bim. Rv1039c-/-Cterm also reduced the Cytochrome-C release from the mitochondria and the expression of AnnexinV/PI positive and TUNEL positive cells as compared to Rv1039c. Additionally, Rv1039c was observed to upregulate the TLR4-NF-κB-TNF-α signalling whereas the same was downregulated in response to Rv1039c-/-Cterm. These findings suggested that the C-terminal region of Rv1039c is a molecular mimic of pro-apoptotic host proteins which induce mitochondria-dependent macrophage apoptosis and evoke host immune response. These observations enhance our understanding about the role of PE/PPE proteins at host-pathogen interface.

Parameter Sensitivity of Transient Community Dynamics.

AbstractTransient dynamics have always intrigued ecologists, but current rapid environmental change (inducing transients even in previously undisturbed systems) has highlighted their importance more than ever. Here, I introduce a method for analyzing the sensitivity of transient ecological dynamics to parameter perturbations. The question the method answers is: how would the community dynamics have unfolded for some time horizon had the parameters been slightly different? I apply the method to three empirically parameterized models: competition between native forbs and exotic grasses in California, a host-parasitoid system, and an experimental chemostat predator-prey model. These applications showcase the ecological insights one can gain from models using transient sensitivity analysis. First, one can find parameters and their combinations whose perturbations disproportionately affect a system. Second, one can identify particular windows of time during which the predicted deviation from the unperturbed trajectories is especially large and utilize this information for management purposes. Third, there is an inverse relationship between transient and long-term sensitivities whenever the interacting populations are ecologically similar; paradoxically, the smaller the immediate response of the system, the more extreme its long-term response will be.

Deciphering Combinatorial Genetics.

High-order interactions among components of interconnected genetic networks regulate complex functions in biological systems, but deciphering these interactions is challenging. New strategies are emerging to decode these combinatorial genetic interactions across a wide range of organisms. Here, we review advances in multiplexed and combinatorial genetic perturbation technologies and high-throughput profiling platforms that are enabling the systematic dissection of complex genetic networks. These rapidly evolving technologies are being harnessed to probe combinatorial gene functions in functional genomics studies and have the potential to advance our understanding of how genetic networks regulate sophisticated biological phenotypes, to generate novel therapeutic strategies, and to enable the engineering of complex artificial gene networks.

Curvilinear walking elevates fall risk and modulates slip and compensatory step attributes after unconstrained human slips.

While much attention has been paid to understanding slip-related falls in humans, little has been focused on curvilinear paths despite their prevalence, distinct biomechanical demands and increased slipping threat. We determined the mechanics, compensatory stepping reactions and fall risk associated with slips during fixed-speed walking across ranges of path curvature, slipped foot and slip onset phase contexts possible in the community, which builds upon previous work by examining speed-independent effects of curvilinear walking. Twenty-one participants experienced 15 unconstrained slips induced by a wearable friction-reducing device as motion capture and harness load cell data were recorded. Falls were most likely after early stance slips to the inside foot and increased at tighter curvatures. Slip distance and peak velocity decreased as slips began later in stance phase, did not differ between feet, and accelerated on tighter paths. Slipping foot directions relative to heading transitioned from anterior (forward) to posterior (backward) as slips began later in stance, were ipsilateral (toward the slipping foot side) and contralateral (toward the opposite side) for the outside and inside foot, respectively, and became increasingly ipsilateral/contralateral on tighter curvatures. Compensatory steps were placed anteriorly and ipsilaterally after outside and inside foot slips, respectively, and lengthened at later onset phases for outside foot slips only. Our findings illustrate slip magnitude and fall risk relationships that suggest slip direction may influence the balance threat posed by a slip, imply that walking speed may modify slip likelihood, and indicate the most destabilizing curved walking contexts to target in future perturbation-based balance training approaches.

Robustness quantification of a mutant library screen revealed key genetic markers in yeast.

BACKGROUND: Microbial robustness is crucial for developing cell factories that maintain consistent performance in a challenging environment such as large-scale bioreactors. Although tools exist to assess and understand robustness at a phenotypic level, the underlying metabolic and genetic mechanisms are not well defined, which limits our ability to engineer more strains with robust functions. RESULTS: This study encompassed four steps. (I) Fitness and robustness were analyzed from a published dataset of yeast mutants grown in multiple environments. (II) Genes and metabolic processes affecting robustness or fitness were identified, and 14 of these genes were deleted in Saccharomyces cerevisiae CEN.PK113-7D. (III) The mutants bearing gene deletions were cultivated in three perturbation spaces mimicking typical industrial processes. (IV) Fitness and robustness were determined for each mutant in each perturbation space. We report that robustness varied according to the perturbation space. We identified genes associated with increased robustness such as MET28, linked to sulfur metabolism; as well as genes associated with decreased robustness, including TIR3 and WWM1, both involved in stress response and apoptosis. CONCLUSION: The present study demonstrates how phenomics datasets can be analyzed to reveal the relationship between phenotypic response and associated genes. Specifically, robustness analysis makes it possible to study the influence of single genes and metabolic processes on stable microbial performance in different perturbation spaces. Ultimately, this information can be used to enhance robustness in targeted strains.

Adverse Environmental Perturbations May Threaten Kelp Farming Sustainability by Exacerbating Enterobacterales Diseases.

Globally kelp farming is gaining attention to mitigate land-use pressures and achieve carbon neutrality. However, the influence of environmental perturbations on kelp farming remains largely unknown. Recently, a severe disease outbreak caused extensive kelp mortality in Sanggou Bay, China, one of the world's largest high-density kelp farming areas. Here, through in situ investigations and simulation experiments, we find indications that an anomalously dramatic increase in elevated coastal seawater light penetration may have contributed to dysbiosis in the kelp Saccharina japonica's microbiome. This dysbiosis promoted the proliferation of opportunistic pathogenic Enterobacterales, mainly including the genera Colwellia and Pseudoalteromonas. Using transcriptomic analyses, we revealed that high-light conditions likely induced oxidative stress in kelp, potentially facilitating opportunistic bacterial Enterobacterales attack that activates a terrestrial plant-like pattern recognition receptor system in kelp. Furthermore, we uncover crucial genotypic determinants of Enterobacterales dominance and pathogenicity within kelp tissue, including pathogen-associated molecular patterns, potential membrane-damaging toxins, and alginate and mannitol lysis capability. Finally, through analysis of kelp-associated microbiome data sets under the influence of ocean warming and acidification, we conclude that such Enterobacterales favoring microbiome shifts are likely to become more prevalent in future environmental conditions. Our study highlights the need for understanding complex environmental influences on kelp health and associated microbiomes for the sustainable development of seaweed farming.

Chronic PM2.5 exposure disrupts intestinal barrier integrity via microbial dysbiosis-triggered TLR2/5-MyD88-NLRP3 inflammasome activation.

BACKGROUND: PM2.5, a known public health risk, is increasingly linked to intestinal disorders, however, the mechanisms of its impact are not fully understood. PURPOSE: This study aimed to explore the impact of chronic PM2.5 exposure on intestinal barrier integrity and to uncover the underlying molecular mechanisms. METHODS: C57BL/6 J mice were exposed to either concentrated ambient PM2.5 (CPM) or filtered air (FA) for six months to simulate urban pollution conditions. We evaluated intestinal barrier damage, microbial shifts, and metabolic changes through histopathology, metagenomics, and metabolomics. Analysis of the TLR signaling pathway was also conducted. RESULTS: The mean concentration of PM2.5 in the CPM exposure chamber was consistently measured at 70.9 ± 26.8 µg/m³ throughout the study period. Our findings show that chronic CPM exposure significantly compromises intestinal barrier integrity, as indicated by reduced expression of the key tight junction proteins Occludin and Tjp1/Zo-1. Metagenomic sequencing revealed significant shifts in the microbial landscape, identifying 35 differentially abundant species. Notably, there was an increase in pro-inflammatory nongastric Helicobacter species and a decrease in beneficial bacteria, such as Lactobacillus intestinalis, Lactobacillus sp. ASF360, and Eubacterium rectale. Metabolomic analysis further identified 26 significantly altered metabolites commonly associated with intestinal diseases. A strong correlation between altered bacterial species and metabolites was also observed. For example, 4 Helicobacter species all showed positive correlations with 13 metabolites, including Lactate, Bile acids, Pyruvate and Glutamate. Additionally, increased expression levels of TLR2, TLR5, Myd88, and NLRP3 proteins were noted, and their expression patterns showed a strong correlation, suggesting a possible involvement of the TLR2/5-MyD88-NLRP3 signaling pathway. CONCLUSIONS: Chronic CPM exposure induces intestinal barrier dysfunction, microbial dysbiosis, metabolic imbalance, and activation of the TLR2/5-MyD88-NLRP3 inflammasome. These findings highlight the urgent need for intervention strategies to mitigate the detrimental effects of air pollution on intestinal health and identify potential therapeutic targets.

Characteristics of Unsuccessful Balance Reactive Responses to Lateral Loss of Balance in Older Adults.

INTRODUCTION: An effective reactive step response to an unexpected balance loss is an important factor that determines if a fall will happen. We investigated reactive step strategies and kinematics of unsuccessful balance recovery responses that ended with falls in older adults. METHODS: We compared the strategies and kinematics of reactive stepping after a lateral loss of balance, i.e., perturbations, between 49 older female adults who were able to successfully recover from perturbations (perturbation-related non-fallers, PNFs) and 10 female older adults who failed to recover (perturbation-related fallers, PFs). In addition, we compared the successful versus unsuccessful recovery responses of PFs matched to perturbation magnitude. RESULTS: The kinematics of the first reactive step response were significantly different between PFs and PNFs, i.e., longer initiation time, step time, swing time, and time to peak swing-leg velocity, larger first-step length, and center-of-mass displacement. Incomplete crossover stepping and leg collision were significant causes of falls among PFs. Similar findings were found when we compared the successful versus unsuccessful recovery responses of PFs. CONCLUSIONS: The crossover step, which requires a complex coordinated leg movement, resulted in difficulty in controlling and decelerating the moving center of mass following a lateral perturbation, affecting the kinematics of the stepping response, leading to a fall.

When can a population spreading across sink habitats persist?

We consider populations with time-varying growth rates living in sinks. Each population, when isolated, would become extinct. Dispersal-induced growth (DIG) occurs when the populations are able to persist and grow exponentially when dispersal among the populations is present. We provide a mathematical analysis of this surprising phenomenon, in the context of a deterministic model with periodic variation of growth rates and non-symmetric migration which are assumed to be piecewise continuous. We also consider a stochastic model with random variation of growth rates and migration. This work extends existing results of the literature on the DIG effects obtained for periodic continuous growth rates and time independent symmetric migration.

Badminton as a dynamic system - A new method for analyzing badminton matches based on perturbations.

This study presents a method for analysing badminton matches based on the concept of perturbations. We transfer this principle to a badminton rally and describe the decisive shot, which turns a balanced situation into an advantage for one team or one player. Our paper proposes an observational system, which models the decisive shots by using four consecutive actions: impulse (the perturbation), follow-up, survival, and convert. To test the objectivity of the operationalization, independent raters analysed six matches in the singles disciplines of the 2022 World Championships. To evaluate rater agreement, Jaccard coefficient and Cohen's kappa were used. Results show an agreement in identifying impulses of J(R1, R2) = .80, while the agreement in classifying the impulse type (positive/negative) reached κ = .70. A comparison of this perturbation-based analysis and last shot analyses shows significantly different results. Direct errors usually occur in the midcourt (56.4%), whereas most negative perturbations originate from the backcourt (40.0%). In contrast to direct winners, mostly originating from a smash (45.5%), most positive perturbations are created by net shots (30.1%). We argue that our method can be complementary to common last shot analyses and provides a possibility to describe players' strengths and weaknesses in more detail.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

INTRODUCTION: We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. METHODS: We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS: Higher sOB-R was associated with lower fractional anisotropy (FA, ß = -0.114 ± 0.02, p < 0.001), and higher free water (FW, ß = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, ß = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (ß = 0.115 ± 0.027, p < 0.001) and lower FW (ß = -0.096 ± 0.029, p = 0.001) and PSMD (ß = -0.085 ± 0.028, p = 0.002). DISCUSSION: Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. HIGHLIGHTS: Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Communication Strategies in Human-Autonomy Teams During Technological Failures.

OBJECTIVE: This study examines low-, medium-, and high-performing Human-Autonomy Teams' (HATs') communication strategies during various technological failures that impact routine communication strategies to adapt to the task environment. BACKGROUND: Teams must adapt their communication strategies during dynamic tasks, where more successful teams make more substantial adaptations. Adaptations in communication strategies may explain how successful HATs overcome technological failures. Further, technological failures of variable severity may alter communication strategies of HATs at different performance levels in their attempts to overcome each failure. METHOD: HATs in a Remotely Piloted Aircraft System-Synthetic Task Environment (RPAS-STE), involving three team members, were tasked with photographing targets. Each triad had two randomly assigned participants in navigator and photographer roles, teaming with an experimenter who simulated an AI pilot in a Wizard of Oz paradigm. Teams encountered two different technological failures, automation and autonomy, where autonomy failures were more challenging to overcome. RESULTS: High-performing HATs calibrated their communication strategy to the complexity of the different failures better than medium- and low-performing teams. Further, HATs adjusted their communication strategies over time. Finally, only the most severe failures required teams to increase the efficiency of their communication. CONCLUSION: HAT effectiveness under degraded conditions depends on the type of communication strategies enacted by the team. Previous findings from studies of all-human teams apply here; however, novel results suggest information requests are particularly important to HAT success during failures. APPLICATION: Understanding the communication strategies of HATs under degraded conditions can inform training protocols to help HATs overcome failures.

Muscle spindles and their role in maintaining robust locomotion.

Muscle spindles, one of the two main classes of proprioceptors together with Golgi tendon organs, are sensory structures that keep the central nervous system updated about the position and movement of body parts. Although they were discovered more than 150 years ago, their function during movement is not yet fully understood. Here, we summarize the morphology and known functions of muscle spindles, with a particular focus on locomotion. Although certain properties such as the sensitivity to dynamic and static muscle stretch are long known, recent advances in molecular biology have allowed the characterization of the molecular mechanisms for signal transduction in muscle spindles. Building upon classic literature showing that a lack of sensory feedback is deleterious to locomotion, we bring to the discussion more recent findings that support a pivotal role of muscle spindles in maintaining murine and human locomotor robustness, defined as the ability to cope with perturbations. Yet, more research is needed to expand the existing mechanistic understanding of how muscle spindles contribute to the production of robust, functional locomotion in real world settings. Future investigations should focus on combining different animal models to identify, in health and disease, those peripheral, spinal and brain proprioceptive structures involved in the fine tuning of motor control when locomotion happens in challenging conditions.

Spatial heterogeneity of biomass turnover has contrasting effects on synchrony and stability in trophic metacommunities.

Spatial heterogeneity is a fundamental feature of ecosystems, and ecologists have identified it as a factor promoting the stability of population dynamics. In particular, differences in interaction strengths and resource supply between patches generate an asymmetry of biomass turnover with a fast and a slow patch coupled by a mobile predator. Here, we demonstrate that asymmetry leads to opposite stability patterns in metacommunities receiving localized perturbations depending on the characteristics of the perturbed patch. Perturbing prey in the fast patch synchronizes the dynamics of prey biomass between the two patches and destabilizes predator dynamics by increasing the predator's temporal variability. Conversely, perturbing prey in the slow patch decreases the synchrony of the prey's dynamics and stabilizes predator dynamics. Our results have implications for conservation ecology and suggest reinforcing protection policies in fast patches to dampen the effects of perturbations and promote the stability of population dynamics at the regional scale.

Voluntary muscle coactivation in quiet standing elicits reciprocal rather than coactive agonist-antagonist control of reactive balance.

Muscle coactivation increases in challenging balance conditions as well as with advanced age and mobility impairments. Increased muscle coactivation can occur both in anticipation of (feedforward) and in reaction to (feedback) perturbations, however, the causal relationship between feedforward and feedback muscle coactivation remains elusive. Here, we hypothesized that feedforward muscle coactivation would increase both the body's initial mechanical resistance due to muscle intrinsic properties and the later feedback-mediated muscle coactivation in response to postural perturbations. Young adults voluntarily increased leg muscle coactivation using visual biofeedback before support-surface perturbations. In contrast to our hypothesis, feedforward muscle coactivation did not increase the body's initial intrinsic resistance to perturbations, nor did it increase feedback muscle coactivation. Rather, perturbations with feedforward muscle coactivation elicited a medium- to long-latency increase of feedback-mediated agonist activity but a decrease of feedback-mediated antagonist activity. This reciprocal rather than coactivation effect on ankle agonist and antagonist muscles enabled faster reactive ankle torque generation, reduced ankle dorsiflexion, and reduced center of mass (CoM) motion. We conclude that in young adults, voluntary feedforward muscle coactivation can be independently modulated with respect to feedback-mediated muscle coactivation. Furthermore, our findings suggest feedforward muscle coactivation may be useful for enabling quicker joint torque generation through reciprocal, rather than coactivated, agonist-antagonist feedback muscle activity. As such our results suggest that behavioral context is critical to whether muscle coactivation functions to increase agility versus stability.NEW & NOTEWORTHY Feedforward and feedback muscle coactivation are commonly observed in older and mobility impaired adults and are considered strategies to improve stability by increasing body stiffness prior to and in response to perturbations. In young adults, voluntary feedforward coactivation does not necessarily increase feedback coactivation in response to perturbations. Instead, feedforward coactivation enabled faster ankle torques through reciprocal agonist-antagonist muscle activity. As such, coactivation may promote either agility or stability depending on the behavioral context.

Whole-brain analyses indicate the impairment of posterior integration and thalamo-frontotemporal broadcasting in disorders of consciousness.

The study of the brain's dynamical activity is opening a window to help the clinical assessment of patients with disorders of consciousness. For example, glucose uptake and the dysfunctional spread of naturalistic and synthetic stimuli has proven useful to characterize hampered consciousness. However, understanding of the mechanisms behind loss of consciousness following brain injury is still missing. Here, we study the propagation of endogenous and in-silico exogenous perturbations in patients with disorders of consciousness, based upon directed and causal interactions estimated from resting-state fMRI data, fitted to a linear model of activity propagation. We found that patients with disorders of consciousness suffer decreased capacity for neural propagation and responsiveness to events, and that this can be related to severe reduction of glucose metabolism as measured with [18 F]FDG-PET. In particular, we show that loss of consciousness is related to the malfunctioning of two neural circuits: the posterior cortical regions failing to convey information, in conjunction with reduced broadcasting of information from subcortical, temporal, parietal and frontal regions. These results shed light on the mechanisms behind disorders of consciousness, triangulating network function with basic measures of brain integrity and behavior.