Functional observability and target state estimation in large-scale networks.

The quantitative understanding and precise control of complex dynamical systems can only be achieved by observing their internal states via measurement and/or estimation. In large-scale dynamical networks, it is often difficult or physically impossible to have enough sensor nodes to make the system fully observable. Even if the system is in principle observable, high dimensionality poses fundamental limits on the computational tractability and performance of a full-state observer. To overcome the curse of dimensionality, we instead require the system to be functionally observable, meaning that a targeted subset of state variables can be reconstructed from the available measurements. Here, we develop a graph-based theory of functional observability, which leads to highly scalable algorithms to 1) determine the minimal set of required sensors and 2) design the corresponding state observer of minimum order. Compared with the full-state observer, the proposed functional observer achieves the same estimation quality with substantially less sensing and fewer computational resources, making it suitable for large-scale networks. We apply the proposed methods to the detection of cyberattacks in power grids from limited phase measurement data and the inference of the prevalence rate of infection during an epidemic under limited testing conditions. The applications demonstrate that the functional observer can significantly scale up our ability to explore otherwise inaccessible dynamical processes on complex networks.

Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

SARS-CoV-2 Proteins Induce Endotoxin Tolerance Hallmarks: A Demonstration in Patients with COVID-19.

According to a large number of reported cohorts, sepsis has been observed in nearly all deceased patients with COVID-19. We and others have described sepsis, among other pathologies, to be an endotoxin tolerance (ET)-related disease. In this study, we demonstrate that the culture of human blood cells from healthy volunteers in the presence of SARS-CoV-2 proteins induced ET hallmarks, including impairment of proinflammatory cytokine production, low MHC class II (HLA-DR) expression, poor T cell proliferation, and enhancing of both phagocytosis and tissue remodeling. Moreover, we report the presence of SARS-CoV-2 blood circulating proteins in patients with COVID-19 and how these levels correlate with an ET status, the viral RNA presence of SARS-CoV-2 in plasma, as well as with an increase in the proportion of patients with secondary infections.

Galactomannan as a Potential Modulator of Intestinal Ischemia-Reperfusion Injury.

BACKGROUND: Galactomannan (GAL), a polysaccharide present on the cell wall of several fungi, has shown an ability to modulate inflammatory responses through the dectin-1 receptor in human macrophages. However, studies evaluating the modulatory properties of this polysaccharide in in vivo inflammatory scenarios are scarce. We hypothesized that GAL pretreatment would modulate local and remote damage related to intestinal reperfusion after an ischemic insult. MATERIALS AND METHODS: Adult male Balb/c mice were subjected to intestinal ischemia-reperfusion injury by reversible occlusion of the superior mesenteric artery, consisting of 45 min of ischemia followed by 3 or 24 h of reperfusion. Intragastric GAL (70 mg/kg) was administered 12 h before ischemia, and saline solution was used in the control animals. Jejunum, lung, and blood samples were taken for the analysis of histology, gene expression, plasma cytokine levels, and nitrosative stress. RESULTS: Intestinal and lung histologic alterations were attenuated by GAL pretreatment, showing significant differences compared with nontreated animals. Interleukin 1ß, monocyte chemoattractant protein 1, and IL-6 messenger RNA expression were considerably downregulated in the small intestine of the GAL group. In addition, GAL treatment significantly prevented plasma interleukin 6 and monocyte chemoattractant protein 1 upregulation and diminished nitrate and nitrite levels after 3 h of intestinal reperfusion. CONCLUSIONS: GAL pretreatment constitutes a novel and promising therapy to reduce local and remote damage triggered by intestinal ischemia-reperfusion injury. Further in vivo and in vitro studies to understand GAL's modulatory effects are warranted.

Herbivory and Time Since Flowering Shape Floral Rewards and Pollinator-Pathogen Interactions.

Herbivory can induce chemical changes throughout plant tissues including flowers, which could affect pollinator-pathogen interactions. Pollen is highly defended compared to nectar, but no study has examined whether herbivory affects pollen chemistry. We assessed the effects of leaf herbivory on nectar and pollen alkaloids in Nicotiana tabacum, and how herbivory-induced changes in nectar and pollen affect pollinator-pathogen interactions. We damaged leaves of Nicotiana tabacum using the specialist herbivore Manduca sexta and compared nicotine and anabasine concentrations in nectar and pollen. We then pooled nectar and pollen by collection periods (within and after one month of flowering), fed them in separate experiments to bumble bees (Bombus impatiens) infected with the gut pathogen Crithidia bombi, and assessed infections after seven days. We did not detect alkaloids in nectar, and leaf damage did not alter the effect of nectar on Crithidia counts. In pollen, herbivory induced higher concentrations of anabasine but not nicotine, and alkaloid concentrations rose and then fell as a function of days since flowering. Bees fed pollen from damaged plants had Crithidia counts 15 times higher than bees fed pollen from undamaged plants, but only when pollen was collected after one month of flowering, indicating that both damage and time since flowering affected interaction outcomes. Within undamaged treatments, bees fed late-collected pollen had Crithidia counts 10 times lower than bees fed early-collected pollen, also indicating the importance of time since flowering. Our results emphasize the role of herbivores in shaping pollen chemistry, with consequences for interactions between pollinators and their pathogens.

Age-dependent hypoxia-induced PD-L1 upregulation in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model. METHODS: PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice. RESULTS: In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA. CONCLUSION: PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.

Particle filtering of dynamical networks: Highlighting observability issues.

In a network of high-dimensionality, it is not feasible to measure every single node. Thus, an important goal is to define the optimal choice of sensor nodes that provides a reliable state reconstruction of the network system state-space. This is an observability problem. In this paper, we propose a particle filtering (PF) framework as a way to assess observability properties of a dynamical network, where each node is composed of an individual dynamical system. The PF framework is applied to two benchmarks, networks of Kuramoto and Rössler oscillators, to investigate how the interplay between dynamics and topology impacts the network observability. Based on the numerical results, we conjecture that, when the network nodal dynamics are heterogeneous, better observability is conveyed for sets of sensor nodes that share some dynamical affinity to its neighbourhood. Moreover, we also investigate how the choice of an internal measured variable of a multidimensional sensor node affects the PF performance. The PF framework effectiveness as an observability measure is compared with a well-consolidated nonlinear observability metric for a small network case and some chaotic system benchmarks.

The reliability of recurrence network analysis is influenced by the observability properties of the recorded time series.

Recurrence network analysis (RNA) is a remarkable technique for the detection of dynamical transitions in experimental applications. However, in practical experiments, often only a scalar time series is recorded. This requires the state-space reconstruction from this single time series which, as established by embedding and observability theory, is shown to be hampered if the recorded variable conveys poor observability. In this work, we investigate how RNA metrics are impacted by the observability properties of the recorded time series. Following the framework of Zou et al. [Chaos 20, 043130 (2010)], we use the Rössler and Duffing-Ueda systems as benchmark models for our study. It is shown that usually RNA metrics perform badly with variables of poor observability as for recurrence quantification analysis. An exception is the clustering coefficient, which is rather robust to observability issues. Along with its efficacy to detect dynamical transitions, it is shown to be an efficient tool for RNA-especially when no prior information of the variable observability is available.

PD-L1 Overexpression During Endotoxin Tolerance Impairs the Adaptive Immune Response in Septic Patients via HIF1α.

Sepsis, among other pathologies, is an endotoxin tolerance (ET)-related disease. On admission, we classified 48 patients with sepsis into 3 subgroups according to the ex vivo response to lipopolysaccharide. This response correlates with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the ET degree. Moreover, the ET-related classification determines the outcome of these patients. Programmed cell death-ligand 1 (PD-L1) expression on septic monocytes is also linked with ET status. In addition to the regulation of cytokine production, one of the hallmarks of ET that significantly affects patients with sepsis is T-cell proliferation impairment or a poor switch to the adaptive response. PD-L1/programmed cell death-1 (PD-1) blocking and knockdown assays on tolerant monocytes from both patients with sepsis and the in vitro model reverted the impaired adaptive response. Mechanistically, the transcription factor hypoxia-inducible factor-1α (HIF1α) has been translocated into the nucleus and drives PD-L1 expression during ET in human monocytes. This fact, together with patient classification according to the ex vivo lipopolysaccharide response, opens an interesting field of study and potential personalized clinical applications, not only for sepsis but also for all ET-associated pathologies.

PD-L1/PD-1 crosstalk in colorectal cancer: are we targeting the right cells?

BACKGROUND: The analysis of tumour-infiltrating immune cells within patients' tumour samples in colorectal cancer (CRC) has become an independent predictor of patient survival. The tumour microenvironment and the immune checkpoints, such as PD-L1/PD-1, are relevant to the prognoses and also appear to be relevant for further CRC therapies. METHODS: We analysed the presence and features of the infiltrated monocyte/macrophage and lymphocyte populations in both tumour and peritumour samples from patients with CRC (n = 15). RESULTS: We detected a large number of CD14+ monocytes/macrophages with an alternative phenotype (CD64+CD163+) and CD4+ lymphocytes that infiltrated the tumour, but not the peritumour area. The monocytes/macrophages expressed PD-L1, whereas the lymphocytes were PD-1+; however, we did not find high PD-L1 levels in the tumour cells. Coculture of circulating naïve human monocytes/macrophages and lymphocytes with tumour cells from patients with proficient mismatch repair CRC induced both an alternative phenotype with higher expression of PD-L1 in CD14+ cells and the T-cell exhaustion phenomenon. The addition of an α-PD-1 antibody restored lymphocyte proliferation. CONCLUSION: These results emphasise the interesting nature of immune checkpoint shifting therapies, which have potential clinical applications in the context of colorectal cancer.

Obstructive Sleep Apnea Monocytes Exhibit High Levels of Vascular Endothelial Growth Factor Secretion, Augmenting Tumor Progression.

Obstructive sleep apnea (OSA) is a syndrome characterized by repeated pauses in breathing induced by a partial or complete collapse of the upper airways during sleep. Intermittent hypoxia (IH), a hallmark characteristic of OSA, has been proposed to be a major determinant of cancer development, and patients with OSA are at a higher risk of tumors. Both OSA and healthy monocytes have been found to show enhanced HIF1α expression under IH. Moreover, these cells under IH polarize toward a tumor-promoting phenotype in a HIF1α-dependent manner and influence tumor growth via vascular endothelial growth factor (VEGF). Monocytes from patients with OSA increased the tumor-induced microenvironment and exhibited an impaired cytotoxicity in a 3D tumor in vitro model as a result of the increased HIF1α secretion. Adequate oxygen restoration both in vivo (under continuous positive airway pressure treatment, CPAP) and in vitro leads the monocytes to revert the tumor-promoting phenotype, demonstrating the plasticity of the innate immune system and the oxygen recovery relevance in this context.

Recurrence plots for the assessment of patient-ventilator interactions quality during invasive mechanical ventilation.

Inappropriate patient-ventilator interactions' (PVI) quality is associated with adverse clinical consequences, such as patient anxiety/fear and increased need of sedative and paralytic agents. Thus, technological devices/tools to support the recognition and monitoring of different PVI quality are of great interest. In the present study, we investigate two tools based on a recent landmark study which applied recurrence plots (RPs) and recurrence quantification analysis (RQA) techniques in non-invasive mechanical ventilation. Our interest is in how this approach could be a daily part of critical care professionals' routine (which are not familiar with dynamical systems theory methods and concepts). Two representative time series of three typical PVI "scenarios" were selected from 6 critically ill patients subjected to invasive mechanical ventilation. First, both the (i) main signatures in RPs and the (ii) respective signals that provide the most (visually) discriminant RPs were identified. This allows one to propose a visual identification protocol for PVIs' quality through the RPs' overall aspect. Support for the effectiveness of this visual based assessment tool is given by a RQA-based assessment tool. A statistical analysis shows that both the recurrence rate and the Shannon entropy are able to identify the selected PVI scenarios. It is then expected that the development of an objective method can reliably identify PVI quality, where the results corroborate the potential of RPs/RQA in the field of respiratory pattern analysis.

Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

Monocytes inhibit NK activity via TGF-ß in patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry and in vitro assays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-ß (TGF-ß), in contrast to those from the HV and CPAP groups. High levels of TGF-ß were detected in OSA sera. TGF-ß release by GARP+ monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+ monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-ß. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.

Observability and synchronization of neuron models.

Observability is the property that enables recovering the state of a dynamical system from a reduced number of measured variables. In high-dimensional systems, it is therefore important to make sure that the variable recorded to perform the analysis conveys good observability of the system dynamics. The observability of a network of neuron models depends nontrivially on the observability of the node dynamics and on the topology of the network. The aim of this paper is twofold. First, to perform a study of observability using four well-known neuron models by computing three different observability coefficients. This not only clarifies observability properties of the models but also shows the limitations of applicability of each type of coefficients in the context of such models. Second, to study the emergence of phase synchronization in networks composed of neuron models. This is done performing multivariate singular spectrum analysis which, to the best of the authors' knowledge, has not been used in the context of networks of neuron models. It is shown that it is possible to detect phase synchronization: (i) without having to measure all the state variables, but only one (that provides greatest observability) from each node and (ii) without having to estimate the phase.

Enhancing multivariate singular spectrum analysis for phase synchronization: The role of observability.

Multivariate singular spectrum analysis (M-SSA) was recently adapted to study systems of coupled oscillators. It does not require an a priori definition for phase nor detailed knowledge of the individual oscillators, but it uses all the variables of each system. This aspect could be restrictive for practical applications, since usually just a few (sometimes only one) variables are measured. Based on dynamical systems and observability theories, we first show how to apply the M-SSA with only one variable and show the conditions to achieve good performance. Next, we provide numerical evidence that this single-variable approach enhances the explanatory power compared to the original M-SSA when computed with all the system variables. This could have important practical implications, as pointed out using benchmark oscillators.

Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP.

BACKGROUND: Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown. RESULTS: To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity. CONCLUSIONS: Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.

Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss.

The fact that hereditary hearing loss is the most common sensory disorder in humans is reflected by, among other things, an extraordinary allelic and nonallelic genetic heterogeneity. X-chromosomal hearing impairment represents only a minor fraction of all cases. In a study of a Spanish family the locus for one of the X-chromosomal forms was assigned to Xp22 (DFNX4). We mapped the disease locus in the same chromosomal region in a large German pedigree with X-chromosomal nonsyndromic hearing impairment by using genome-wide linkage analysis. Males presented with postlingual hearing loss and onset at ages 3-7, whereas onset in female carriers was in the second to third decades. Targeted DNA capture with high-throughput sequencing detected a nonsense mutation in the small muscle protein, X-linked (SMPX) of affected individuals. We identified another nonsense mutation in SMPX in patients from the Spanish family who were previously analyzed to map DFNX4. SMPX encodes an 88 amino acid, cytoskeleton-associated protein that is responsive to mechanical stress. The presence of Smpx in hair cells and supporting cells of the murine cochlea indicates its role in the inner ear. The nonsense mutations detected in the two families suggest a loss-of-function mechanism underlying this form of hearing impairment. Results obtained after heterologous overexpression of SMPX proteins were compatible with this assumption. Because responsivity to physical force is a characteristic feature of the protein, we propose that long-term maintenance of mechanically stressed inner-ear cells critically depends on SMPX function.

Individuality of breathing patterns in patients under noninvasive mechanical ventilation evidenced by chaotic global models.

Autonomous global models based on radial basis functions were obtained from data measured from patients under noninvasive mechanical ventilation. Some of these models, which are discussed in the paper, turn out to have chaotic or quasi-periodic solutions, thus providing a first piece of evidence that the underlying dynamics of the data used to estimate the global models are likely to be chaotic or, at least, have a chaotic component. It is explicitly shown that one of such global models produces attractors characterized by a Horseshoe map, two models produce toroidal chaos, and one model produces a quasi-periodic regime. These topologically inequivalent attractors evidence the individuality of breathing profiles observed in patient under noninvasive ventilation.

Interacting Antagonisms: Parasite Infection Alters Bombus impatiens (Hymenoptera: Apidae) Responses to Herbivory on Tomato Plants.

Little is known about how simultaneous antagonistic interactions on plants and pollinators affect pollination services, even though herbivory can alter floral traits and parasites can change pollinator learning, perception, or behavior. We investigated how a common herbivore and bumble bee (Bombus spp.) parasite impact pollination in tomatoes (Solanum lycopersicum L.) (Solanales: Solanaceae). We exposed half the plants to low-intensity herbivory by the specialist Manduca sexta L. (Lepidoptera: Sphigidae), and observed bumble bee visits and time spent on flowers of damaged and control plants. Following observations, we caught the foraging bees and assessed infection by the common gut parasite, Crithidia bombi Lipa & Triggiani (Trypanosomatida: Trypanosomatidae). Interestingly, we found an interactive effect between herbivory and Crithidia infection; bees with higher parasite loads spent less time foraging on damaged plants compared to control plants. However, bees did not visit higher proportions of flowers on damaged or control plants, regardless of infection status. Our study demonstrates that multiple antagonists can have synergistic negative effects on the duration of pollinator visits, such that the consequences of herbivory may depend on the infection status of pollinators. If pollinator parasites indeed exacerbate the negative effects of herbivory on pollination services, this suggests the importance of incorporating bee health management practices to maximize crop production.