Single cell multi-omic analysis identifies key genes differentially expressed in innate lymphoid cells from COVID-19 patients.

Introduction: Innate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing. Methods: To gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection, we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression, transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls. Results: We found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover, all ILC subsets displayed a significantly higher frequency of CD69-expressing cells, indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation, activation and homeostasis. In addition, differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC. Discussion: Overall, this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection.

Congruence Concept for Comparison of Spectra.

This paper introduces an alternative, easy-to-implement spectrum comparison concept. The evaluation procedure is illustrated by artificial and attenuated total reflection Fourier transform infrared (ATR FT-IR) spectra, which it can also be extended to other spectrometries (e.g., ultraviolet-visible or UV-Vis and Raman). The evaluation for the comparison of two spectra is divided into four phases: (i) spectrum pre-treatment (e.g., smoothing and background correction), (ii) standard normal variate (SNV) transformation, (iii) regression analysis of SNV spectra, and (iv) calculation of the quantification index (FG). The FG is derived from the formula of R2. It characterizes and quantifies the identity and/or similarity of the compared spectra.

Cellular and molecular mechanisms of allergic asthma.

Asthma is a chronic disease of the airways, which affects more than 350 million people worldwide. It is the most common chronic disease in children, affecting at least 30 million children and young adults in Europe. Asthma is a complex, partially heritable disease with a marked heterogeneity. Its development is influenced both by genetic and environmental factors. The most common, as well as the most well characterized subtype of asthma is allergic eosinophilic asthma, which is characterized by a type 2 airway inflammation. The prevalence of asthma has substantially increased in industrialized countries during the last 60 years. The mechanisms underpinning this phenomenon are incompletely understood, however increased exposure to various environmental pollutants probably plays a role. Disease inception is thought to be enabled by a disadvantageous shift in the balance between protective and harmful lifestyle and environmental factors, including exposure to protective commensal microbes versus infection with pathogens, collectively leading to airway epithelial cell damage and disrupted barrier integrity. Epithelial cell-derived cytokines are one of the main drivers of the type 2 immune response against innocuous allergens, ultimately leading to infiltration of lung tissue with type 2 T helper (TH2) cells, type 2 innate lymphoid cells (ILC2s), M2 macrophages and eosinophils. This review outlines the mechanisms responsible for the orchestration of type 2 inflammation and summarizes the novel findings, including but not limited to dysregulated epithelial barrier integrity, alarmin release and innate lymphoid cell stimulation.

A Novel Measure Inspired by Lyapunov Exponents for the Characterization of Dynamics in State-Transition Networks.

The combination of network sciences, nonlinear dynamics and time series analysis provides novel insights and analogies between the different approaches to complex systems. By combining the considerations behind the Lyapunov exponent of dynamical systems and the average entropy of transition probabilities for Markov chains, we introduce a network measure for characterizing the dynamics on state-transition networks with special focus on differentiating between chaotic and cyclic modes. One important property of this Lyapunov measure consists of its non-monotonous dependence on the cylicity of the dynamics. Motivated by providing proper use cases for studying the new measure, we also lay out a method for mapping time series to state transition networks by phase space coarse graining. Using both discrete time and continuous time dynamical systems the Lyapunov measure extracted from the corresponding state-transition networks exhibits similar behavior to that of the Lyapunov exponent. In addition, it demonstrates a strong sensitivity to boundary crisis suggesting applicability in predicting the collapse of chaos.

Comparative activity of ozenoxacin and other quinolones in Staphylococcus aureus strains overexpressing the efflux pump-encoding genes mepA and norA.

BACKGROUND: To evaluate the activity of ozenoxacin (OZN) in Staphylococcus aureus strains overexpressing the efflux pump-encoding genes mepA and norA. METHODS: S. aureus NCTC-8325-1, S. aureus NCTC 8225-2 (overexpressing mepA), S. aureus SA 1199 and S. aureus SA 1199B (overexpressing norA) were used. The minimum inhibitory concentrations (MICs) of OZN, moxifloxacin (MOX), levofloxacin (LVX), ciprofloxacin (CIP) and norfloxacin (NOR) in the presence and absence of reserpine (20 mg/L) were determined using the microdilution method. RESULTS: The MIC of OZN was lower in all evaluated strains compared with the other studied quinolones and was independent of the pump being overexpressed. MIC values of OZN ranged from 0.005 to 0.007 mg/L. Similar results were observed with MOX, with MIC values between 0.021 and 0.031 mg/L, without variations in the presence of reserpine. MIC values for LVX were between 0.167 and 1 mg/L with a slight increase in MIC observed in strains overexpressing the mepA or norA genes (from 0.250 to 0.833 mg/L and 0.167 to 1 mg/L, respectively). Overproduction of the efflux pump MepA did not affect CIP whereas it increased 8-fold the MIC of NOR. Overproduction of NorA increased ~5-fold and ~40-fold the MICs of CIP and NOR, respectively, resulting in a high-level of resistance to these antibiotics compared with OZN (0.007 mg/L). CONCLUSION: OZN does not seem to be a substrate for the efflux pumps MepA and NorA, which are commonly found in Gram-positive bacteria and that affect other quinolones.

Mutant prevention concentration of ozenoxacin for quinolone-susceptible or -resistant Staphylococcus aureus and Staphylococcus epidermidis.

Ozenoxacin (OZN) belongs to a new generation of non-fluorinated quinolones for the topical treatment of skin infections which has shown to be effective in the treatment of susceptible and resistant Gram-positive cocci. The mutant prevention concentration (MPC) of ozenoxacin, levofloxacin and ciprofloxacin was determined in quinolone-susceptible and -resistant strains including methicillin-susceptible S. aureus, methicillin-resistant S. aureus, methicillin-susceptible S. epidermidis and methicillin-resistant S. epidermidis with different profile of mutation in the quinolone resistance determining regions (QRDR). The MPC value of OZN for the methicillin-susceptible S. aureus strain susceptible to quinolones, without mutations in QRDR, was 0.05 mg/L, being 280-fold lower than that observed with ciprofloxacin and levofloxacin. In methicillin-susceptible and-resistant S. aureus strains with mutations in the gyrA or/and grlA genes the MPC of OZN went from 0.1 to 6 mg/L, whereas the MPC of levofloxacin and ciprofloxacin was > 50 mg/L for the same strains. For methicillin-susceptible and-resistant S. epidermidis the results were similar to those abovementioned for S. aureus. According to our results, the MPC of OZN was far below the quantity of ozenoxacin achieved in the epidermal layer, suggesting that the in vivo selection of mutants, if it occurs, will take place at low frequency. Ozenoxacin is an excellent candidate for the treatment of bacterial infections caused by susceptible and quinolone-resistant staphylococci isolated usually from skin infections.

Infraslow oscillations in human sleep spindle activity.

BACKGROUND: It has previously been reported that EEG sigma (10-15 Hz) activity during sleep exhibits infraslow oscillations (ISO) with a period of 50 s. However, a detailed analysis of the ISO of individually identified sleep spindles is not available. NEW METHOD: We investigated basic properties of ISO during baseline sleep of 34 healthy young human participants using new and established methods. The analyses focused on fast sleep spindle and sigma activity (13-15 Hz) in NREM stage 2 and slow wave sleep (SWS). To describe ISO in sigma activity we analyzed power of power of the EEG signal. For the study of ISO in sleep spindle activity we applied a new method in which the EEG signal was reduced to a spindle on/off binary square signal. Its spectral properties were contrasted to that of a square signal wherein the same spindles and also the inter spindle intervals were permutated randomly. This approach was validated using surrogate data with imposed ISO modulation. RESULTS: We confirm the existence of ISO in sigma activity albeit with a frequency below the previously reported 0.02 Hz. These ISO are most prominent in the high sigma band and over the centro-parieto-occipital regions. A similar modulation is present in spindle activity. ISO in sleep spindles are most prominent in the centro-parieto-occipital regions, left hemisphere and second half of the night independent of the number of spindles. CONCLUSIONS: The comparison of spectral properties of binary event signals and permutated event signals is effective in detecting slow oscillatory phenomena.

Human CD40 ligand-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells.

BACKGROUND: Type 3 innate lymphoid cells (ILC3s) are involved in maintenance of mucosal homeostasis; however, their role in immunoregulation has been unknown. Immature transitional regulatory B (itBreg) cells are innate-like B cells with immunosuppressive properties, and the in vivo mechanisms by which they are induced have not been fully clarified. OBJECTIVE: We aimed to investigate the ILC3-B-cell interaction that probably takes place in human tonsils. METHODS: ILC3s were isolated from peripheral blood and palatine tonsils, expanded, and cocultured with naive B cells. Tonsillar ILC3s and regulatory B cells were visualized with immunofluorescence histology. ILC3 frequencies were measured in tonsil tissue of allergic and nonallergic patients and in peripheral blood of allergic asthmatic patients and healthy control subjects. RESULTS: A mutually beneficial relationship was revealed between ILC3s and B cells: ILC3s induced IL-15 production in B cells through B cell-activating factor receptor, whereas IL-15, a potent growth factor for ILC3s, induced CD40 ligand (CD40L) expression on circulating and tonsillar ILC3s. IL-15-activated CD40L+ ILC3s helped B-cell survival, proliferation, and differentiation of IL-10-secreting, PD-L1-expressing functional itBreg cells in a CD40L- and B cell-activating factor receptor-dependent manner. ILC3s and regulatory B cells were in close connection with each other in palatine tonsils. ILC3 frequency was reduced in tonsil tissue of allergic patients and in peripheral blood of allergic asthmatic patients. CONCLUSION: Human CD40L+ ILC3s provide innate B-cell help and are involved in an innate immunoregulatory mechanism through induction of itBreg cell differentiation, which takes place in palatine tonsils in vivo. This mechanism, which can contribute to maintenance of immune tolerance, becomes insufficient in allergic diseases.

Association of symptoms of insomnia and sleep parameters among kidney transplant recipients.

OBJECTIVE: Insomnia complaints are frequent among kidney transplant (kTx) recipients and are associated with fatigue, depression, lower quality of life and increased morbidity. However, it is not known if subjective insomnia symptoms are associated with objective parameters of sleep architecture. Thus, we analyze the association between sleep macrostructure and EEG activity versus insomnia symptoms among kTx recipients. METHODS: Participants (n1=100) were selected from prevalent adult transplant recipients (n0=1214) followed at a single institution. Insomnia symptoms were assessed by the Athens Insomnia Scale (AIS) and standard overnight polysomnography was performed. In a subgroup of patients (n2=56) sleep microstructure was also analyzed with power spectral analysis. RESULTS: In univariable analysis AIS score was not associated with sleep macrostructure parameters (sleep latency, total sleep time, slow wave sleep, wake after sleep onset), nor with NREM and REM beta or delta activity in sleep microstructure. In multivariable analysis after controlling for covariables AIS score was independently associated with the proportion of slow wave sleep (ß=0.263; CI: 0.026-0.500) and REM beta activity (ß=0.323; CI=0.041-0.606) (p<0.05 for both associations). CONCLUSIONS: Among kTx recipients the severity of insomnia symptoms is independently associated with higher proportion of slow wave sleep and increased beta activity during REM sleep but not with other parameters sleep architecture. The results suggest a potential compensatory sleep protective mechanism and a sign of REM sleep instability associated with insomnia symptoms among this population.

Stochastic graph Voronoi tessellation reveals community structure.

Given a network, the statistical ensemble of its graph-Voronoi diagrams with randomly chosen cell centers exhibits properties convertible into information on the network's large scale structures. We define a node-pair level measure called Voronoi cohesion which describes the probability for sharing the same Voronoi cell, when randomly choosing g centers in the network. This measure provides information based on the global context (the network in its entirety), a type of information that is not carried by other similarity measures. We explore the mathematical background of this phenomenon and several of its potential applications. A special focus is laid on the possibilities and limitations pertaining to the exploitation of the phenomenon for community detection purposes.