Advancements in non-invasive skin sampling: Clinical conditions characterization via the assessment of skin surface cytokine biomarkers.

The skin is increasingly recognized as a biological active organ interacting with the immune system. Given that the epidermal skin layer actively releases various cytokines, non-invasive skin sampling methods could detect these cytokines, offering insights into clinical conditions. This study aims non-invasively measuring cytokine levels directly from the skin surface to characterize different inflammatory chronic disorders in the adult and elderly population: psoriasis, diabetes type 2, rosacea, chronic kidney disease (CKD) and aging. Cytokines IL-1ß, IL-8 and IL-10 were sampled from healthy subjects and patients aged 18-80 using skin surface wash technique. A well with sterile phosphate-buffered saline solution was placed on the skin for 30 min, and the extracted solution was collected from the well for further cytokine levels analysis using ELISA assay. Results show distinct cytokine profiles in different pathological processes, healthy controls, affected and unaffected areas. Aging was associated with increased IL-1ß, IL-8, and IL-10 levels in skin. In diabetes, IL-1ß and IL-8 levels were elevated in lesional areas, while IL-10 levels were decreased in non-lesional skin. Psoriatic lesions showed elevated levels of IL-1ß and IL-8. Rosacea patients had lower IL-10 levels in both lesional and non-lesional areas. CKD patients exhibited significantly lower IL-10 levels compared to healthy individuals. In conclusion, skin surface wash-derived cytokine profiles could serve as "alert biomarkers" for disease prediction, enabling early detection. Additionally, this method's cost-effectiveness allows pre-screening of molecules in clinical studies and holds potential as a tool for biomarkers and omics analysis, enhancing disorder characterization and disease management.

RNAlysis: analyze your RNA sequencing data without writing a single line of code.

BACKGROUND: Among the major challenges in next-generation sequencing experiments are exploratory data analysis, interpreting trends, identifying potential targets/candidates, and visualizing the results clearly and intuitively. These hurdles are further heightened for researchers who are not experienced in writing computer code since most available analysis tools require programming skills. Even for proficient computational biologists, an efficient and replicable system is warranted to generate standardized results. RESULTS: We have developed RNAlysis, a modular Python-based analysis software for RNA sequencing data. RNAlysis allows users to build customized analysis pipelines suiting their specific research questions, going all the way from raw FASTQ files (adapter trimming, alignment, and feature counting), through exploratory data analysis and data visualization, clustering analysis, and gene set enrichment analysis. RNAlysis provides a friendly graphical user interface, allowing researchers to analyze data without writing code. We demonstrate the use of RNAlysis by analyzing RNA sequencing data from different studies using C. elegans nematodes. We note that the software applies equally to data obtained from any organism with an existing reference genome. CONCLUSIONS: RNAlysis is suitable for investigating various biological questions, allowing researchers to more accurately and reproducibly run comprehensive bioinformatic analyses. It functions as a gateway into RNA sequencing analysis for less computer-savvy researchers, but can also help experienced bioinformaticians make their analyses more robust and efficient, as it offers diverse tools, scalability, automation, and standardization between analyses.

Masking important information to assess the robustness of a multimodal classifier for emotion recognition.

Deep neural networks have been proven effective in classifying human interactions into emotions, especially by encoding multiple input modalities. In this work, we assess the robustness of a transformer-based multimodal audio-text classifier for emotion recognition, by perturbing the input at inference time using attacks which we design specifically to corrupt information deemed important for emotion recognition. To measure the impact of the attacks on the classifier, we compare between the accuracy of the classifier on the perturbed input and on the original, unperturbed input. Our results show that the multimodal classifier is more resilient to perturbation attacks than the equivalent unimodal classifiers, suggesting that the two modalities are encoded in a way that allows the classifier to benefit from one modality even when the other one is slightly damaged.

Cutaneous Nrf2-Keap1 pathway modulation by environmental factors: The Dead Sea area as a test case.

The skin is constantly exposed to exogenous environmental stressors and has to cope with excessive oxidative stress and tissue damage. However, exposure to moderate environmental stressors may be beneficial for the cutaneous tissue and assist in protecting against oxidative damage via the enhanced activation of the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) pathway. Such moderate stressors can be found in various locations around the globe. In this manuscript, we chose to focus on the Dead Sea (DS) area as a test case to study the effect of moderate stressors on the cutaneous tissue because of the unique combinations of moderate stressors in this area. The exceptional location of the DS at an altitude of -438 meters below sea level (the lowest place on earth) is responsible for its rare accumulation of moderate stressors such as high-water salinity, high atmospheric pressure, and unique solar radiation. In this manuscript, we hypothesized that the unique solar radiation in the DS area generates moderate oxidative stress in the skin leading to the induction of intracellular electrophiles, which in turn can activate the protecting Nrf2-Keap1 pathway. We showed that exposure of human skin organ culture from the same donor to solar radiation at the DS resulted in significant activation of the Nrf2-Keap1 pathway, induction of phase II enzymes, and lower apoptotic activity compared to a nearby location at a higher altitude (Jerusalem +700 m). This remarkable effect of activating the Nrf2 protecting pathway and the importance and characteristics of the solar irradiation at the DS is discussed.

Brain networks are decoupled from external stimuli during internal cognition.

Our cognition can be directed to external stimuli or to internal information. While there are many different forms of internal cognition (mind-wandering, recall, imagery etc.), their essential feature is independence from the immediate sensory input, conceptually referred to as perceptual decoupling. Perceptual decoupling is thought to be reflected in brain activity transitioning from a stimulus-processing to internally-processing mode, but a direct investigation of this remains outstanding. Here we present a conceptual and analysis framework that quantifies the extent to which brain networks reflect stimulus processing. We tested this framework by presenting subjects with an audiovisual stimulus and instructing them to either attend to the stimulus (external task) or engage in mental imagery, recall or arithmetic (internal tasks) while measuring the evoked brain activity using functional MRI. We found that stimulus responses were generally attenuated for the internal tasks, though they increased in a subset of tasks and brain networks. However, using our new framework, we showed that brain networks became less reflective of stimulus processing, even in the subset of tasks and brain networks in which stimulus responses increased. These results quantitatively demonstrate that during internal cognition brain networks become decoupled from the external stimuli, opening the door for a fundamental and quantitative understanding of internal cognition.

Integrated information structure collapses with anesthetic loss of conscious arousal in Drosophila melanogaster.

The physical basis of consciousness remains one of the most elusive concepts in current science. One influential conjecture is that consciousness is to do with some form of causality, measurable through information. The integrated information theory of consciousness (IIT) proposes that conscious experience, filled with rich and specific content, corresponds directly to a hierarchically organised, irreducible pattern of causal interactions; i.e. an integrated informational structure among elements of a system. Here, we tested this conjecture in a simple biological system (fruit flies), estimating the information structure of the system during wakefulness and general anesthesia. Consistent with this conjecture, we found that integrated interactions among populations of neurons during wakefulness collapsed to isolated clusters of interactions during anesthesia. We used classification analysis to quantify the accuracy of discrimination between wakeful and anesthetised states, and found that informational structures inferred conscious states with greater accuracy than a scalar summary of the structure, a measure which is generally championed as the main measure of IIT. In stark contrast to a view which assumes feedforward architecture for insect brains, especially fly visual systems, we found rich information structures, which cannot arise from purely feedforward systems, occurred across the fly brain. Further, these information structures collapsed uniformly across the brain during anesthesia. Our results speak to the potential utility of the novel concept of an "informational structure" as a measure for level of consciousness, above and beyond simple scalar values.

Validating reported cause of death using integrated electronic health records from a nation-wide database.

BACKGROUND: To compare the underlying cause of death reported by the Israeli Central Bureau of Statistics (CBS) with diagnoses in the electronic health records (EHR) of a fully integrated payer/provider healthcare system. METHODS: Underlying cause of death was obtained from the CBS for deaths occurring during 2009-2012 of all Clalit Health Service members in Israel. The final cohort consisted of members who had complete medical records. The frequency of a supportive diagnosis in the EHR was reported for 10 leading causes of death (malignancies, heart disease, cerebrovascular disease, diabetes, kidney disease, septicemia, accidents, chronic lower respiratory disease, dementia and pneumonia and influenza). RESULTS: Of the 45 680 members included in the study, the majority of deaths had at least one diagnosis in the EHR that could support the cause of death. The lowest frequency of supportive diagnosis was for septicemia (52.2%) and the highest was for malignancies (94.3%). Sensitivity analysis did not suggest an alternative explanation for the missing documentation. CONCLUSIONS: The underlying cause of death coded by the CBS is often supported by diagnoses in Clalit's EHR. Exceptions are septicemia or accidents that cannot be anticipated from a patient's EHR, and dementia which may be under-reported.

A general spectral decomposition of causal influences applied to integrated information.

BACKGROUND: Quantifying interactions among many neurons is fundamental to understanding system-level phenomena such as attention, learning and even conscious experience. Causal influences in the brain, quantified as integrated information, are thought to support subjective conscious experience. Recent empirical work has shown that the spectral decomposition of causal influences, for example using Granger causality, can reveal frequency-specific influences that are not observed in the time domain. However, a spectral decomposition of integrated information has not been put forward, limiting its adoption for analyzing neural data. NEW METHOD: We present a general and flexible framework for deriving the spectral decomposition of causal influences in autoregressive processes. RESULTS: We use the framework to derive a spectral decomposition of integrated information. We show that other well-known measures, including Granger causality, can be derived using the same framework. Using simulations, we demonstrate a complex interplay between the spectral decomposition of integrated information and other measures that is not observed in the time domain. COMPARISON WITH EXISTING METHODS: This paper provides a spectral decomposition of integrated information for the first time. Although a spectral decomposition of Granger causality has been derived, that approach is only applicable to uni-directional causal influences, not multi-directional causal influences as required for integrated information. CONCLUSIONS: Our novel framework can be used to derive the spectral decomposition of uni- and multi-directional measures of causal influences. We use this framework to derive a spectral decomposition of integrated information, paving the way for better understanding how frequency-specific causal influences in the brain relate to cognition.

Bounded rationality in C. elegans is explained by circuit-specific normalization in chemosensory pathways.

Rational choice theory assumes optimality in decision-making. Violations of a basic axiom of economic rationality known as "Independence of Irrelevant Alternatives" (IIA) have been demonstrated in both humans and animals and could stem from common neuronal constraints. Here we develop tests for IIA in the nematode Caenorhabditis elegans, an animal with only 302 neurons, using olfactory chemotaxis assays. We find that in most cases C. elegans make rational decisions. However, by probing multiple neuronal architectures using various choice sets, we show that violations of rationality arise when the circuit of olfactory sensory neurons is asymmetric. We further show that genetic manipulations of the asymmetry between the AWC neurons can make the worm irrational. Last, a context-dependent normalization-based model of value coding and gain control explains how particular neuronal constraints on information coding give rise to irrationality. Thus, we demonstrate that bounded rationality could arise due to basic neuronal constraints.

Dead Sea minerals: New findings on skin and the biology beyond.

BACKGROUND: Therapeutic effects of Dead Sea (DS) minerals are well established, and their unique combination is analysed and reported. DS water (DSW) is a key source for DS minerals, and various studies report the capability of DSW to alleviate symptoms of different skin disorders and to contribute to skin maintenance. However, the biological mechanisms beyond reported effects are not fully understood yet. OBJECTIVE: To elucidate the effect of topically applied DSW via the expression of different skin biomarkers related to barrier function, homeostasis, inflammation and irritation. METHODS: In vitro skin equivalents and ex vivo human skin organ culture were used to assess the biological effects of DSW. Epidermal barrier protein expression and DSW ions transdermal penetration were analysed on skin equivalents. ß-endorphin secretion was tested on human skin organ culture. The capability of DSW to protect against skin inflammation and irritation was tested on ex vivo human skin organ culture by lipopolysaccharides and sodium dodecyl sulphate addition, respectively. RESULTS: Topical application of DSW encouraged the expression of the barrier-related proteins: filaggrin, involucrin and transglutaminase, while transdermal penetration of calcium ions was not detected. Additionally, DSW application had increased skin secretion of ß-endorphin and attenuated the expression of inflammatory and irritation-related cytokines. CONCLUSIONS: This study reports new findings of DSW effects on skin. Signalling pathway activation is proposed as a key step that may result in a vast range of proven biological activities following skin exposure to DS minerals, and specifically DSW.

The Effect of Common Signals on Power, Coherence and Granger Causality: Theoretical Review, Simulations, and Empirical Analysis of Fruit Fly LFPs Data.

When analyzing neural data it is important to consider the limitations of the particular experimental setup. An enduring issue in the context of electrophysiology is the presence of common signals. For example a non-silent reference electrode adds a common signal across all recorded data and this adversely affects functional and effective connectivity analysis. To address the common signals problem, a number of methods have been proposed, but relatively few detailed investigations have been carried out. As a result, our understanding of how common signals affect neural connectivity estimation is incomplete. For example, little is known about recording preparations involving high spatial-resolution electrodes, used in linear array recordings. We address this gap through a combination of theoretical review, simulations, and empirical analysis of local field potentials recorded from the brains of fruit flies. We demonstrate how a framework that jointly analyzes power, coherence, and quantities based on Granger causality reveals the presence of common signals. We further show that subtracting spatially adjacent signals (bipolar derivations) largely removes the effects of the common signals. However, in some special cases this operation itself introduces a common signal. We also show that Granger causality is adversely affected by common signals and that a quantity referred to as "instantaneous interaction" is increased in the presence of common signals. The theoretical review, simulation, and empirical analysis we present can readily be adapted by others to investigate the nature of the common signals in their data. Our contributions improve our understanding of how common signals affect power, coherence, and Granger causality and will help reduce the misinterpretation of functional and effective connectivity analysis.

Isoflurane Impairs Low-Frequency Feedback but Leaves High-Frequency Feedforward Connectivity Intact in the Fly Brain.

Hierarchically organized brains communicate through feedforward (FF) and feedback (FB) pathways. In mammals, FF and FB are mediated by higher and lower frequencies during wakefulness. FB is preferentially impaired by general anesthetics in multiple mammalian species. This suggests FB serves critical functions in waking brains. The brain of Drosophila melanogaster (fruit fly) is also hierarchically organized, but the presence of FB in these brains is not established. Here, we studied FB in the fly brain, by simultaneously recording local field potentials (LFPs) from low-order peripheral structures and higher-order central structures. We analyzed the data using Granger causality (GC), the first application of this analysis technique to recordings from the insect brain. Our analysis revealed that low frequencies (0.1-5 Hz) mediated FB from the center to the periphery, while higher frequencies (10-45 Hz) mediated FF in the opposite direction. Further, isoflurane anesthesia preferentially reduced FB. Our results imply that the spectral characteristics of FF and FB may be a signature of hierarchically organized brains that is conserved from insects to mammals. We speculate that general anesthetics may induce unresponsiveness across species by targeting the mechanisms that support FB.

Integration of Inverse Supercritical Fluid Extraction and Miniaturized Asymmetrical Flow Field-Flow Fractionation for the Rapid Analysis of Nanoparticles in Sunscreens.

We report the use of inverse supercritical fluid extraction (SFE) and miniaturized asymmetrical flow field-flow fractionation (mAF4) for the preparation and subsequent analysis of titanium dioxide nanoparticles in model and commercial sunscreens. The approach allows for the fast and reliable fractionation and sizing of TiO2 nanoparticles and their quantitation in commercial products. This new method represents a powerful and efficient tool for the verification of nanoparticle content in a wide range of matrixes, as demanded by recently introduced regulatory requirements. Furthermore, the use of carbon dioxide as an environmentally friendly solvent is in line with the increasing need for ecologically compatible analytical techniques.

Antipollution skin protection - a new paradigm and its demonstration on two active compounds.

BACKGROUND: Urban pollution is a major source of concern for human health and is a complex of many environmental factors. The topical exposure to pollution activates cutaneous stress. OBJECTIVE: In this study, we tested the antipollution protection of two active components: Dead Sea minerals (Dead Sea mineral-rich water [DSW]) and anionic polysaccharide (PolluStop® [PS]). MATERIALS AND METHODS: Two representative pollution models were studied using reconstructed epidermis: 1) mixture of pollutants (MOP) containing heavy metals and atmospheric particulate matter and 2) ozone exposure. DSW and PS were topically applied alone or in combination, and their protection against pollution was assessed by testing the levels of the inflammation markers interleukin 1α (IL-1α) and prostaglandin E2 (PGE2). RESULTS: MOP exposure induced IL-1α release, which was attenuated following pre-application with DSW and PS alone or in combination. Ozone exposure induced IL-1α and PGE2 release. Pre-application with DSW or PS alone did not inhibit IL-1α and PGE2 overproduction. Only when DSW and PS were mixed together, inhibition of these inflammatory markers was observed. CONCLUSION: The observations reveal the potential use of active agents in combination for a selective mode of protection from urban pollution. This is because many active materials cannot solely provide a broad protection against different types of pollutants. This strategy might be beneficial for future antipollution regimen formulated in both pharmaceutical and cosmetic products.

Local Versus Global Effects of Isoflurane Anesthesia on Visual Processing in the Fly Brain.

What characteristics of neural activity distinguish the awake and anesthetized brain? Drugs such as isoflurane abolish behavioral responsiveness in all animals, implying evolutionarily conserved mechanisms. However, it is unclear whether this conservation is reflected at the level of neural activity. Studies in humans have shown that anesthesia is characterized by spatially distinct spectral and coherence signatures that have also been implicated in the global impairment of cortical communication. We questioned whether anesthesia has similar effects on global and local neural processing in one of the smallest brains, that of the fruit fly (Drosophila melanogaster). Using a recently developed multielectrode technique, we recorded local field potentials from different areas of the fly brain simultaneously, while manipulating the concentration of isoflurane. Flickering visual stimuli ('frequency tags') allowed us to track evoked responses in the frequency domain and measure the effects of isoflurane throughout the brain. We found that isoflurane reduced power and coherence at the tagging frequency (13 or 17 Hz) in central brain regions. Unexpectedly, isoflurane increased power and coherence at twice the tag frequency (26 or 34 Hz) in the optic lobes of the fly, but only for specific stimulus configurations. By modeling the periodic responses, we show that the increase in power in peripheral areas can be attributed to local neuroanatomy. We further show that the effects on coherence can be explained by impacted signal-to-noise ratios. Together, our results show that general anesthesia has distinct local and global effects on neuronal processing in the fruit fly brain.

Oxidation mechanism of porous Zr2Fe used as a hydrogen getter.

We determined the oxidation mechanism of porous ST-198, which mainly comprises Zr2Fe. Oxidation kinetics depended on temperature, oxygen partial pressure, and oxidation extent. The passivation role of oxidation in hydrogen scavenging is probably due to the development of a surface oxide, independent of oxygen concentration. Zr2Fe would be a superior hydrogen getter in oxygen-contaminated environments at high temperatures, as most oxygen will be consumed at the outer shell by mass transfer limitations, protecting the bulk of the getter for hydrogen scavenging.

Bursting reverberation as a multiscale neuronal network process driven by synaptic depression-facilitation.

Neuronal networks can generate complex patterns of activity that depend on membrane properties of individual neurons as well as on functional synapses. To decipher the impact of synaptic properties and connectivity on neuronal network behavior, we investigate the responses of neuronal ensembles from small (5-30 cells in a restricted sphere) and large (acute hippocampal slice) networks to single electrical stimulation: in both cases, a single stimulus generated a synchronous long-lasting bursting activity. While an initial spike triggered a reverberating network activity that lasted 2-5 seconds for small networks, we found here that it lasted only up to 300 milliseconds in slices. To explain this phenomena present at different scales, we generalize the depression-facilitation model and extracted the network time constants. The model predicts that the reverberation time has a bell shaped relation with the synaptic density, revealing that the bursting time cannot exceed a maximum value. Furthermore, before reaching its maximum, the reverberation time increases sub-linearly with the synaptic density of the network. We conclude that synaptic dynamics and connectivity shape the mean burst duration, a property present at various scales of the networks. Thus bursting reverberation is a property of sufficiently connected neural networks, and can be generated by collective depression and facilitation of underlying functional synapses.

Evaluation of topically applied copper(II) oxide nanoparticle cytotoxicity in human skin organ culture.

The increasing use of nano-sized materials in our environment, and in many consumer products, dictates new safety concerns. In particular, adequate experimental models are needed to evaluate skin toxicity of metal oxide ions, commonly found in cosmetic and dermatologic preparations. We have addressed the biological effects of topically applied copper oxide (CuO) nanoparticles in human skin organ cultures, using light and electron microscopy, and biochemical tests. Nanoparticles were more toxic than micro-sized particles, and their effects were stronger when supplied in growth medium than in topical application. Still topically applied CuO nanoparticles induced inflammatory cytokine secretion and necrosis, especially in epidermis deprived of its protective cornea. Since nanoparticle penetration was not seen, we propose that they may adhere to skin surface, react with the local acidic environment, and generate soluble ions that make their way to inner sites. This work illustrates the abilities of skin organ culture to evaluate the biological effects of topically-applied materials on skin in vitro.

Photo-damage protective effect of two facial products, containing a unique complex of Dead Sea minerals and Himalayan actives.

BACKGROUND: Skin appearance is badly affected when exposed to solar UV rays, which encourage physiological and structural cutaneous alterations that eventually lead to skin photo-damage. AIMS: To test the capability of two facial preparations, extreme day cream (EXD) and extreme night treatment (EXN), containing a unique complex of Dead Sea water and three Himalayan extracts, to antagonize biological effects induced by photo-damage. METHODS: Pieces of organ cultures of human skin were used as a model to assess the biological effects of UVB irradiation and the protective effect of topical application of two Extreme preparations. Skin pieces were analyzed for mitochondrial activity by MTT assay, for apoptosis by caspase 3 assay, and for cytokine secretion by solid phase ELISA. Human subjects were tested to evaluate the effect of Extreme preparations on skin wrinkle depth using PRIMOS and skin hydration by a corneometer. RESULTS: UVB irradiation induced cell apoptosis in the epidermis of skin organ cultures and increased their pro-inflammatory cytokine, tumor necrosis α (TNFα) secretion. Topical applications of both preparations significantly attenuated all these effects. Furthermore, in human subjects, a reduction in wrinkle depth and an elevation in the intense skin moisture were observed. CONCLUSIONS: The observations clearly show that EXD and EXN preparations have protective anti-apoptotic and anti-inflammatory properties that can attenuate biological effects of skin photo-damage. Topical application of the preparations improves skin appearance by reducing its wrinkles depth and increasing its moisturizing impact.