Mapping ethical and social aspects of biomarker research and its application in atopic dermatitis and psoriasis: a systematic review of reason.

Biomarker research is associated with high hopes for atopic dermatitis and psoriasis research. Although various effective treatments have been developed, many challenges remain concerning diagnostics and the development of targeted treatments, but also regarding a number of ethical and social issues. In this paper, building on a systematic literature review and review of reason, we examine the ethical and social debate on biomarker research for atopic dermatitis and psoriasis. We discuss topics such as risks and benefits of stratification of patient groups, ethical aspects of big data and advanced analytics for biomarker use in atopic dermatitis and psoriasis. Our systematic literature review of reason, based on established methodological standards, includes argument-based ethics publications and scientific literature with implicitly ethically relevant aspects. The first search of biomarker research in dermatology and adjacent fields (e.g., oncology) resulted in a large amount of literature concerning general normative aspects of biomarker research, but suggested a lack of explicit argument-based ethical literature in atopic dermatitis and psoriasis research. We, therefore, conducted a second systematic search, focusing specifically on atopic dermatitis and psoriasis biomarker research. The 43 relevant articles identified through both systematic searches were clustered into three topic groups: (i) ethical aspects of stratification and precision medicine, (ii) digital ethics and (iii) research ethics with a focus on complexity and validation. We found that compared to other fields, such as cancer research, the ethical aspects of atopic dermatitis and psoriasis are rarely explained and addressed in detail. In particular, more work is required on scientific standards, digital ethics and responsible clinical application of biomarkers for atopic dermatitis and psoriasis, patient participation and ethical implications of biomarker use for children or young people with atopic dermatitis and psoriasis. We close with suggestions on how to address the ethical and social dimension of atopic dermatitis and psoriasis research and practice more directly in future.

Requirements and expectations of high-quality biomarkers for atopic dermatitis and psoriasis in 2021-a two-round Delphi survey among international experts.

BACKGROUND: Chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO) present major challenges in health care. Thus, biomarkers to identify disease trajectories and response to treatments to improve the lives of affected individuals warrant great research consideration. The requirements that these biomarkers must fulfil for use as practical clinical tools have not yet been adequately investigated. AIM: To identify the core elements of high-quality AD and PSO biomarkers to prepare recommendations for current biomarker research. METHOD: A cross-sectional two-round Delphi survey was conducted from August to October 2019 and October to November 2020. All participants were members of the BIOMAP project, an EU-funded consortium of clinicians, researchers, patient organizations and pharmaceutical industry partners. The first round consisted of three open-ended questions. Responses were qualitatively analysed, and 26 closed statements were developed. For the second round, 'agreement' was assumed when the responses of ≥70% of the participants were ≥5 points on a 7-point Likert scale for each statement. Priority classification was based on mean scores (<20th percentile = low, 20th to 60th percentile = medium, >60th percentile = high). RESULTS: Twenty-one and twenty-six individuals participated in rounds one and two, respectively. From 26 statements that were included in round 2, 18 achieved agreement (8 concerning the performance, 8 for the purpose and 2 on current obstacles). Seven statements were classified as high priority, e.g. those concerning reliability, clinical validity, a high positive predictive value, prediction of the therapeutic response and disease progression. Another seven statements were assigned medium priority, e.g. those about analytical validity, prediction of comorbidities and therapeutic algorithm. Low priority included four statements, like those concerning cost effectiveness and prediction of disease flares. CONCLUSION: The core requirements that experts agreed on being essential for high-quality AD and PSO biomarkers require rapid validation. Biomarkers can therefore be assessed based on these prioritized requirements.

Dissecting the actin cortex density and membrane-cortex distance in living cells by super-resolution microscopy.

Nanoscale spacing between the plasma membrane and the underlying cortical actin cytoskeleton profoundly modulates cellular morphology, mechanics, and function. Measuring this distance has been a key challenge in cell biology. Current methods for dissecting the nanoscale spacing either limit themselves to complex survey design using fixed samples or rely on diffraction-limited fluorescence imaging whose spatial resolution is insufficient to quantify distances on the nanoscale. Using dual-color super-resolution STED (stimulated-emission-depletion) microscopy, we here overcome this challenge and accurately measure the density distribution of the cortical actin cytoskeleton and the distance between the actin cortex and the membrane in live Jurkat T-cells. We found an asymmetric cortical actin density distribution with a mean width of 230 (+105/-125) nm. The spatial distances measured between the maximum density peaks of the cortex and the membrane were bi-modally distributed with mean values of 50 ± 15 nm and 120 ± 40 nm, respectively. Taken together with the finite width of the cortex, our results suggest that in some regions the cortical actin is closer than 10 nm to the membrane and a maximum of 20 nm in others.

Self-organizing actin patterns shape membrane architecture but not cell mechanics.

Cell-free studies have demonstrated how collective action of actin-associated proteins can organize actin filaments into dynamic patterns, such as vortices, asters and stars. Using complementary microscopic techniques, we here show evidence of such self-organization of the actin cortex in living HeLa cells. During cell adhesion, an active multistage process naturally leads to pattern transitions from actin vortices over stars into asters. This process is primarily driven by Arp2/3 complex nucleation, but not by myosin motors, which is in contrast to what has been theoretically predicted and observed in vitro. Concomitant measurements of mechanics and plasma membrane fluidity demonstrate that changes in actin patterning alter membrane architecture but occur functionally independent of macroscopic cortex elasticity. Consequently, tuning the activity of the Arp2/3 complex to alter filament assembly may thus be a mechanism allowing cells to adjust their membrane architecture without affecting their macroscopic mechanical properties.

Application of orthogonality-relation for the separation of Lamb modes at a plate edge: numerical and experimental predictions.

In this study the orthogonality relation-based method for post-processing finite element (FE) predictions and experimental measurements is applied in order to separate Lamb modes at a plate edge at normal incidence. The scattered wave field from the free edge is assumed to be a superposition of all the eigenmodes of an infinite plate. The eigenmode amplitudes of the reflected wave field are determined by implementing the orthogonality-based method on the measured plate edge displacements. Overlapping wavepackets of Lamb modes at a plate edge are simulated by using the FE model and the experiment in the case of an incident S0 mode in a plate with a notch. In the experiment a 3D Scanning Laser Doppler Vibrometer (3D SLDV) (Johansmann and Sauer, 2005) is used to measure 3 dimensional vibrations and thus the edge two-dimensional displacement components simultaneously. It is demonstrated that it is possible to extract signals of various propagating and non-propagating modes in time-domain. The influences of the errors in practical measurements on the extraction procedure have also been studied.

Magnetic properties of granular CoCrPt:SiO 2 thin films deposited on GaSb nanocones.

We report on the effect of microstructure and geometrically induced modifications of the magnetic properties of granular CoCrPt:SiO2 films with weakly interacting magnetic grains deposited on pre-structured GaSb nanocone templates fabricated by an ion erosion technique. By tuning the irradiation conditions, nanocone patterns of different cone sizes were prepared (from 28 to 120 nm in diameter and 32 to 330 nm high, respectively). The influence of the intergranular exchange coupling was also investigated by varying the SiO2 content from 8 to 12 at.%. Deposition of CoCrPt:SiO2 on samples with small nanocones leads to a close magnetic grain packing, which results in the formation of extended magnetic domains larger than the average distance between the GaSb cones. In contrast, on larger nanocones, the magnetic coating grows on the side-walls, with a large separation between neighboring cones, leading to magnetic single-domain regions, which are correlated to the underlying structure. Magnetometry indicates that both remanence and coercivity decrease with increasing cone size and/or SiO2 content due to a combined effect of the angular distribution of the magnetic easy axis of the grains and the intergranular exchange coupling strength.

Micromechanical measurements on P-protein aggregates (forisomes) from Vicia faba plants.

Forisomes are chemomechanically active P-protein aggregates found in the phloem of legumes. They can convert chemical energy into mechanical work when induced by divalent metal ions or changes in pH, which control the folding state of individual forisome proteins. We investigated the changing geometric parameters of individual forisomes and the strength and dynamics of the forces generated during this process. Three different divalent ions were tested (Ca2+, Sr2+ and Ba2+) and were shown to induce similar changes to the normalized length and diameter. In the concentration range from 0.1 to 4 M, K+ and Cl(-) ions had no influence on the contraction behaviour of the forisomes induced by 10 mM Ca2+. In the absence of dissolved oxygen, these changes were independent of the radius of the metal ion, water uptake and the strength of binding between the selected metal ions and those protein molecules responsible for forisome conformational transformation. In the absence of any load, bound Ca2+, Sr2+ and Ba2+ ions showed apparent and averaged dissociation constants of 14, 62 and 1070 microM, respectively. Various forisomes generated bending on a quartz glass fibre with a diameter of 9 microm. The fibre bending was measured microscopically also by correlation between the digital patterns of a predefined window of observation before and after bending. Similar bending forces of approximately 90 nN were measured for a single forisome sequentially exposed to 10 mM Ca2+, Sr2+ and Ba2+. In the absence of dissolved oxygen, the same conditions resulted in averaged bending forces of (93+/-40) nN, (58+/-20) nN, and (91+/-20) nN after contacting different forisomes with 10 mM Ca2+, 10 mM Sr2+, and 10 mM Ba2+ respectively, demonstrating that the force generated was independent on ion concentrations above a certain threshold value.

Fine structure of the pygmy dipole resonance in (136)Xe.

The photoresponse of the semimagic N=82 nucleus (136)Xe was measured up to the neutron separation energy S(n) using the (gamma, gamma') reaction. A concentration of strong dipole excitations is observed well below S(n) showing a fragmented resonancelike structure. Microscopic calculations in the quasiparticle phonon model including complex configurations of up to three phonons agree well with the experimental data in the total integrated strength, in the shape and the fragmentation of the resonance, which allows us to draw conclusions on the damping mechanism of the pygmy dipole resonance.

Phenylene-ethynylene macrocycles as model systems of interchromophoric interactions in pi-conjugated macromolecules.

Unraveling the complex photophysics of macromolecular pi-conjugated systems requires both the development of suitable model systems to access a particular subset of a material's parameter space and the choice of matching spectroscopic techniques. We address the question of the strength of interchromophoric interactions in macromolecular systems by studying the fluorescence depolarization kinetics of a family of prototypical conjugated macrocycles. Shrinking the size of the molecular system decelerates fluorescence depolarization even though the radius of gyration decreases. Although the smaller macrocycles show faster rotational diffusion, the larger compounds exhibit an additional initial depolarization mechanism, attributed to intramolecular interchromophoric energy transfer. Comparison with fragments of the molecule illustrates that the larger macrocycles can be interpreted as bichromophoric systems, whereas the effectively parallel chromophoric elements of the smaller ring are indistinguishable in terms of polarization. The potential role of strong interchromophoric interaction is discussed. The results illustrate a subtle link between interchromophoric arrangement and ultrafast fluorescence depolarization, phenomena, which are often considered in the context of conjugated polymers: chromophoric alignment can potentially counteract the effect of polarization memory loss through energy transfer.

Fibre-related nitric oxide synthase (NOS) in Duchenne muscular dystrophy.

Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The loss of NO synthase (NOS) from the sarcolemma was assumed to be associated with development of Duchenne muscular dystrophy (DMD). We have, however, recently reported that, in contrast to the commonly accepted view, NOS expression in DMD myofibres is up-regulated. This poses the question of the fibre type-specific NOS expression in DMD muscles and how the NOS expression is related to the regeneration or degeneration status. To address this issue, we examined localization of NOS isoforms I, II and III in skeletal muscles of DMD patients employing immunohistochemical labelling with tyramide signal amplification complemented with enzyme histochemistry. We found that NOS immunolabelling as well as metabolic enzyme activity in DMD muscles were heterogeneously distributed along the fibre length of DMD muscle fibres revealing regenerating and degenerate (hypercontracted) fibres as well as normal segments. Like in normal muscles, positive NOS immunoreactivity was found to be associated with fast-oxidative glycolytic (FOG) phenotype. The regeneration status of NOS-positive segments was deduced from the presence of neonatal and developmental myosin heavy chains. High NOS expression in regenerating DMD muscle fibres can be well reconciled with reports about the protective role of endogenous NO in inflammatory diseases and in muscle repair.

In vitro investigation of the geometric contraction behavior of chemo-mechanical P-protein aggregates (forisomes).

We investigated the contracting behavior of forisomes from Vicia faba by carrying out precise measurements of their changing geometric parameters in vitro in the absence and in the presence of dissolved oxygen. Furthermore, we investigated the fine structure of forisomes by scanning electron microscopy. For the first time, single forisomes were titrated with Ca(2+), protons, and hydroxide ions recording the complete progression of their contractions. An apparent Ca(2+)-binding constant of (22+/-3) muM was calculated from two complete titration curves. The forisomes also contracted in the presence of Ba(2+) and Sr(2+) ions, but the amplitudes of contraction were smaller under the same measuring conditions. The time taken to change from the longitudinally expanded into the longitudinally contracted state was up to 2 s shorter in 10 mM Ca(2+) in comparison to 0.2mM Ca(2+). However, the contraction time was prolonged by decreasing the Ca(2+) concentration. In the absence of dissolved oxygen, the transition between the two final states of the forisomes was almost reversible and the amplitude of contraction remained almost constant during the first 25 contraction cycles. In the presence of dissolved oxygen the forisomes denaturated after a few cycles and lost their ability to contract, just after only a few cycles with 10 min in the contracted state. Denaturation of the forisomes occurred appreciably in the contracted state. We propose a cycle process to explain the thermodynamic basis of the Ca(2+)-induced contraction and its reversal by EDTA. Reducing the pH-value from 7.3 to 4.0 caused the forisomes to shorten by approximately 15%, while increasing the pH to 11.0 caused them to shorten by 28 to 30%. In both cases, the increases of the forisomes volume were greater than during the Ca(2+) induced contraction. The pH values of 4.7+/-0.3, and 10.2+/-0.2 marked the inflection points of the acid base titration of different forisomes.

The origin of brain asymmetry and its psychotic reversal.

Ontogenetic brain-asymmetry and its reversal in schizophrenia constitute special cases of a more fundamental principle of sensory-motor integration. Transmitted through an immature optical system, asymmetric inputs from the left visual field induce the infant's right hemispheric preference for lower spatial frequencies during early mother-child interaction. The emerging classical features of hemispheric specialisation later in life can be accounted for by a transformation law of the neuronal reference frames based on relativistic non-linear information processing. Accordingly, the asymmetric distributions of the cannabinoid receptor CB1 in the right basal ganglia and the left area of Wernicke reflect the preferences for lateralised posture, positioning, and speech. Epigenetic development of brain asymmetry thus unifies the different aspects related to cradling and breast-feeding, speech- and visuospatial processing, the dimensional conversion of spatiotemporal information and, in the case of a dysbalanced cannabinoid system, its psychotic reversal. The predicted right hemispheric shift and the inverse relationship between Kolmogorov entropy and its dimensional embedding (Shannon entropy) has ultimately been confirmed by non-linear EEG analysis of a fluoro-methyl-anadamide induced model psychosis splitting conscious from unconscious mental processes.

Impaired information processing triggers altered states of consciousness.

Schizophrenia, intoxication with tetrahydrocannabinol (Delta-THC), and cannabis psychosis induce characteristic time and space distortions suggesting a common psychotic dysfunction. Since genetic research into schizophrenia has led into disappointing dead ends, the present study is focusing on this phenotype. It is shown that information theory can account for the dynamical basis of higher sensorimotor information processing and consciousness under physiologic as well as pathologic conditions. If Kolmogorov entropy (inherent in the processing of action and time) breaks down in acute psychosis, it is predicted that Shannon entropy (inherent in the processing of higher dimensional perception) will increase, provoking positive symptoms and altered states of consciousness. In the search for candidate genes and the protection of vulnerable individuals from cannabis abuse, non-linear EEG analysis of Kolmogorov information could thus present us with a novel diagnostic tool to directly assess the breakdown of information processing in schizophrenia.

[Sleep deprivation as a predictor of response to light therapy in major depression]. / Schlafentzug als Prädiktor für das Ansprechen auf Lichttherapie bei Major Depression.

Light therapy (LT) is regarded as the treatment of choice for seasonal affective disorder (SAD). In nonseasonal depression the results of light therapy are nonconclusive. Sleep deprivation (SD), however, is effective in 50-60% of the patients with major depression. The predictive value of Total Sleep Deprivation (TSD) for the treatment outcome of antidepressiva has been already examined. Purpose of the present study was to test whether light therapy is more beneficial in TSD responders than in TSD nonresponders. 40 inpatients with major depressive disorder completed one night of TSD. Twenty TSD responders and 20 TSD nonresponders were randomly assigned to 14 days of bright light therapy (2500 lux, 7-9 a.m.) or 14 days of dim light therapy (red light 50 lux, 7-9 a.m.). Manova with repeated measurements revealed a significant difference in the course of depression over the time between TSD responders and nonresponders, but no significant difference between bright and dim light. Questions of placebo effect, of SAD and of personality variables as predictors of response to SD and LT are being discussed.

Are cannabinoid receptor knockout mice animal models for schizophrenia?

Schizophrenia is a devastating psychiatric disorder with a high prevalence worldwide. There is therefore a need for animal models allowing the development of new therapeutic interventions and reliable diagnostic tests. In the temporal domain, cannabinoid receptor gene (CB1) knockout mice exhibit behavioural alterations, which parallel symptoms in schizophrenia, cannabis intoxication and dopamine D2 activation. While a specific nucleotide homology between CB1 and D2 accounts for the pathophysiology, pre-inserted spirochaetal DNA on the polyadenylation signal of CB1 reveals the aetiology of schizophrenia. If, in analogy to thalassaemia, mutations occur within this 3' regulatory domain, the genetic expression of CB1 is disrupted and sequential information lost in time. CB1, previously unrecognized as a candidate gene, thus unifies the different aspects of schizophrenic psychosis: cannabis-induced model psychosis, disrupted information processing, spatio-temporal distortions and other psychotic symptoms, disturbed neuronal migration, schizophrenic brain disorder, familial transmission, and prenatal infection by Borrelia burgdorferi.

Sleep deprivation as a predictor of response to light therapy in major depression.

BACKGROUND: While the majority of depressed patients benefit from total sleep deprivation (TSD), light therapy is regarded as a first-line treatment only for seasonal affective disorder (SAD). The results of light therapy in nonseasonal major depressive disorder have been non-conclusive. We examined the correlation of TSD response and light therapy response in major depressed patients. METHODS: 40 inpatients with major depressive disorder (seven with seasonal pattern, 33 without seasonal pattern) were deprived of a night's sleep. The TSD responders, as well as the TSD nonresponders, were randomly assigned to receive adjunct light therapy either with bright white light (2500 lux) or dim red light (50 lux) during 2 weeks beginning on the third day after TSD. RESULTS: The 20 TSD responders improved significantly better under the light therapy than the 20 TSD nonresponders (according to the Hamilton Depression Rating Scale and the self-rating depression scale Bf-S; v. Zerssen). LIMITATIONS: No significant difference could be found between the two light intensities. Since the patients were additionally treated with medication an interaction with the two adjunctive therapies cannot be excluded. CONCLUSION: Our results indicate that a positive TSD response in major depressed patients can be predicative of beneficial outcome of subsequent light therapy.

Neurophysiologic tests during antidepressive treatment - an exploratory study.

This is a non-randomized exploratory study showing the sensitivity of neurophysiological parameters for autonomic side-effects during the application of antidepressant drugs. Inpatients on tricyclic antidepressants (TCA: amitriptyline or doxepine), inpatients on serotonine-reuptake inhibitors (SSRI: fluvoxamine or paroxetin) and a control group of healthy volunteers underwent neurophysiological examination. The treatment group was investigated after at least 7 days of continuous treatment with the final dose. Adjustment of the autonomic nervous system was studied, first, by measuring latency and amplitude of the sympathetic skin response (SSR), elicited by electric stimuli and by deep inspiration, and second, by analysis of the heart rate variation (HRV) during rest and inspiration. Relevant affections of the peripheral parts of the reflex arc under discussion were excluded by taking the nerve conduction velocity (NCV) and F-wave referring to cervical segment C7. In total, 48 individuals were examined. The TCA group showed delayed latencies and smaller amplitudes of the SSR in comparison with the controls. In the SSRI group, these parameters did not differ significantly from those of the controls. Analysis of HRV put further emphasis on the impaired adjustment of the autonomic nervous system in the TCA group. To sum up, our test battery indicated a specific vegetative alteration due to TCA.

Attraction of parasitic wasps by caterpillar-damaged plants.

Plant volatiles emitted in response to herbivory have been suggested to function as signals to attract natural enemies of herbivores. Most known examples of induced plant volatiles used by natural enemies involve parasitoids that locate caterpillars by means of odours emitted by plants after caterpillar attack. We study the tritrophic system that comprises the parasitoid Cotesia marginiventris, host caterpillars from the genus Spodoptera, and maize plants. Among the volatiles emitted by caterpillar-damaged maize plants, sesquiterpenes and indole are particularly attractive to the parasitoid. The usefulness of these plant volatiles for parasitoids is obvious. Less clear is their benefit to plants that emit them, as in most cases parasitization does not immediately stop caterpillars from damaging plants. However, plants appear to benefit directly from attracting C. marginiventris, as parasitized caterpillars consume considerably less plant tissue than unparasitized caterpillars. It is expected that in systems where parasitoids significantly reduce herbivory, they have contributed to selective pressures that have shaped the phenomenon of herbivore-induced volatile emissions by plants.

Altered Ca(2+)-homeostasis in single T-lymphocytes of depressed patients.

After stimulation of T-lymphocytes from healthy volunteers with the mitogen phytohemagglutinin (PHA) 40% of the cells exhibit an oscillatory increase in intracellular calcium concentration ([Ca2+]i). During depression the number of cells responding to PHA is reduced to 20%. These cells show a marked decrease in [Ca2+]i-reaction to stimulation and flattened oscillations. This reduction of mitogen-induced Ca2+ signals in T-cells of depressed patients appears to be a reliable state marker in depressive illness and is reversed upon successful treatment with interpersonal psychotherapy (IPT).