Beyond the “at risk mental state” concept: transitioning to transdiagnostic psychiatry

The “at risk mental state” for psychosis approach has been a catalytic, highly productive research paradigm over the last 25 years. In this paper we review that paradigm and summarize its key lessons, which include the valence of this phenotype for future psychosis outcomes, but also for comorbid, persistent or incident non‐psychotic disorders; and the evidence that onset of psychotic disorder can at least be delayed in ultra high risk (UHR) patients, and that some full‐threshold psychotic disorder may emerge from risk states not captured by UHR criteria. The paradigm has also illuminated risk factors and mechanisms involved in psychosis onset. However, findings from this and related paradigms indicate the need to develop new identification and diagnostic strategies. These findings include the high prevalence and impact of mental disorders in young people, the limitations of current diagnostic systems and risk identification approaches, the diffuse and unstable symptom patterns in early stages, and their pluripotent, transdiagnostic trajectories. The approach we have recently adopted has been guided by the clinical staging model and adapts the original “at risk mental state” approach to encompass a broader range of inputs and output target syndromes. This approach is supported by a number of novel modelling and prediction strategies that acknowledge and reflect the dynamic nature of psychopathology, such as dynamical systems theory, network theory, and joint modelling. Importantly, a broader transdiagnostic approach and enhancing specific prediction (profiling or increasing precision) can be achieved concurrently. A holistic strategy can be developed that applies these new prediction approaches, as well as machine learning and iterative probabilistic multimodal models, to a blend of subjective psychological data, physical disturbances (e.g., EEG measures) and biomarkers (e.g., neuroinflammation, neural network abnormalities) acquired through fine‐grained sequential or longitudinal assessments. This strategy could ultimately enhance our understanding and ability to predict the onset, early course and evolution of mental ill health, further opening pathways for preventive interventions.     

Nachtrag zur “Wurmtheorie” der Vertebraten-Evolution1

This paper presents some new arguments for the metameric-wonn-theory for the evolution of the Vertebrates (Gutmann 1966a). Metameric coelomoducts in Enteropneust larvae (Goodrich 1947) which should be interpreted as metanephridia show that the Enteropneusts can be derived from metameric Chordate-like predecessors. The myomeres of Branchiostoma are no solid organs as there exist sclerocoels. These must be interpreted as vestigial coelomic cavities. They can be cited as a proof for the metameric worm-theory. They function as a canal system, which gathers excretory stuff in the myomeres which these organs could otherwise not get rid of. The coelom-cavities are cleaned by the protonephridia in the gill region. Some additional details of the phylogenetic transformation of metameric coelom cavities into myomeres are reconstructed. It is shown that the problem of coelomic and myomeric metamerism cannot be solved in the way proposed in the literature concerned with this question. The metameric-worm-theory for the evolution of the Vertebrates pretends that metameric metanephridia were fused on the lower level of Vertebrate phylogeny and formed the archinephric ducts. A paper of Goodrich (1947) shows that there are similar cases of fused metanephridia in some Annelids. These are parallels to the postulated formation of the metanephridia in the lowest Vertebrates. The archinephric duct acquired its muscular coat when it was formed by fusion of metanephridia in the bodywall. Muscles of the body wall took over a new function by making peristaltic movements of the newly formed archinephric ducts possible. When the archinephric duct was moved back into the coelom it did not lose the still functioning muscular coat.     

Application of the “-Omic-” technologies in phytomedicine

The proof of efficacy of phytopreparations and the determination of their mode of action are permanent challenges for an evidence-based phytotherapy. The technology platform of genomics, proteomics and metabolomics ("-omic-" technologies) are high-throughput technologies. They increase substantially the number of proteins/genes that can be detected simultaneously and have the potential to relate complex mixtures to complex effects in the form of gene/protein expression profiles. Provided that phytopreparation-specific signatures in the form of gene/protein expression profiles can be developed, these technologies will be useful for the chemical and pharmacological standardization and the proof of the toxicological potential of a plant extract. Over a long-term perspective they may economize the proof of efficacy, the determination of the mode of action of phytomedicines and allow to investigate herbal extracts without prominent active principle(s). The application of this genomics revealed already that gene expression profiles induced by single drugs and the ones induced by the combination of the same drugs can be entirely different. These results make the information of the mode of action of isolated "active principles/lead substances" of phytopreparations questionable. The application of the "-omic-" technologies may lead to a change of paradigms towards the application of complex mixtures in medicine and open the new field of phytogenomics, -proteomics and -metabolomics.     

Isoprene research – 60 years later,the biology is still enigmatic

Isoprene emission is a major component of biosphere–atmosphere interactions. It is the single largest source of non‐methane hydrocarbon in the atmosphere. The first report of isoprene emission from plants was published in 1957 by Professor Guivi Sanadze. While humans have smelled the monoterpene hydrocarbons made by coniferous trees since their earliest migrations, only in 1957 did the world became aware that other trees make a type of hydrocarbon in even greater amounts but one to which the human nose is much less sensitive. For this 60th anniversary of the first report of isoprene emission from leaves, we trace the discovery and development of the research field, highlighting some of the most seminal observations and theoretical interpretations. This is not an exhaustive review, and many important papers are not cited, but we hope it will be of general interest to read how research in this field developed, how new observations forced us to reevaluate our theories about the significance of isoprene biosynthesis to plant physiology and adaptation and how scientific serendipity can sometimes drive a topic forward.     

Restoring Intertidal Boulder‐Fields as Habitat for “Specialist” and “Generalist” Animals

Restoration is important in urban areas where habitat destruction is greatest. It incorporates many levels of intervention, with creation of new habitat the most extreme form. Most research on habitat creation has been terrestrial, or in marine habitats dominated by large structuring biota, such as mangroves. Intertidal boulder‐fields in urban areas are vulnerable to disturbances and habitat loss, which adversely affect numerous habitat specialists. This study describes experiments in which quarried stones were used to create new habitat outside natural boulder‐fields as a practical approach to restoring habitat. Colonization by specialist fauna and by common algae and invertebrates was measured for a year after deployment. Despite sessile assemblages on new boulders differing from those on natural boulders, common and rare animals rapidly colonized the new habitat. There was no clear succession, but colonization was variable and patchy at all scales examined, although diversities and abundances of some species in this novel habitat matched those of natural boulders within a few months. Rare and common animals generally colonized the new habitat as adults moving in from surrounding areas. Creating new boulder‐fields using quarried rocks is a successful approach to restoration and conservation of fauna where natural boulder‐fields are threatened.     

Upgrading of Existing Municipal Wastewater Treatment Plants with the “Non‐Conventional Low MLSS MBR Technology”

In the future, upgrading of existing wastewater treatment plants (wwtps) will be more important than the erection of entirely new plants, as most of the plants necessary in Germany already exist. Thus far, membrane bioreactor (MBR) technology is not used as an alternative for plant upgrading in Germany. However, at several locations the preconditions indicate that the application of the MBR technology for upgrading of plants may be favorable. These preconditions include the need for a substantial enlargement of the aeration tank volume and/or the need to improve the efficiency of the final sedimentation tanks, and also require that the existing tanks be in a good state, so that the tanks can be used in the future. The relevant preconditions and the basic upgrading concept using the MBR technology were presented earlier. Depending on the local preconditions regarding the existing tank volume, a specific aspect of this application can be an operation mode using “non‐conventional low MLSS (mixed liquor suspended solids) concentrations” (5 kg MLSS/m³ through 7 kg MLSS/m³) due to the amount of the existing tank volume. Two research projects were carried out covering the operation of five pilot plants on a cubic meter scale to demonstrate the feasibility of this kind of MBR process. This paper presents the core results of this research work.     

Multistate Luminescent Solar Concentrator “Smart” Windows

A supertwist liquid crystalline luminescent solar concentrator (LSC) “smart” window is fabricated which can be switched electrically between three states: one designed for increased light absorption and electrical generation (the “dark” state), one for transparency (the “light” state), and one for enhanced haziness (“scattering” state). In the scattering state, the absorption and edge emissions decrease while the face emissions are enhanced. This new LSC “smart” window state can find application as a privacy feature in housing, but could also allow for a new “smart” window application as a diffuse glazing to increase plant growth in horticultural applications.     

A striking example of developmental bias in an evolutionary process: The “domestication syndrome”

The question of whether “developmental bias” can influence evolution is still controversial, despite much circumstantial evidence and a good theoretical argument. Here, I will argue that the domestication of mammalian species, which took place independently more than two dozen times, provides a particularly convincing example of developmental bias in evolution. The singular finding that underlies this claim is the repeated occurrence in domesticated mammals of a set of distinctive traits, none of which were deliberately selected. This phenomenon has been termed “the domestication syndrome”. In this article, I will: (a) describe the properties of the domestication syndrome; (b) show how it can be explained in terms of the operation of a specific genetic regulatory network, that which governs neural crest cell development; and (c) discuss Dmitry Belyaev's idea of “destabilizing selection,” which holds that selecting for a new behavior often entails neuroendocrine alterations that alter many aspects of development. Finally, I will argue for the potential general significance of such destabilizing selection, in combination with developmental bias, in animal evolution.     

“Macroscopic pattern analysis” based on formal analogies as a scientific methodology for complex systems

Bioprocess engineering at present concentrates on the enormous problems in the environment. What is therefore needed is a sound methodology, which should be based on the interactions between the physiology of biological reaction networks and physical processes in the environment and which should be an analogy to bioreactor performance. The conventional methodology is empirically oriented, using pilot plant data for the experimental estimates of process economics, where all further details are elucidated following the mechanistic approach on the microscopic level based on assumed mechanisms (causalities). According to the new view, the new systems-based methodology uses mathematical models as approximations and includes all the interactions. Pilot plant data are needed for model falsification, using analogies on the formal macroscopic level. Bioreactor scale-up as one application is a more rapid procedure of reasonable accuracy, where both the biokinetics as well as the fluid dynamics are quantified using formal macroscopic analogies. Model consistency and plausibility are the basic criteria when using model computer simulations as a decisive aid, while experiments lose their central role and are on longer the basis for evaluating the scientific work; they are simply the basis of the researcher's intuition. Another typical feature of complex systems is that model parameters are interdependent. The final decisive fact will be the mental experiment (“thinking” with the left and right side of the brain), which can be supported using computer simulations. This evolutionary interplay between the three realities of thinking, experimenting and simulating leads to a holistic progress towards the better understanding of highly complex systems. It offers the solution to the problems, which is needed in future.     

Dopamine for “Wanting” and Opioids for “Liking”: A Comparison of Obese Adults With and Without Binge Eating

Obesity research suffers from an overinclusion paradigm whereby all participants with a BMI beyond a certain cutoff value (e.g., 30) are typically combined in a single group and compared to those of normal weight. There has been little attempt to identify meaningful subgroups defined by their salient biobehavioral differences. In order to address this limitation, we examined genetic and psychological indicators of hedonic eating in obese adults with (n = 66) and without (n = 70) binge eating disorder (BED). Our analyses focused on dopamine (DA) and opioid genetic markers because of their conjoint association with the functioning of brain reward mechanisms. We targeted three functional polymorphisms related to the D2 receptor (DRD2) gene, as well as the functional A118G polymorphism of the mu‐opioid receptor (OPRM1) gene. We found that significantly more obese controls had the “loss‐of‐function” A1 allele of Taq1A compared to their BED counterparts, whereas the “gain‐of‐function” G allele of A118G occurred with greater frequency in the BED group. A significant gene–gene combination χ² analysis also indicated that of those participants with the gain‐gain genotype (G⁺ and A1), 80% were in the BED group whereas only 35% with the loss‐loss genotype (G^? and A1⁺) were in this group. Finally, BED subjects had significantly higher scores on a self‐report measure of hedonic eating. Our findings suggest that BED is a biologically based subtype of obesity and that the proneness to binge eating may be influenced by a hyper‐reactivity to the hedonic properties of food—a predisposition that is easily exploited in our current environment with its highly visible and easily accessible surfeit of sweet and fatty foods.     

“Capacity”, “best interests”, “will and preferences” and the UN Convention on the Rights of Persons with Disabilities

The United Nations (UN) Convention on the Rights of Persons with Disabilities (CRPD) is the most up‐to‐date international legal instrument concerning the rights of persons with disabilities. Such persons are taken to include those with serious mental disorders. According to an authoritative interpretation of a crucial Article (Article 12 ‐ Equal recognition before the law) by the UN CRPD Committee, involuntary detention and treatment of people with mental health disabilities are prohibited under the Convention. Both conventional mental health law and “capacity‐based” law are deemed to violate the Convention. However, some other UN bodies are not in full agreement (for example, the UN Human Rights Committee and the Subcommittee on Prevention of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment), while others are less explicitly absolutist (for example, the Human Rights Council). Furthermore, strong criticisms of the position of the CRPD Committee have been mounted from a number of academic quarters. These criticisms center on whether the role of a person's ability to make a decision can be ignored, no matter the circumstances. Much of the above debate turns on the concept of “legal capacity” and the now often‐repeated precept that one must always respect the “will and preferences” of the person with a disability. However, “will and preferences” remains undefined. In this paper, I offer an analysis of “will and preferences” that can clarify interventions that may be acceptable or non‐acceptable under the terms of the UN Convention.     

Thomas Kuhn is alive and well: the evolutionary relationships of simple life form--a paradigm under siege ?

A Kuhnian framework is used to analyze the current controversy over whether two or three fundamental types of life forms exist. Until the 1980s, all life was classified into two primary forms: eukaryotes and prokaryotes. Using molecular sequencing data, Carl Woese suggested the archaebacteria constituted a third domain. In the mid-1990s, Radhey S. Gupta challenged the three-domain hypothesis. While this dispute may seem to be a purely technical debate over the analysis of protein and nucleic acid sequence data, the controversy encompasses broader issues such as the aims of classification and the role of microorganisms in the biosphere. At the heart of this dispute is what kinds of data are relevant to constructing an overall taxonomy. The prestige of molecular biology played a large role in why the three-domain hypothesis was accepted so readily, but supporters of the two-domain hypothesis argue that the fossil record, morphology, and cell physiology should all play a role in taxonomy. This case study provides a good example of a paradigm shift in the making, demonstrating that issues beyond the raw data will be significant factors in deciding whether the three-domain hypothesis will prevail or a new classificatory scheme will emerge.     

Trends in biotechnology: Sustainable technology development: From high tech to Eco Tech

Biotechnology as a multidisciplinary and transdisciplinary field of science and engineering is regarded to be a key technology for the future, able to essentially contribute to sustainable development. In the first part of this paper, a critical analysis of the status quo in biotechnologies is given in the area of pharmaceutical, agricultural, environmental, and industrial biotechnology as well as food biotechnology. Here the general potential becomes clear, but also a series of disadvantages which are partly the result of the existing paradigm in science and technology and partly in direct connection to bioprocessing itself. Nevertheless, these biotechnologies will contribute to sustainable development, but mainly in a shallow sense of survival and livelihood. In the second part of this paper, another new dimension in bioprocessing is elucidated, which is in agreement with the new ecological, holistic world view. Here the so-called “eco-principles” are derived from a systems analysis of the ecosphere and represent the intelligence of nature as the result of evolution. The eco-principles will serve as guidelines for the general eco-restructuring of technology, being a drastic change within the next 2–5 decades. For the applying of eco-principles, a quantitative measure for sustainability in technology was developed (“sustainable process index”), which will enable us to design the new technology paradigm called “Eco Tech”. Ecological security and social equity, together with economic efficiency will define sustainable technology development in a deeper sense. Following this route, a completely new dimension of biotechnology will be reached, where the technosphere is fully embedded into the natural cycles of the ecosphere on a local basis.     

“Harpoon” Model for Cell–Cell Adhesion and Recognition of Target Cells by the Natural Killer Cells

The mechanism of recognition by natural killer (NK) cells is still unknown. A dynamic model is formulated describing recognition or NK-sensitive target cells (TCs) by NK cells of NK-like cells. This model does not assume the presence of the specific NK-receptor(s) on the membrane of NK cells and corresponding specific ligands on the NK-sensitive TCs. We suggest: (1) the expression of various kinds of “non-NK receptors” and corresponding ligands (counter-receptors) on the plasma membrane of the same NK cell and, possibly, of TCs (e.g. LFA-1 and ICAM-1-ICAM3, CD2 and LFA-3; receptors for TNF and corresponding ligand etc.); (2) the presence of multiple disorders in the organization of “extracellular matrix-surface membrane-submembrane cytoskeleton” assembly of the NK-sensitive TCs; (3) non-specific primary linking of NK cell with TCs, which induces a transfer of vesicles or membrane fragments from the NK surface to the target cell surface (and perhaps vice versa). These processes may also permit the transfer of many types of receptor and counter-receptor molecules from the surface of one conjugated cell to another by vesicles or membrane fragments. After transferral through the intercellular cleft, the free receptors and counter-receptors will be localized on both cell surfaces at the contact region between conjugated cells. By this model the NK cell can “harpoon” the TC and enhance the binding forces between cells up to the critical level and then switch on killing mechanisms for the TC. By means of this “harpoon” model of cell recognition, it seems possible to explain the nature of the wide polymorphism of TCs which are sensitive to the effect of NK and NK-like cells. A mathematical model of the NK cell cytotoxic reaction is described. The model describes many nonlinear peculiarities of the cytotoxic process and predicts some new phenomena. We suggest new approaches of manipulation of cell membranes which can transform NK-resistant target cells in NK sensitive cells and vice versa.     

Post‐GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post‐genome‐wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.     

An evolutionary interpretation of the “motivation to oviposit”

The ovipositional behavior of parasitoids and other insects is often described by phrases such as “motivation to oviposit” or “ovipositional drive”. This paper shows how an evolutionary (i.e. functional) interpretation can be given to such phrases. A detailed model for the parasitisation of Sycamore aphids by M. pseudoplatani is developed, using experiments by Collins and Dixon (1986). Two models are developed: i) one in which egg complement is the only state variable and ii) one in which egg complement and information concerning host densities are state variables. Comparisons of the behaviour of simulated parasitoids, using the decisions associated with the models, and the experiments suggest that both egg complement and information are important for the parasitoid's decision making. Accepting previously parasitized hosts may be optimal, and not simply an error in parasitoid perception. A number of other detailed predictions are made, such as the relative fitness of first and second eggs in superparasitized hosts and the nature of the memory of the parasitoid.     

Quantitative phosphoproteomics

Cells are highly responsive to their environment. One of the main strategies used by cells in signal transduction is protein phosphorylation, a reversible modification that regulates numerous biological processes. Misregulation of phosphorylation-mediated processes is often implicated in many human diseases and cancers. A global and quantitative analysis of protein phosphorylation provides a powerful new approach and has the potential to reveal new insights in signaling pathways. Recent technological advances in high resolution mass spectrometers and multidimensional liquid chromatography, combined with the use of stable isotope labeling of proteins, have led to the application of quantitative phosphoproteomics to study in vivo signal transduction events on a proteome-wide scale. Here we review recent advancements in quantitative phosphoproteomic technologies, discuss their potentials, and identify areas for future development. A key objective of proteomic technology is its application to addressing biological questions. We will therefore describe how current quantitative phosphoproteomic technology can be used to study the molecular basis of phosphorylation events in the DNA damage response.     

Raising consciousness in ecosystem health

New knowledge and theory developed by physicists in the first half of the 20th century radically changed our concepts of the nature of reality and the place of the human species in it. This information has not yet penetrated the other natural sciences nor day-to-day life. This paper argues that it is essential that we leave behind the World as Machine world view, or paradigm, which has led us to global crisis. Instead we must more rapidly incorporate the information from the 20th century new physics, and shift the dominant social paradigm to a Systems view of the world, in our efforts towards defining and implementing ecosystem health and the closely-related sustainable development. Some of the key implications of new physics to ecosystem health are that the biosphere and the surrounding universe is an indivisible whole; that the human species, especially our consciousness, is integral to the biosphere; that nothing is static; and that dynamism and function are primary, whereas structure is secondary. It is suggested that the understanding of the connectedness of humans to the rest of the biosphere will alter the behaviour of the human species towards more ecologically sustainable actions.