We survey the theory of quasi-periodic Schrödinger-type operators, focusing on the advances made since the early 2000s by adopting a dynamical systems point of view.
The direct geodetic problem is regarded on the biaxial and triaxial ellipsoid. A known solution method suitable for low eccentricities, which uses differential equations in Cartesian coordinates and ...Taylor series expansions of these coordinates, is advanced in view of its practical application. According to previous works, this approach has the advantages that no singularities occur in the determination of the coordinates, its mathematical formulation is simple and it is not computationally intensive. The formulas of the solution method are simplified in the present contribution. A test of this method using an extensive test data set on a biaxial earth ellipsoid shows its accuracy and practicability for distances of any length. Based on the convergence behavior of the series of the test data set, a truncation criterion for the series expansions is compiled taking into account accuracy requirements of the coordinates. Furthermore, a procedure is shown which controls the truncation of the series expansions by accuracy requirements of the direction to be determined in the direct problem. The conducted tests demonstrate the correct functioning of the methods for the series truncation. However, the considered solution method turns out to be significantly slower than another current method for biaxial ellipsoids, which makes it more relevant for triaxial ellipsoids.
The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the ...availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.
Long-term records of combined stream flow and water chemistry can be an invaluable source of information on changes in the quantity and quality of water resources. To understand the effect of ...hydroclimate and water management on the heavily urbanized Panke catchment in Berlin, Germany, an extensive search, collation and digitization of historic data from various sources was undertaken. This integrated a unique 66-year spatially distributed record of stream water quality, a 21-year record of groundwater quality and a 31-year stream flow record. These data were analysed in the context of hydroclimatic variability, as well as the history and technological evolution of water resource management in the catchment. To contextualize the effect of droughts, “average” and wet years the Standard Precipitation Index (SPI) was applied. As upstream sites have been less regulated by human impacts, the flow regime is most sensitive to changes in hydroclimatic conditions, while downstream sites are more influenced by wastewater effluents, urban storm drains and inter-basin transfers for flood alleviation. However, at all sites, a general increase in maximum event discharge was observed until a recent drought, starting in 2018. In general, water quality in the catchment has gradually improved as a result of management change and increasingly effective wastewater treatment, though in some places legacy and/or contemporary urban and rural groundwater contamination may be affecting the stream. Hydroclimatic changes, particularly drought years can affect water quality classes, and alter the chemostatic/dynamic behaviour of catchment export patterns. These insights from the Panke catchment underline the importance of strategic adaptation and improvement of water treatment and water resource management in order to enhance the quality of urban water courses. It also demonstrates the importance of long-term integrated data sets.
Changes in water quality related to hydroclimate. Display omitted
•Hydrological, spatial distributed long term time series for urban catchments.•Water management development during 1985–1995 drastically improved water quality.•Hydroclimate impacts stream connectivity and subsequently water quality.•The catchment becomes increasingly chemodynamic during dry conditions.
In the last few years, increased attention has been focused on a class of organisms called psychrophiles. These organisms, hosts of permanently cold habitats, often display metabolic fluxes more or ...less comparable to those exhibited by mesophilic organisms at moderate temperatures. Psychrophiles have evolved by producing, among other peculiarities, “cold-adapted” enzymes which have the properties to cope with the reduction of chemical reaction rates induced by low temperatures. Thermal compensation in these enzymes is reached, in most cases, through a high catalytic efficiency associated, however, with a low thermal stability. Thanks to recent advances provided by X-ray crystallography, structure modelling, protein engineering and biophysical studies, the adaptation strategies are beginning to be understood. The emerging picture suggests that psychrophilic enzymes are characterized by an improved flexibility of the structural components involved in the catalytic cycle, whereas other protein regions, if not implicated in catalysis, may be even more rigid than their mesophilic counterparts. Due to their attractive properties, i.e., a high specific activity and a low thermal stability, these enzymes constitute a tremendous potential for fundamental research and biotechnological applications.
The extended Harper’s model, proposed by D.J. Thouless in 1983, generalizes the famous almost Mathieu operator, allowing for a wider range of lattice geometries (parametrized by three
coupling ...parameters
) by permitting 2D electrons to hop to both nearest and next nearest neighboring (NNN) lattice sites, while still exhibiting its characteristic symmetry (Aubry–André duality). Previous understanding of the spectral theory of this model was restricted to two dual regions of the parameter space, one of which is characterized by the positivity of the Lyapunov exponent. In this paper, we complete the picture with a description of the spectral measures over the entire remaining (self-dual) region, for all irrational values of the frequency parameter (the magnetic flux in the model). Most notably, we prove that in the entire interior of this regime, the model exhibits a collapse from purely ac spectrum to purely sc spectrum when the NNN interaction becomes symmetric. In physics literature, extensive numerical analysis had indicated such “spectral collapse,” however so far not even a heuristic argument for this phenomenon could be provided. On the other hand, in the remaining part of the self-dual region, the spectral measures are singular continuous irrespective of such symmetry. The analysis requires some rather delicate number theoretic estimates, which ultimately depend on the solution of a problem posed by Erdős and Szekeres (On the product
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We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and ...statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.
Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of ...pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs.
For an adjustment of a similarity transformation, it is often appropriate to consider that both the source and the target coordinates of the transformation are affected by errors. For the least ...squares adjustment of this problem, a direct solution is possible in the cases of specific-weighing schemas of the coordinates. Such a problem is considered in the present contribution and a direct solution is generally derived for the m-dimensional space. The applied weighing schema allows (fully populated) point-wise weight matrices for the source and target coordinates, both weight matrices have to be proportional to each other. Additionally, the solutions of two borderline cases of this weighting schema are derived, which only consider errors in the source or target coordinates. The investigated solution of the rotation matrix of the adjustment is independent of the scaling between the weight matrices of the source and the target coordinates. The mentioned borderline cases, therefore, have the same solution of the rotation matrix. The direct solution method is successfully tested on an example of a 3D similarity transformation using a comparison with an iterative solution based on the Gauß-Helmert model.
Abstract Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions ...in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABAA receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy Marx et al. (2006a) Pharmacol Biochem Behav 84:598–608. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects Marx et al. (2006c) Neuropsychopharmacology 31:1249–1263, suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements Marx et al. (2009) Neuropsychopharmacology 34:1885–1903. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance Ritsner et al. (2010) J Clin Psychiatry 71:1351–1362. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
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