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LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration
(2020)
Background
There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration.
Objective
To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception.
Methods
Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire.
Conclusion
LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD.
Objective
To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples.
Methods
We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barre syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively.
Results
We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4.
Conclusion
Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.
FinO-domain proteins are a widespread family of bacterial RNA-binding proteins with regulatory functions. Their target spectrum ranges from a single RNA pair, in the case of plasmid-encoded FinO, to global RNA regulons, as with enterobacterial ProQ. To assess whether the FinO domain itself is intrinsically selective or promiscuous, we determine in vivo targets of Neisseria meningitidis, which consists of solely a FinO domain. UV-CLIP-seq identifies associations with 16 small non-coding sRNAs and 166 mRNAs. Meningococcal ProQ predominantly binds to highly structured regions and generally acts to stabilize its RNA targets. Loss of ProQ alters transcript levels of >250 genes, demonstrating that this minimal ProQ protein impacts gene expression globally. Phenotypic analyses indicate that ProQ promotes oxidative stress resistance and DNA damage repair. We conclude that FinO domain proteins recognize some abundant type of RNA shape and evolve RNA binding selectivity through acquisition of additional regions that constrain target recognition. FinO-domain proteins are bacterial RNA-binding proteins with a wide range of target specificities. Here, the authors employ UV CLIP-seq and show that minimal ProQ protein of Neisseria meningitidis binds to various small non-coding RNAs and mRNAs involved in virulence.
Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.
It is a challenge in chemical education to understand basic principles of chemical reaction kinetics on an experimental basis because of the relatively extensive experimental setup and the often time-consuming measurement series. This contribution offers an introduction into the field of the temperature dependence of reaction rate with easy-to-use experiments. Data logging systems have been used to get sufficient data-sets to evaluate different measurements in reaction kinetics. Several experiments were designed for practical courses in chemistry, which allow students to derive the simple van‘t Hoff rule on the one hand. On the other hand, the Arrhenius equation can only be derived on the basis of experimental data with the help of information from collision theory and Maxwell-Boltzmann distribution.
An Overview of Design Patterns for Self-Adaptive Systems in the Context of the Internet of Things
(2020)
The Internet of Things (IoT) requires the integration of all available, highly specialized, and heterogeneous devices, ranging from embedded sensor nodes to servers in the cloud. The self-adaptive research domain provides adaptive capabilities that can support the integration in IoT systems. However, developing such systems is a challenging, error-prone, and time-consuming task. In this context, design patterns propose already used and optimized solutions to specific problems in various contexts. Applying design patterns might help to reuse existing knowledge about similar development issues. However, so far, there is a lack of taxonomies on design patterns for self-adaptive systems. To tackle this issue, in this paper, we provide a taxonomy on design patterns for self-adaptive systems that can be transferred to support adaptivity in IoT systems. Besides describing the taxonomy and the design patterns, we discuss their applicability in an Industrial IoT case study.
Diplatinum A‐frame complexes with a bridging (di)boron unit in the apex position were synthesized in a single step by the double oxidative addition of dihalo(di)borane precursors at a bis(diphosphine)‐bridged Pt\(^{0}\)\(_{2}\) complex. While structurally analogous to well‐known μ‐borylene complexes, in which delocalized dative three‐center‐two‐electron M‐B‐M bonding prevails, theoretical investigations into the nature of Pt−B bonding in these A‐frame complexes show them to be rare dimetalla(di)boranes displaying two electron‐sharing Pt−B σ‐bonds. This is experimentally reflected in the low kinetic stability of these compounds, which are prone to loss of the (di)boron bridgehead unit.
Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.
The NaOtBu‐catalyzed mixed 1,1‐diboration of terminal alkynes using the unsymmetrical diboron reagent BpinBdan (pin = pinacolato; dan = 1,8‐diaminonaphthalene) proceeds in a regio‐ and stereoselective fashion affording moderate to high yields of 1,1‐diborylalkenes bearing orthogonal boron protecting groups. It is applicable to gram‐scale synthesis without loss of yield or selectivity. The mixed 1,1‐diborylalkene products can be utilized in Suzuki–Miyaura cross‐coupling reactions which take place selectivly at the C–B site. DFT calculations suggest the NaOtBu‐catalyzed mixed 1,1‐diboration of alkynes occurs through deprotonation of the terminal alkyne, stepwise addition of BpinBdan to the terminal carbon followed by protonation with tBuOH. Experimentally observed selective formation of (Z)‐diborylalkenes is supported by our theoretical studies.
Recent years have witnessed remarkable advances in radical reactions involving main‐group metal complexes. This includes the isolation and detailed characterization of main‐group metal radical compounds, but also the generation of highly reactive persistent or transient radical species. A rich arsenal of methods has been established that allows control over and exploitation of their unusual reactivity patterns. Thus, main‐group metal compounds have entered the field of selective bond formations in controlled radical reactions. Transformations that used to be the domain of late transition‐metal compounds have been realized, and unusual selectivities, high activities, as well as remarkable functional‐group tolerances have been reported. Recent findings demonstrate the potential of main‐group metal compounds to become standard tools of synthetic chemistry, catalysis, and materials science, when operating through radical pathways.
Magnetic particle imaging is an emerging tomographic method used for evaluation of the spatial distribution of iron‐oxide nanoparticles. In this work, the effect of the polymer coating on the response of particles was studied. Particles with covalently crosslinked coating showed improved signal and image resolution.
Background
Autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for a selected group of systemic sclerosis (SSc) patients with good available evidence but can be associated with considerable morbidity and mortality. The aim of this study was to describe infectious complications and distinct immune reconstitution patterns after aHSCT and to detect risk factors in lymphocyte subsets, which are associated with an elevated rate of infections after aHSCT.
Methods
Seventeen patients with SSc were included in this single-center retrospective cohort study. Clinical and laboratory data was collected before and for 12 months after aHSCT, including immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting.
Results
Cytomegalovirus (CMV) reactivations were common in CMV-IgG-positive patients (50%) and needed treatment. Mycotic infections occurred in 17.6%. One patient died (resulting in a mortality of 5.9%) due to pneumonia with consecutive sepsis. All patients showed decreased T helper cells (CD3\(^+\)/CD4\(^+\)) and within the B cell compartment decreased post-switched memory B cells (CD19\(^+\)/CD27\(^+\)/IgD\(^-\)) and elevated naive B cells (CD19\(^+\)/CD27\(^-\)/IgD\(^+\)) until 12 months after aHSCT. Patients who developed infections had significantly lower B cells before aHSCT than patients who did not develop infections.
Conclusion
After aHSCT, monitoring for infectious complications, especially for CMV reactivations, is crucial as the reconstitution of the immune system takes longer than 12 months. Low peripheral B cells might be a risk factor for an elevated infection rate.
Micron‐sized supraparticles, consisting of a plurality of discrete nano‐ and microscale functional units, are assembled and fused by means of a droplet extrusion process. By combining nano magnetite, activated carbon, and conductive carbon with a polymeric binder matrix, particles are obtained which unite good magnetic properties, electrical conductivity, and adsorber activity through the high accessible surface area of the incorporated activated carbon of about 570 m\(^{2}\) g\(^{-1}\), thereby enabling a new approach toward sustainable water treatment processes. Due to the interplay of the components, it is possible to adsorb target substances, dissolved in the water which is demonstrated by the adsorption of the model dye methylene blue. A very fast adsorption kinetic and an adsorption capacity of about 400 mg g\(^{-1}\) is determined. By using the developed composite particles, it is also possible to electrochemically alter substances flowing through a magnetically‐stabilized fluidized‐bed reactor by electrochemically charging/discharging, significantly supported by the magnetic field enabling alternatingly optimum mobility/adsorption phases with contact/charging intervals. The electrochemical conversion can be increased up to 151% depending on the applied flow‐rate and electrical voltage. By applying an external magnetic field, a further increase of electrochemical conversion of up to 70% can be observed.
Our body is colonized by a vast array of bacteria the sum of which forms our microbiota. The gut alone harbors >1,000 bacterial species. An understanding of their individual or synergistic contributions to human health and disease demands means to interfere with their functions on the species level. Most of the currently available antibiotics are broad‐spectrum, thus too unspecific for a selective depletion of a single species of interest from the microbiota. Programmable RNA antibiotics in the form of short antisense oligonucleotides (ASOs) promise to achieve precision manipulation of bacterial communities. These ASOs are coupled to small peptides that carry them inside the bacteria to silence mRNAs of essential genes, for example, to target antibiotic‐resistant pathogens as an alternative to standard antibiotics. There is already proof‐of‐principle with diverse bacteria, but many open questions remain with respect to true species specificity, potential off‐targeting, choice of peptides for delivery, bacterial resistance mechanisms and the host response. While there is unlikely a one‐fits‐all solution for all microbiome species, I will discuss how recent progress in bacterial RNA biology may help to accelerate the development of programmable RNA antibiotics for microbiome editing and other applications.
Visualizing movement data is challenging: While traditional spatial data can be sufficiently displayed as two‐dimensional plots or maps, movement trajectories require the representation of time in a third dimension. To address this, we present moveVis, an R package, which provides tools to animate movement trajectories, overlaying simultaneous uni‐ or multi‐temporal raster imagery or vector data.
moveVis automates the processing of movement and environmental data to turn such into an animation. This includes (a) the regularization of movement trajectories enforcing uniform time instances and intervals across all trajectories, (b) the frame‐wise mapping of movement trajectories onto temporally static or dynamic environmental layers, (c) the addition of customizations, for example, map elements or colour scales and (d) the rendering of frames into an animation encoded as GIF or video file.
moveVis is designed to display interactions and concurrencies of animal movement and environmental data. We present examples and use cases, ranging from data exploration to visualizing scientific findings.
Static spatial plots of movement data disregard the temporal dimension that distinguishes movement from other spatial data. In contrast, animations allow to display relocation in both time and space. We deem animations a powerful way to visually explore movement data, frame analytical findings and display potential interactions with spatially continuous and temporally dynamic environmental covariates.
Background
The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB).
Methods
We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro.
Results
The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment.
Conclusion
We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13.
ABSTRACT The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism.
IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast."
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.
The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor–protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable \(^{19}\)F chemical‐shift predictions to deduce ligand‐binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM study to predict the \(^{19}\)F NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein–inhibitor conformations as well as monomeric and dimeric inhibitor–protein complexes, thus rendering it the largest computational study on chemical shifts of \(^{19}\)F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.
In organic thin‐film transistors (TFTs) fabricated in the inverted (bottom‐gate) device structure, the surface roughness of the gate dielectric onto which the organic‐semiconductor layer is deposited is expected to have a significant effect on the TFT characteristics. To quantitatively evaluate this effect, a method to tune the surface roughness of a gate dielectric consisting of a thin layer of aluminum oxide and an alkylphosphonic acid self‐assembled monolayer over a wide range by controlling a single process parameter, namely the substrate temperature during the deposition of the aluminum gate electrodes, is developed. All other process parameters remain constant in the experiments, so that any differences observed in the TFT performance can be confidently ascribed to effects related to the difference in the gate‐dielectric surface roughness. It is found that an increase in surface roughness leads to a significant decrease in the effective charge‐carrier mobility and an increase in the subthreshold swing. It is shown that a larger gate‐dielectric surface roughness leads to a larger density of grain boundaries in the semiconductor layer, which in turn produces a larger density of localized trap states in the semiconductor.