Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats.

Alcohol Use Disorder (AUD) adversely affects the lives of millions of people, but still lacks effective treatment options. Recent advancements in psychedelic research suggest psilocybin to be potentially efficacious for AUD. However, major knowledge gaps remain regarding (1) psilocybin's general mode of action and (2) AUD-specific alterations of responsivity to psilocybin treatment in the brain that are crucial for treatment development. Here, we conducted a randomized, placebo-controlled crossover pharmaco-fMRI study on psilocybin effects using a translational approach with healthy rats and a rat model of alcohol relapse. Psilocybin effects were quantified with resting-state functional connectivity using data-driven whole-brain global brain connectivity, network-based statistics, graph theory, hypothesis-driven Default Mode Network (DMN)-specific connectivity, and entropy analyses. Results demonstrate that psilocybin induced an acute wide-spread decrease in different functional connectivity domains together with a distinct increase of connectivity between serotonergic core regions and cortical areas. We could further provide translational evidence for psilocybin-induced DMN hypoconnectivity reported in humans. Psilocybin showed an AUD-specific blunting of DMN hypoconnectivity, which strongly correlated to the alcohol relapse intensity and was mainly driven by medial prefrontal regions. In conclusion, our results provide translational validity for acute psilocybin-induced neural effects in the rodent brain. Furthermore, alcohol relapse severity was negatively correlated with neural responsivity to psilocybin treatment. Our data suggest that a clinical standard dose of psilocybin may not be sufficient to treat severe AUD cases; a finding that should be considered for future clinical trials.

[Complex Regional Pain Syndrome (CRPS) - State of the Art in Diagnostics and Therapy]. / Complex Regional Pain Syndrome (CRPS).

The complex regional pain syndrome (CRPS) usually occurs within a few weeks in 2-5% of all patients after trauma or surgery or subsequent measures of the distal extremities. There are certain risk factors for its occurrence but no "CRPS personality", instead there are factors that negatively influence the course. The prognosis is generally good ("rule of thirds"), but remaining limitations are common. The diagnosis is clinically possible according to the "Budapest criteria". Additional examinations are possible in case of doubt but are neither conclusive nor exclusive. Corticoids and bisphosphonates are used alongside drugs that have an effect on neuropathic pain. Invasive therapies do not have good evidence and have therefore lost their importance. The rehabilitative therapy is carried out actively and with a lot of self-exercises at an early stage. Invasive anesthetic, passive therapies are obsolete. Special forms of treatment are "graded exposure" (GEXP) in the case of dominant anxiety and, e.g., "graded motor imagery" (GMI) in case of neglect-like symptoms. In addition to educational and behavioral therapy elements, psychotherapy for CRPS also includes participation as part of graded exposure.

Pilot-Scale Electrospinning of PLA Using Biobased Dyes as Multifunctional Additives.

Fibers with diameters in the lower micrometer range have unique properties suitable for applications in the textile and biomedical industries. Such fibers are usually produced by solution electrospinning, but this process is environmentally harmful because it requires the use of toxic solvents. Melt electrospinning is a sustainable alternative but the high viscosity and low electrical conductivity of molten polymers produce thicker fibers. Here, we used multifunctional biobased dyes as additives to improve the spinnability of polylactic acid (PLA), improving the spinnability by reducing the electrical resistance of the melt, and incorporating antibacterial activity against Staphylococcus aureus. Spinning trials using our 600-nozzle pilot-scale melt-electrospinning device showed that the addition of dyes produced narrower fibers in the resulting fiber web, with a minimum diameter of ~9 µm for the fiber containing 3% (w/w) of curcumin. The reduction in diameter was low at lower throughputs but more significant at higher throughputs, where the diameter reduced from 46 µm to approximately 23 µm. Although all three dyes showed antibacterial activity, only the PLA melt containing 5% (w/w) curcumin retained this property in the fiber web. Our results provide the basis for the development of environmentally friendly melt-electrospinning processes for the pilot-scale manufacturing of microfibers.

Molecular Imaging of Dopamine Partial Agonists in Humans: Implications for Clinical Practice.

Positron emission tomography (PET) has been used since the late 1980s for the assessment of relationships between occupancy of D2/3 receptors by antipsychotic drugs in the human brain and the clinical effects and side effects of these compounds in patients. It is now well established for most D2/3 antagonists, both of the first and the second generation, that the ideal occupancy of their target receptors is between approximately 65 and 80%. If the occupancy is below 65%, the probability of treatment response is reduced, if the occupancy is higher than 80%, the risk for extrapyramidal side-effects increases substantially. However, partial agonist antipsychotics behave different from these rules. It has been shown for all three available drugs of this class (aripiprazole, brexpiprazole, cariprazine) that, due to their special pharmacology, a very high target engagement (>90%) not only is not harmful but represents a prerequisite for antipsychotic efficacy. The available PET studies for these drugs are reviewed in this work. It is demonstrated that optimal plasma levels for partial agonist antipsychotics can be derived from these studies, which can guide individual treatment in routine patient care.

[Are psychedelics fast acting antidepressant agents?] / Sind Psychedelika schnell wirksame Antidepressiva?

BACKGROUND: Psychedelics, such as psilocybin represent one of the most promising current therapeutic approaches in psychiatry. OBJECTIVE: Psychedelics seem to have not only potent antidepressant effects. Do they also work particularly quickly, i.e. within one day? MATERIAL AND METHODS: The available literature on clinical studies of psychedelics in depressive syndromes is presented both from the period up to the prohibition of these substances in the late 1960s as well as after the resumption of research in the 2000s. One focus is the speed of onset of antidepressant action. RESULTS: Only the clinical studies published since 2016 that meet modern methodological standards have also systematically examined the speed of the antidepressant onset of action. The published studies, which were almost exclusively carried out with psilocybin, so far show small sample sizes (the total number of patients with depression treated in published clinical studies is < 200) and some of them have methodological weaknesses; however, they suggest a pronounced and very rapid onset of action within one day for depression, treatment-resistant depression and depression in the context of life-threatening cancer. CONCLUSION: The available studies indicate a potent, rapid onset and in many cases long-lasting antidepressant effect over several months. The currently conducted studies with three-digit patient numbers will provide final information about the potential of psilocybin for depression.

Photophysics and photochemistry of NIR absorbers derived from cyanines: key to new technologies based on chemistry 4.0.

Cyanines derived from heptamethines were mainly discussed regarding their functionalization to broaden the solubility in different surroundings exhibiting either hydrophilic or hydrophobic properties and to tailor made the ΔG et photopysical properties with respect to absorption and fluorescence. Electrochemical properties were additionally considered for some selected examples. The cyanines chosen comprised as end groups either indolenine, benzo[e]- or benzo[cd]indolium pattern, which facilitated to shift the absorption between 750-1000 nm. This enabled their use in applications with light sources emitting in the near-infrared (NIR) region selected from high power LEDs or lasers with line-shaped focus. The absorbers considered were discussed regarding their function as sensitizer for applications related to Chemistry 4.0 standards. These were mainly photopolymer coatings, which can be found for applications in the graphic industry or to protect selected substrates. The huge release of heat on demand upon turning ON or OFF the NIR light source enables them for photothermal treatment in processes requesting heat to initiate either chemical (activated reactions) or physical (melting, evaporation) events.

Conversion of Chitin to Defined Chitosan Oligomers: Current Status and Future Prospects.

Chitin is an abundant polysaccharide primarily produced as an industrial waste stream during the processing of crustaceans. Despite the limited applications of chitin, there is interest from the medical, agrochemical, food and cosmetic industries because it can be converted into chitosan and partially acetylated chitosan oligomers (COS). These molecules have various useful properties, including antimicrobial and anti-inflammatory activities. The chemical production of COS is environmentally hazardous and it is difficult to control the degree of polymerization and acetylation. These issues can be addressed by using specific enzymes, particularly chitinases, chitosanases and chitin deacetylases, which yield better-defined chitosan and COS mixtures. In this review, we summarize recent chemical and enzymatic approaches for the production of chitosan and COS. We also discuss a design-of-experiments approach for process optimization that could help to enhance enzymatic processes in terms of product yield and product characteristics. This may allow the production of novel COS structures with unique functional properties to further expand the applications of these diverse bioactive molecules.

Photochemistry with Cyanines in the Near Infrared: A Step to Chemistry 4.0 Technologies.

Cyanines covering the absorption in the near infrared (NIR) are attractive for distinct applications. They can interact either with lasers exhibiting line-shaped focus emitting at both 808 and 980 nm or bright high intensity NIR-LEDs with 805 nm emission, respectively. This is drawing attention to Industry 4.0 applications. The major deactivation occurs through a non-radiative process resulting in the release of heat into the surrounding, although a small fraction of radiative deactivation also takes place. Most of these NIR-sensitive systems possess an internal activation barrier to react in a photonic process with initiators resulting in the generation of reactive radicals and acidic cations. Thus, the heat released by the NIR absorber helps to bring the system, consisting of an NIR sensitizer and initiator, above such internal barriers. Molecular design strategies making these systems more compatible with distinct applications in a certain oleophilic surrounding are considered as a big challenge. This includes variations of the molecular pattern and counter ions derived from super acids exhibiting low coordinating properties. Further discussion focusses on the use of such systems in Chemistry 4.0 related applications. Intelligent software tools help to improve and optimize these systems combining chemistry, engineering based on high-throughput formulation screening (HTFS) technologies, and machine learning algorithms to open up novel solutions in material sciences.

New High-Power LEDs Open Photochemistry for Near-Infrared-Sensitized Radical and Cationic Photopolymerization.

Cyanines derived from heptamethines were investigated in combination with iodonium salts as initiators of the radical polymerization of tripropylene glycol diacrylate and epoxides derived from bisphenol-A-diglycidylether. A new near-infrared (NIR) LED prototype emitting at 805 nm with an exposure intensity of 1.2 W cm-2 facilitated initiation of both radical and cationic polymerization using sensitizers derived from cyanines. This new light-emitting device has brought new insight into the photochemistry of cyanines with the general structure 1 because a combination of photonic and thermal processes strongly influences reaction pathways. In particular, cationic cyanines comprising a cyclopentene moiety and diphenylamino group in the center initiated the cationic polymerization of epoxides. Selective oxidation of this unit explains why specifically these derivatives may function as initiators for cationic polymerization. In contrast, when the diphenylamino group was replaced by a barbital group at the meso-position cationic polymerization of epoxides was not initiated.

Near-Infrared Sensitized Photoinduced Atom-Transfer Radical Polymerization (ATRP) with a Copper(II) Catalyst Concentration in the ppm Range.

NIR-sensitized photoinduced atom-transfer radical polymerization (ATRP) is possible by using ppm of CuII /tris(2-pyridylmethyl)amine (TPMA) as the catalyst, a polymethine as the photosensitizer, and α-bromophenylacetate as the alkyl halide initiator. Among the polymethines investigated with cationic, zwitterionic, or anionic structures, only the zwitterionic 2 exhibited sensitization activity under NIR light at room temperature resulting in the formation of polymers with controlled molecular weight characteristics and functionalities. The barbital group placed at the meso-position of 2 caused the activity in this photo-ATRP framework. The chain-end fidelity of the polymers was confirmed by chain extension and block copolymerization experiments. The polymerization system exhibits high photostability under NIR light exposure and irradiation dependency as demonstrated by light on/off experiments.

Variations in Physicochemical Properties and Bioconversion Efficiency of Ulva lactuca Polysaccharides After Different Biomass Pretreatment Techniques.

Green macroalgae are an abundant and undervalued biomass with a specific cell wall structure. In this context, different pretreatments, namely ethanol organosolv (Org), alkaline, liquid hot water (LHW), and ionic liquid (IL) pretreatments, were applied to the green macroalgae Ulva lactuca biomass and then evaluated. Their effects on chemical composition, biomass crystallinity, enzymatic digestibility, and theoretical ethanol potential were studied. The chemical composition analysis showed that the Org and LHW pretreatments allowed the highest glucan recovery (80.8 ± 3.6 and 62.9 ± 4.4 g/100 g DM, respectively) with ulvan (80.0 and 99.1%) and hemicellulose (55.0 and 42.3%) removal. These findings were in agreement with both thermogravimetric analysis and scanning electron microscopy results that confirm significant structural changes of the pretreated biomasses. It was found that the employed pretreatments did not significantly affect the cellulose crystallinity; however, they both increased the whole crystallinity and the enzymatic digestibility. This later reached 97.5% in the case of LHW pretreatment. Our results showed high efficiency saccharification of Ulva lactuca biomass that will constitute the key step of the implementation of a biorefinery process.

Statistical experimental designs for the production of secondary metabolites in plant cell suspension cultures.

Statistical experimental designs, also known as the "design of experiments" (DoE) approach, are widely used to improve not only technical processes but also to answer questions in the agricultural, medical and social sciences. Although many articles have been published about the application of DoE in these fields, few studies have addressed the use of DoE in the plant sciences, particularly in the context of plant cell suspension cultures (PCSCs). Compounds derived from PCSCs can be developed as pharmaceuticals, chemical feedstocks and cosmetic ingredients, and statistical experimental designs can be used to improve the productivity of the cells and the yield and/or quality of the target compounds in a cost efficient manner. In this article, we summarize recent findings concerning the application of statistical approaches to improve the performance of PCSCs and discuss the potential future applications of this approach.

Ni-Catalyzed Asymmetric Cycloisomerization of Dienes by Using TADDOL Phosphoramidites.

A library of α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites has been synthesized and applied in the Ni-catalyzed cycloisomerization of different dienes. Through the systematic variation of the three structural motifs of the lead structure, that is, the amine moiety, the protecting group, and the aryl substituents, the ligand features could be optimized for the asymmetric cycloisomerization of the model substrate diethyl diallylmalonate. The substrate scope of the new catalytic system was extended to other diallylic substrates, including unsymmetrical dienes. Overall remarkably high activities of up to approximately 13 500 h(-1) , very high selectivities toward five-membered exo-methylenecyclopentanes, and enantioselectivities of up to 92 % ee have been achieved.

Assessment of cultivation factors that affect biomass and geraniol production in transgenic tobacco cell suspension cultures.

A large-scale statistical experimental design was used to determine essential cultivation parameters that affect biomass accumulation and geraniol production in transgenic tobacco (Nicotiana tabacum cv. Samsun NN) cell suspension cultures. The carbohydrate source played a major role in determining the geraniol yield and factors such as filling volume, inoculum size and light were less important. Sucrose, filling volume and inoculum size had a positive effect on geraniol yield by boosting growth of plant cell cultures whereas illumination of the cultures stimulated the geraniol biosynthesis. We also found that the carbohydrates sucrose and mannitol showed polarizing effects on biomass and geraniol accumulation. Factors such as shaking frequency, the presence of conditioned medium and solubilizers had minor influence on both plant cell growth and geraniol content. When cells were cultivated under the screened conditions for all the investigated factors, the cultures produced ∼ 5.2 mg/l geraniol after 12 days of cultivation in shaking flasks which is comparable to the yield obtained in microbial expression systems. Our data suggest that industrial experimental designs based on orthogonal arrays are suitable for the selection of initial cultivation parameters prior to the essential medium optimization steps. Such designs are particularly beneficial in the early optimization steps when many factors must be screened, increasing the statistical power of the experiments without increasing the demand on time and resources.

Phenotypic effects of HPV-16 E2 protein expression in human keratinocytes.

Expression of the HPV E2 open reading frame in cervical cancer cells has been shown to affect the expression of both viral and cellular genes. We have examined the phenotypic effects of the expression of human papillomavirus 16 E2 open reading frame in the human keratinocyte cell line HaCaT. Increased levels of apoptotic cell death were seen within 24h of the transfection of HPV-16 E2 expression constructs. However, in those cells which survived selection and retained the intact E2 ORF, long-term stable expression of E2, as detected by RT-PCR, produced cells which developed phenotypes typical of terminally differentiated cells. These included characteristic morphological changes and expression of involucrin, filaggrin and senescence markers. This provides the first evidence of a role for E2 in stimulation of the normal epithelial differentiation programme, which would promote the progression of the HPV life cycle.

Effect of a biplanar osteotomy on primary stability following high tibial osteotomy: a biomechanical cadaver study.

Open-wedge high tibial osteotomy (HTO) is becoming increasingly popular for the treatment of varus gonarthrosis in the active patient. The various implants used in HTO differ with regard to its design, the fixation stability and osteotomy technique. It is assumed that the combination of a plate fixator with a biplanar, v-shaped osteotomy supports bone healing. So far, there are no biomechanical studies that quantify the stabilizing effect of a biplanar versus uniplanar osteotomy. We hypothesized that a significant increase in primary stability of bone-implant constructs is achieved when using a biplanar as opposed to a uniplanar osteotomy. Twenty-four fresh-frozen human tibiae were mounted in a metal cylinder, and open-wedge osteotomy (12 mm wedge size) was performed in a standardized fashion. Proximal and distal tibial segments were marked with tantalum markers of 0.8 mm diameter. Two different plates with locking screws were used for fixation: a short spacer plate (group 1, n = 12) and a plate fixator (group 2, n = 12). In six specimens of each group, a biplanar V-shaped osteotomy with a 110 degrees angulated anterior cut behind the tuberosity parallel to the ventral tibial shaft axis was performed. In the remaining six specimens of each group, a simple uniplanar osteotomy was performed in an oblique fashion. Axial compression of the tibiae was performed using a material testing machine under standardized alignment of the loading axis. Load-controlled cyclical staircase loading tests were performed. The specimens were radiographed simultaneously in two planes together with a biplanar calibration cage in front of a film plane with and without load after each subcycle. Radiostereometry allowed for serial quantification of plastic and elastic micromotion at the osteotomy site reflecting the stability provided by the combination of implant and osteotomy technique. No significant additional stabilizing effect of a biplanar osteotomy in craniocaudal and mediolateral plane was found. However, additional stability was achieved in anteroposterior (AP) and all rotational planes in those specimens fixated with a short spacer plate. In this biomechanical set-up with axial load, the additional stabilizing effect of a biplanar osteotomy did not come into effect in the presence of a long and rigid plate fixator. However, biplanar osteotomy increased the fixation stability significantly in AP and rotational planes when a short spacer plate was used. Clinically, the biplanar osteotomy promotes bone healing regardless of the implant used. Biomechanically, biplanar osteotomy is advantageous for shorter plate designs to increase primary stability of the bone-implant construct.

Optical force sensor array in a microfluidic device based on holographic optical tweezers.

Holographic optical tweezers (HOT) are a versatile technology, with which complex arrays and movements of optical traps can be realized to manipulate multiple microparticles in parallel and to measure the forces affecting them in the piconewton range. We report on the combination of HOT with a fluorescence microscope and a stop-flow, multi-channel microfluidic device. The integration of a high-speed camera into the setup allows for the calibration of all the traps simultaneously both using Boltzmann statistics or the power spectrum density of the particle diffusion within the optical traps. This setup permits complete spatial, chemical and visual control of the microenvironment applicable to probing chemo-mechanical properties of cellular or subcellular structures. As an example we constructed a biomimetic, quasi-two-dimensional actin network on an array of trapped polystyrene microspheres inside the microfluidic chamber. During crosslinking of the actin filaments by Mg(2+) ions, we observe the build up of mechanical tension throughout the actin network. Thus, we demonstrate how our integrated HOT-microfluidics platform can be used as a reconfigurable force sensor array with piconewton resolution to investigate chemo-mechanical processes.

Dropspots: a picoliter array in a microfluidic device.

We present a simple microfluidic device that uses an array of well-defined chambers to immobilize thousands of femtoliter- to picoliter-scale aqueous drops suspended in inert carrier oil. This device enables timelapse studies of large numbers of individual drops, while simultaneously enabling subsequent drop recovery.

Drop-based microfluidic devices for encapsulation of single cells.

We use microfluidic devices to encapsulate, incubate, and manipulate individual cells in picoliter aqueous drops in a carrier fluid at rates of up to several hundred Hz. We use a modular approach with individual devices for each function, thereby significantly increasing the robustness of our system and making it highly flexible and adaptable to a variety of cell-based assays. The small volumes of the drops enables the concentrations of secreted molecules to rapidly attain detectable levels. We show that single hybridoma cells in 33 pL drops secrete detectable concentrations of antibodies in only 6 h and remain fully viable. These devices hold the promise of developing microfluidic cell cytometers and cell sorters with much greater functionality, allowing assays to be performed on individual cells in their own microenvironment prior to analysis and sorting.

Carnosine as molecular probe for sensitive detection of Cu(II) ions using localized 1H NMR spectroscopy.

Complex formation of carnosine (Csn) with Cu(II) is suspected to be of significant biochemical importance and can be detected by NMR via ion-induced paramagnetic relaxation of Csn signals. Here, we present quantification of the sensitivity achieved with localized (1)H NMR spectroscopy at physiological pH and high ligand-to-metal ratios. While characterizing the highly effective relaxation transfer onto a huge Csn pool due to fast ligand exchange, it is demonstrated that a metal-to-ligand ratio of approximately 100 ppm suffices to reduce Csn signals by approximately 50% in vitro, thus making the dipeptide a sensitive probe for such ions. Variation of the donor accessibility reveals that the paramagnetic effect is transferred onto a approximately 1370-fold donor abundance for a given ion concentration. A method is presented to characterize such effective ligand exchange relaxation transfer. These studies focus on the monomer formation since comparison with (1)H NMR data of human calf muscle demonstrates that the dimer complex is insignificant in vivo. Observed line broadening in living tissue yields an upper limit of ca. 195 ppm for the Csn-related copper concentration in human skeletal muscle.