A global blueberry phylogeny: Evolution, diversification, and biogeography of Vaccinieae (Ericaceae).

Vaccinieae is a morphologically diverse and species-rich (∼1430 species) tribe in Ericaceae. Although the majority of diversity is tropical, Vaccinieae are best known for temperate crops (i.e., blueberries, cranberries, huckleberries, lingonberries) in Vaccinium. Vaccinium itself (∼500 species) has been previously suggested as highly polyphyletic and taxonomic boundaries among many of the other genera in the tribe remain uncertain. We assessed the evolutionary history of Vaccinieae with phylogenomic analyses based on a target-enrichment dataset containing 256 low-copy nuclear loci and 210 species representing 30 of the 35 genera in the tribe and 25 of the 29 sections of Vaccinium. We conducted time-calibrated biogeographic analyses and diversification analyses to explore the area of origin and global dispersal history of the tribe. The analysis recovered a temperate North American origin for Vaccinieae approximately 30 million years ago. Tropical diversity of Vaccinieae was inferred to result from multiple, independent movements into the tropics from north-temperate ancestors. Diversification rate increases corresponded to radiation into the Andes and SE Asia. The pseudo-10-locular ovary evolved once in the tribe from the five-locular state, coinciding with the diversification of a major clade that includes most Asian Vaccinium and the group from which commercial blueberries are derived (V. sect. Cyanococcus). A reconstruction from available chromosome counts suggests that a major polyploid event predated the evolution of nearly half the diversity of Vaccinieae. The extent of polyphyly in Vaccinium documented here supports the need for a generic reclassification of the tribe.

The presence of free palmitic acid modulates the effects of lutein on structural and dynamic properties of lipid membranes.

Free fatty acids, like palmitic acid (PA), and xanthophyll pigments, like lutein (LUT) are the natural membrane compounds in plants. To study the effect of PA on LUT and their organization, a model membrane of 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC) enriched with 2 mol% PA and 1 mol% LUT was formed. Molecular mechanisms underlying the interaction between these two compounds were examined with application of molecular spectroscopy techniques, e.g., visible spectroscopy, electron paramagnetic resonance and Fourier transform infrared. We determined the monomeric/dimeric organization of LUT in the membrane. We proved that the presence of PA in the lipid phase facilitated and stabilized the formation of LUT structures in the membrane. Lutein with PA did not form strong molecular aggregates like H- and J-structures. We presented the simplified model membrane that could be a suitable representation of the physiological process of de-esterification of PA from LUT appearing in natural biomembranes in humans.

Which roads lead to access? A global landscape of six COVID-19 vaccine innovation models.

BACKGROUND: Unequal and inequitable access to Covid-19 vaccines in low- and middle-income countries (L&MICs) was a major political, ethical and public health failure in the pandemic. However, vaccine developers' practices were not monolithic, but rather, took diverse approaches to supplying different countries, with important implications for global access. RESULTS: Using data on R&D investments, regulatory approvals, manufacturing and purchase agreements, and vaccine deliveries, we identified six distinct innovation models that apply across the 14 COVID-19 vaccines with more international presence from 2020-2022. "Western Early Arrivers" Pfizer/BioNTech and Moderna supplied the largest volumes quickly and prioritized high-income countries (HICs) from registration to vaccine delivery. "Western Latecomers" Janssen and Novavax supplied intermediate volumes later, also prioritizing HICs but with a greater proportion to L&MICs. "Major Chinese Developers" Sinopharm and Sinovac supplied intermediate volumes early, primarily to middle-income countries (MICs). "Russian Developer" Gamaleya completed development early but ultimately supplied small volumes, primarily to middle-income countries (MICs). "Cosmopolitan Developer" Oxford/AstraZeneca supplied large volumes early to HICs and MICs at the lowest prices. Finally, "Small MIC Developers" CanSino, Bharat Biotech, Medigen, Finlay Institute and the Center for Genetic Engineering and Biotechnology (CGEB), exported relatively small volumes to a few MICs. Low-income countries (LICs) were not targeted by any developer, and received far fewer doses, later, than any other income group. Almost all developers received public funding and other forms of support, but we found little evidence that such support was leveraged to expand global access. CONCLUSIONS: Each of the six innovation models has different implications for which countries get access to which vaccines, how quickly, and at which prices. Each offers different strengths and weaknesses for achieving equitable access. Our findings also suggest that Western firms had the greatest capacity to develop and deliver vaccines quickly during the pandemic, but such capacity is rapidly becoming more globally distributed with MICs playing a significant role, especially in supplying other MICs. Given the critical role of public support in enabling pandemic vaccine development and supply, governments have both the capacity and responsibility to craft international rules that will make responses to future pandemics more equitable and effective.

Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.

BACKGROUND: Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD. METHODS: We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours. RESULTS: Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD. CONCLUSIONS: These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy. TRIAL REGISTRY: ClinicalTrials.gov (NCT04558294).

Spontaneous activity of specific C-nociceptor subtypes from diabetic patients and mice: Involvement of reactive dicarbonyl compounds and (sensitized) transient receptor potential channel A1.

BACKGROUND: Diabetic metabolism causes changes of the chemical milieu including accumulation of reactive carbonyl species, for example, methylglyoxal (MGO). MGO activates chemosensitive TRPA1 on nociceptors, but the contribution to neuronal pathophysiology causing pain and hyperalgesia in diabetic neuropathy is not fully understood. METHODS: We employed single-nerve-fiber recordings in type 2 diabetes patients with (spDN) and without cutaneous pain (DN) and in streptozotocin-diabetic and healthy mice. In mice, we measured Ca++ transients in cultured DRG neurons and stimulated CGRP release from hairy skin. RESULTS: In diabetic patients, we recorded a large proportion of pathologically altered nerve C-fibers (79%). In spDN patients we found a higher percentage (72%) of spontaneously active C-nociceptors than in DN patients (15%). The proportion of spontaneous activity was highest among pathological fibers with mechanoinsensitive fiber properties which are particularly sensitive to MGO in contrast to mechanosensitive fibers. Mouse polymodal nociceptors, in contrast to purely mechanosensitive C-fibers, showed highest prevalence of TRPA1-related chemosensitivity. In diabetic mice about 37% of polymodal nociceptors developed spontaneous activity and exhibited significantly greater MGO responses, indicating sensitized TRPA1 receptors. Low-threshold mechanosensitive Aδ-fibers were vigorously activated by MGO but independently of TRPA1 activation. INTERPRETATION: Our translational findings suggest that TRPA1-expressing C-nociceptors, which in human correspond to mechanoinsensitive and in mice to polymodal nociceptors, are especially vulnerable to develop spontaneous activity. Those two different nociceptor classes might share the functional role as dicarbonyl-sensitive chemosensors and represent the critical nociceptor population that support the development of pain and hyperalgesia in diabetic neuropathy.

Purification and concentration of infectious koi herpesvirus using steric exclusion chromatography.

Koi herpesvirus (KHV) is the causative agent of a koi herpesvirus disease (KHVD) inducing high mortality rates in common carp and koi (Cyprinus carpio). No widespread effective vaccination strategy has been implemented yet, which is partly due to side effects of the immunized fish. In this study, we present an evaluation of the purification of infectious KHV from host cell protein and DNA, using the steric exclusion chromatography. The method is related to conventional polyethylene glycol (PEG) precipitation implemented in a chromatographic set-up and has been applied for infectious virus particle purification with high recoveries and impurity removal. Here, we achieved a yield of up to 55% of infectious KHV by using 12% PEG (molecular weight of 6 kDa) at pH 7.0. The recoveries were higher when using chromatographic cellulose membranes with 3-5 µm pores in diameter instead of 1 µm. The losses were assumed to originate from dense KHV precipitates retained on the membranes. Additionally, the use of >0.6 M NaCl was shown to inactivate infectious KHV. In summary, we propose a first step towards a purification procedure for infectious KHV with a possible implementation in fish vaccine manufacturing.

Preclinical Investigations to Explore the Difference between the Diastereomers [177Lu]Lu-SibuDAB and [177Lu]Lu-RibuDAB toward Prostate Cancer Therapy.

[177Lu]Lu-Ibu-DAB-PSMA, a radioligand modified with ibuprofen as the albumin binder, showed higher accumulation in PSMA-positive tumors of mice than the clinically used [177Lu]Lu-PSMA-617 but lower retention in non-targeted tissues than previously developed albumin-binding PSMA radioligands. The aim of this study was to investigate whether the stereochemistry of the incorporated ibuprofen affects the radioligand's in vitro and in vivo properties and to select the more favorable radioligand for further development. For this purpose, SibuDAB and RibuDAB containing (S)- and (R)-ibuprofen, respectively, were synthesized and labeled with lutetium-177. In vitro, the two isomers had similar properties; however, [177Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [177Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). In vivo, [177Lu]Lu-SibuDAB was metabolically more stable than [177Lu]Lu-RibuDAB with ∼90 vs ∼67% intact radioligand detected in the blood at 4 h post injection (p.i.). In line with the lower albumin-binding affinity, the blood clearance of [177Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [177Lu]Lu-SibuDAB (50% IA, 1 h p.i.). Time-dependent biodistribution studies performed in tumor-bearing athymic nude mice showed high PSMA-specific tumor uptake for both isomers. A twofold increased area under the curve (AUC0→8d) of the blood retention was determined for [177Lu]Lu-SibuDAB as compared to [177Lu]Lu-RibuDAB, whereas the kidney AUC0→8d value of [177Lu]Lu-SibuDAB was only half as high as for [177Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC0→8d ratio was obtained for [177Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [177Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [177Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [177Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [177Lu]Lu-SibuDAB as compared to those injected with [177Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.

Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum.

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene-Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.

Novel Synthetic Strategies Enable the Efficient Development of Folate Conjugates for Cancer Radiotheranostics.

The folate receptor (FR) is an interesting target for radiotheranostics due to its overexpression in several tumor types. The progress in developing novel folate radioconjugates is, however, slow due to the synthetic challenges that folate chemistry presents. The goal of this study was, thus, to establish versatile solid-phase synthetic strategies for a convenient preparation of novel folate conjugates. Two approaches were established based on an orthogonal fluorenylmethyloxycarbonyl (Fmoc)-protection strategy to enable a modular buildup of an albumin-binding DOTA conjugate (known as OxFol-1) using folic acid (oxidized folate version) as a targeting agent. The main difference between the two approaches was the sequence of conjugating the single structural units. The approach that introduced the folate entity as the last unit appeared particularly useful for the preparation of conjugates based on 6R- or 6S-5-methyltetrahydrofolic acid (5-MTHF; a reduced folate version) as targeting entity. Three types of folate conjugates were synthesized either with a p-iodophenyl-based albumin binder (OxFol-1, 6R-RedFol-1, and 6S-RedFol-1) or without an albumin-binding entity (OxFol-14, 6R-RedFol-14, and 6S-RedFol-14). All six conjugates were obtained with high chemical purity (>98%) after 9-13 synthesis steps and a single final HPLC purification. Radiolabeling with lutetium-177 was feasible at high molar activity, and the resulting radioconjugates were stable over at least 24 h. Biodistribution and SPECT/CT imaging studies confirmed the favorable effect of an albumin-binding entity to increase the tumor uptake and reduce kidney retention of folate radioconjugates. The increased tumor-to-kidney ratios obtained with [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 as compared to [177Lu]Lu-OxFol-1 indicated that 5-MTHF is the preferred FR-targeting agent for albumin-binding radioconjugates. This was, however, not the case for folate radioconjugates without an albumin binder. Thanks to the established synthesis strategy, the preparation of further folate radioconjugates will be facilitated, potentially enabling the optimization of the tissue distribution characteristics even more.

Towards rare earth element recovery from wastewaters: biosorption using phototrophic organisms.

Whilst the biosorption of metal ions by phototrophic (micro)organisms has been demonstrated in earlier and more recent research, the isolation of rare earth elements (REEs) from highly dilute aqueous solutions with this type of biomass remains largely unexplored. Therefore, the selective binding abilities of two microalgae (Calothrix brevissima, Chlorella kessleri) and one moss (Physcomitrella patens) were examined using Neodym and Europium as examples. The biomass of P. patens showed the highest sorption capacities for both REEs (Nd3+: 0.74 ± 0.05 mmol*g-1; Eu3+: 0.48 ± 0.05 mmol*g-1). A comparison with the sorption of precious metals (Au3+, Pt4+) and typical metal ions contained in wastewaters (Pb2+, Fe2+, Cu2+, Ni2+), which might compete for binding sites, revealed that the sorption capacities for Au3+ (1.59 ± 0.07 mmol*g-1) and Pb2+ (0.83 ± 0.02 mmol*g-1) are even higher. Although different patterns of maximum sorption capacities for the tested metal ions were observed for the microalgae, they too showed the highest affinities for Au3+, Pb2+, and Nd3+. Nd-sorption experiments in the pH range from 1 to 6 and the recorded adsorption isotherms for this element showed that the biomass of P. patens has favourable properties as biosorbent compared to the microalgae investigated here. Whilst the cultivation mode did not influence the sorption capacities for the target elements of the two algal species, it had a great impact on the properties of the moss. Thus, further studies are necessary to develop effective biosorption processes for the recovery of REEs from alternative and so far unexploited sources. KEY POINTS: • The highest binding capacity for selected REEs was registered for P. patens. • The highest biosorption was found for Au and the biomass of the examined moss. • Biosorption capacities of P. patens seem to depend on the cultivation mode.

Stability of viral haemorrhagic septicaemia virus, infectious hematopoietic necrosis virus and cyprinid herpesvirus 3 in various water samples.

Rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio) are the two most common species in traditional fish farming in Germany. Their aquaculture is threatened upon others by viruses that can cause a high mortality. Therefore, this work focuses on three viruses-viral haemorrhagic septicaemia virus, infectious hematopoietic necrosis virus and cyprinid herpesvirus 3 (CyHV-3)-that endanger these species. To prevent their spread and contain further outbreaks, it is essential to know how long they can outlast in environmental waters and what affects their infectivity outside the host. Hence, the stability of the target viruses in various water matrices was examined and compared in this work. In general, all three viruses were quite stable within sterile water samples (showing mostly ≤1 log reduction after 96 hr) but were inactivated faster and to a higher extent (up to five log steps within 96 hr) in unsterile environmental water samples. The inactivation of the viruses correlated well with the increasing bacterial load of the samples, suggesting that bacteria had the greatest effect on their stability in the examined samples. In comparison, CyHV-3 seemed to be the most sensitive and maintained its infectivity for the shortest period.

Virucidal effects of various agents-including protease-against koi herpesvirus and viral haemorrhagic septicaemia virus.

In a search for alternative, environmentally friendly and effective disinfecting agents, a commercially available protease-Neutrase® -was tested in this work for inactivation of koi herpesvirus (KHV) and of viral haemorrhagic septicaemia virus (VHSV). For comparison, the stability of these viral pathogens in similar configurations at various pH values and concentrations of peracetic acid or quicklime, typically used for disinfection, was tested. Therefore, virus suspensions were incubated with various concentrations of different agents for 24 hr and the titre of the remaining infectious particles was determined by virus titration. Furthermore, the treatment of both viruses, with the agents at concentrations that were previously appointed as effective, was also examined in the presence of solid material (quartz sand). All procedures investigated in this study, including the protease treatment, were able to reduce the titre of KHV and VHSV below the detection limit of the titration. Although further studies are necessary, this is the first report of the application of a protease for the inactivation of the selected fish pathogens, demonstrating the great potential of the latter for disinfection.

Implications of disturbed photon-counting statistics of Eiger detectors for X-ray speckle visibility experiments.

This paper reports on coherent scattering experiments in the low-count regime with less than one photon per pixel per acquisition on average, conducted with two detectors based on the Eiger single-photon-counting chip. The obtained photon-count distributions show systematic deviations from the expected Poisson-gamma distribution, which result in a strong overestimation of the measured speckle contrast. It is shown that these deviations originate from an artificial increase of double-photon events, which is proportional to the detected intensity and inversely proportional to the exposure time. The observed miscounting effect may have important implications for new coherent scattering experiments emerging with the advent of high-brilliance X-ray sources. Different correction schemes are discussed in order to obtain the correct photon distributions from the data. A successful correction is demonstrated with the measurement of Brownian motion from colloidal particles using X-ray speckle visibility spectroscopy.

Response to Agomelatine Treatment is Independent of Smoking Status and Dosage: Results From the AGOPSYCH Study.

INTRODUCTION: Cigarette smoking influences response to antidepressant treatment. It accelerates the metabolism of several cytochrome P450 (CYP) subtypes, including CYP1A2, and therefore bears the risk of pharmacokinetic interactions with psychotropic drugs using that pathway. Agomelatine is a substrate of CYP1A2; the association between nicotine use and agomelatine dosage, however, has never been studied before. METHODS: Smoking habits were correlated with agomelatine doses and treatment outcomes in a sample of 27 patients with lifetime diagnoses within the schizophrenia spectrum who received agomelatine treatment in addition to their stable antipsychotic treatment regimen because of depressive symptoms. RESULTS: No interactions were found between smoking status and agomelatine dosage, and treatment outcomes did not differ between smokers and nonsmokers. DISCUSSION: Agomelatine efficacy appears to be independent of dosage and smoking status, pointing toward mechanisms beyond mere dose-response relationships. Further research will be necessary to validate these findings.

Neurocognitive Effects of Agomelatine Treatment in Schizophrenia Patients Suffering From Comorbid Depression: Results From the AGOPSYCH Study.

BACKGROUND: Cognitive impairment in schizophrenia is highly disabling and remains one of the major therapeutic challenges. Agomelatine (AGO), an agonist at melatonergic MT1/MT2 receptors and antagonist at 5-HT2C receptors, increases dopamine and norepinephrine in the prefrontal cortex and may therefore have the potential of improving neurocognition in patients with schizophrenia. METHODS: Twenty-seven patients with schizophrenia and comorbid depression were treated with AGO in addition to stable doses of antipsychotic drugs. Cognitive abilities were assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) at study entry and after 12 weeks of AGO treatment after the intention-to-treat principle. RESULTS: We observed statistically significant yet clinically negligible increases of the MCCB composite score and the reasoning/problem solving subscore. Patients with unimpaired sleep at baseline showed greater improvements over time than those with sleep disturbances. Changes on the MCCB were not correlated with other psychometric variables. CONCLUSIONS: Despite statistically significant, cognitive improvements after 12 weeks of AGO treatment were clinically irrelevant. Our findings may be limited by baseline properties of the study sample and the study design. In particular, lacking a control group, it cannot be ruled out that improvements were unrelated to AGO treatment. That is why randomized controlled trials are needed to validate the relevance of AGO as a cognitive enhancer in schizophrenia.

Comparative EPR studies on lipid bilayer properties in nanodiscs and liposomes.

Studies of the membrane proteins suggest their close interaction with the lipid surroundings. Membrane proteins and their activities are affected by the composition and structure of the lipid bilayer. therefore adequate surroundings for studied protein are crucial for the model membrane to ensure its biological relevance. In recent years nanodiscs which are small fragments of lipid bilayer stabilised by derivatives of apolipoprotein, called membrane scaffold protein ( MSP), have been established as alternative tool in structural and functional studies of membrane proteins. In this study, the influence MSP of different length on structure and dynamics of DMPC and POPC bilayer was investigated and compared to bilayer present in liposomes. EPR spectroscopy technique using different PC-based spin probes was employed to show cholesterol-like organising effect of MSPs on lipid bilayer, thus giving a better insight into the nanodiscs model membrane structure, and its possible implications in the research of membrane protein applications.

Stabilizing Superacid Anions: The New [H(S4 O13 )2 ]3- Anion in the Crystal Structure of Li3 [H(S4 O13 )2 ].

The unique hydrogenium-bis-tetrasulfate anion [H(S4 O13 )2 ]3- in the crystal structure of Li3 [H(S4 O13 )2 ] (monoclinic, P21 /n (No. 14), Z=2, a=552.46(4) pm, b=939.70(6) pm, c=1876.6(1) pm, ß=97.492(3)°, V=965.9(1)⋅106  pm3 ) is the longest protonated polysulfate chain ever observed. Very strong symmetrical hydrogen bonds are a bold feature of the crystal structure. The protonation of a very weak base such as [S4 O13 ]2- and accordingly the stabilization of the first base of the superacid H2 S4 O13 is a significant success towards the still elusive polysulfuric acids.

Agomelatine for the Treatment of Major Depressive Episodes in Schizophrenia-Spectrum Disorders: An Open-Prospective Proof-of-Concept Study.

BACKGROUND: Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia. METHODS: Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis. RESULTS: Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms. CONCLUSIONS: Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.

Investigating the efficacy of an individualized metacognitive therapy program (MCT+) for psychosis: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Psychological interventions are increasingly recommended as adjunctive treatments for psychosis, but their implementation in clinical practice is still insufficient. The individualized metacognitive therapy program (MCT+; www.uke.de/mct_plus ) represents a low-threshold psychotherapeutic approach that synthesizes group metacognitive training (MCT) and cognitive behavioral therapy for psychosis, and addresses specific cognitive biases that are involved in the onset and maintenance of psychosis. It aims to "plant the seed of doubt" regarding rigid delusional convictions and to encourage patients to critically reflect, extend and change their approach to problem solving. Its second edition also puts more emphasis on affective symptoms. A recent meta-analysis of metacognitive interventions (MCT, MCT+) indicate small to moderate effects on positive symptoms and delusions, as well as high rates of acceptance. Nonetheless, no long-term studies of MCT+ involving large samples have been conducted. METHODS: The goal of the present multi-center, observer-blind, parallel-group, randomized controlled trial is to compare the efficacy of MCT+ against an active control (cognitive remediation; MyBrainTraining(©)) in 328 patients with psychosis at three time points (baseline, immediately after intervention [6 weeks] and 6 months later). The primary outcome is change in psychosis symptoms over the 6-month follow-up period as assessed by the delusion subscale of the Psychotic Symptom Rating Scale. Secondary outcomes include jumping to conclusions, other positive symptoms of schizophrenia, depressive symptoms, self-esteem, quality of life, and cognitive insight. The study also seeks to elucidate mediating factors that promote versus impede symptom improvement across time. DISCUSSION: This is the first multi-center randomized controlled trial to test the efficacy of individualized MCT+ in a large sample of patients with psychosis. The rationale for the trial, the design, and the strengths and limitations of the study are discussed. TRIAL REGISTRATION: The trial is registered through the German Clinical Trials Register ( www.drks.de ) as DRKS00008001 . Registered 6 May 2015.

Polysulfates [Sn O3n+1 ]2- : With the [S6 O19 ]2- Anion, has the End been Reached?

The S6 O192- ion was obtained both as rubidium and ammonium salt from the reaction of the respective sulfate with SO3 . It is the largest polysulfate ion known to date and exhibits a chain of six vertex-connected [SO4 ] tetrahedra. The unique compound was comprehensively characterized and the bonding within the anion was elucidated by theoretical investigations.