Tris(methylthio)methane produced by Mortierella hyalina affects sulfur homeostasis in Arabidopsis.

Microbial volatiles are important factors in symbiotic interactions with plants. Mortierella hyalina is a beneficial root-colonizing fungus with a garlic-like smell, and promotes growth of Arabidopsis seedlings. GC-MS analysis of the M. hyalina headspace and NMR analysis of the extracted essential oil identified the sulfur-containing volatile tris(methylthio)methane (TMTM) as the major compound. Incorporation of the sulfur from the fungal volatile into plant metabolism was shown by 34S labeling experiments. Under sulfur deficiency, TMTM down-regulated sulfur deficiency-responsive genes, prevented glucosinolate (GSL) and glutathione (GSH) diminishment, and sustained plant growth. However, excess TMTM led to accumulation of GSH and GSL and reduced plant growth. Since TMTM is not directly incorporated into cysteine, we propose that the volatile from M. hyalina influences the plant sulfur metabolism by interfering with the GSH metabolism, and alleviates sulfur imbalances under sulfur stress.

Wafer-scale epitaxial modulation of quantum dot density.

Precise control of the properties of semiconductor quantum dots (QDs) is vital for creating novel devices for quantum photonics and advanced opto-electronics. Suitable low QD-densities for single QD devices and experiments are challenging to control during epitaxy and are typically found only in limited regions of the wafer. Here, we demonstrate how conventional molecular beam epitaxy (MBE) can be used to modulate the density of optically active QDs in one- and two- dimensional patterns, while still retaining excellent quality. We find that material thickness gradients during layer-by-layer growth result in surface roughness modulations across the whole wafer. Growth on such templates strongly influences the QD nucleation probability. We obtain density modulations between 1 and 10 QDs/µm2 and periods ranging from several millimeters down to at least a few hundred microns. This method is universal and expected to be applicable to a wide variety of different semiconductor material systems. We apply the method to enable growth of ultra-low noise QDs across an entire 3-inch semiconductor wafer.

Grouping of chemicals into mode of action classes by automated effect pattern analysis using the zebrafish embryo toxicity test.

A central element of high throughput screens for chemical effect assessment using zebrafish is the assessment and quantification of phenotypic changes. By application of an automated and more unbiased analysis of these changes using image analysis, patterns of phenotypes may be associated with the mode of action (MoA) of the exposure chemical. The aim of our study was to explore to what extent compounds can be grouped according to their anticipated toxicological or pharmacological mode of action using an automated quantitative multi-endpoint zebrafish test. Chemical-response signatures for 30 endpoints, covering phenotypic and functional features, were generated for 25 chemicals assigned to 8 broad MoA classes. Unsupervised clustering of the profiling data demonstrated that chemicals were partially grouped by their main MoA. Analysis with a supervised clustering technique such as a partial least squares discriminant analysis (PLS-DA) allowed to identify markers with a strong potential to discriminate between MoAs such as mandibular arch malformation observed for compounds interfering with retinoic acid signaling. The capacity for discriminating MoAs was also benchmarked to an available battery of in vitro toxicity data obtained from ToxCast library indicating a partially similar performance. Further, we discussed to which extent the collected dataset indicated indeed differences for compounds with presumably similar MoA or whether other factors such as toxicokinetic differences could have an important impact on the determined response patterns.

[In-hospital emergency care in the Federal Republic of Germany. A site survey of hospitals in the German Resuscitation Registry]. / Innerklinische Notfallversorgung in der Bundesrepublik Deutschland. Eine Standortbefragung der Kliniken des Deutschen Reanimationsregisters.

BACKGROUND: In contrast to prehospital care there is a lack of specifications for the organization and equipment of medical emergency teams for in-hospital emergency care. OBJECTIVE: Evaluation of the organization, team composition, training, equipment and tasks of medical emergency teams in the Federal Republic of Germany. MATERIAL AND METHODS: Evaluation of a web-based survey of all hospitals participating in the German Resuscitation Register between February and March2020. The participants were asked about team composition; emergency equipment; type, content and scope of special training or further training as well as other additional tasks in the everyday clinical routine when participating in the medical emergency team. Hospitals with ≤ or >600 beds were compared. RESULTS: A total of 21 (>600 beds: 10, 48%; ≤600 beds: 11, 52%) hospitals participated in the survey. Team composition requirements were present at 76% (n = 16; ≤600 beds: 8, 72% vs. >600 beds: 8, 80%), training requirements for medical emergency teams at 38% (n = 16; ≤600 beds: 4, 36% vs. >600 beds: 4, 40%) of hospitals, with a focus on cardiac life support (n = 6, 28%; ≤600 beds: 3, 27% vs. >600 beds: 3, 30%) and airway management (n = 4, 19%; ≤600 beds: 3, 27% vs. >600 beds: 1, 10%). A 12-lead electrocardiogram (n = 7, 33%; ≤600 beds: 1, 9% vs. >600 beds: 6, 60%; p = 0.02), video laryngoscope (n = 7, 33%; ≤600 beds: 2, 18% vs. >600 beds: 5, 50%), ventilator without (n = 7, 33%; ≤600 beds: 2, 18% vs. >600 beds: 5, 50%) or with the possibility of non-invasive ventilation was part of the standard equipment in n = 4, 19% (≤600 beds: 1, 9% vs. >600 beds: 3, 30%). A total of 85% (n = 18; ≤600 beds: 10, 100% vs. >600 beds 8, 72%), had additional tasks in the daily clinical routine. While clinics with >600 beds staffed medical emergency teams 100% of the time from the intensive care units, in clinics ≤600 beds medical emergency teams were deployed significantly more often in the emergency department (n = 5, 45%) and in the normal wards (n = 5, 45%, p = 0.03). CONCLUSION: Training and equipment of medical emergency teams in the Federal Republic of Germany is heterogeneous. They should at least meet the standards commonly used in prehospital emergency medicine and include the availability of a portable 12-lead electrocardiogram, a ventilator with the possibility of noninvasive ventilation and a video laryngoscope. Regardless of the size of the hospital, continuous availability of all members of the medical emergency teams should be ensured.

[Hospital paramedic. An interprofessional blended learning concept to qualify paramedics and medical personnel for deployment in intensive care units and emergency departments during the COVID-19 pandemic]. / Kliniksanitäter. Ein interprofessionelles Blended-Learning-Konzept zur Weiterqualifikation von Rettungsdienst- und medizinischem Personal zum Einsatz auf Intensivstationen und in Notaufnahmen während der COVID-19-Pandemie.

BACKGROUND: The COVID-19 pandemic necessitated a time-critical expansion of medical staff in intensive care units (ICU) and emergency rooms (ER). OBJECTIVE: This article describes the development, performance and first results of an interprofessional blended learning concept called hospital paramedics, qualifying paramedics and additional medical personnel to support ICUs and ERs. MATERIAL AND METHODS: The Protestant Hospital of the Bethel Foundation (EvKB), University Hospital OWL, University of Bielefeld in cooperation with the Study Institute Westfalen-Lippe, developed a 2-stage blended learning concept (stage 1 e­learning with online tutorials, stage 2 practical deployment) comprising 3 modules: ICU, ER and in-hospital emergency medicine. At the beginning, the participants were asked about their sociodemographic data (age, gender, type of medical qualifications) and subjective feeling of confidence. At the end, a final discussion with the participant, the practice instructor and the supervising physician took place and an evaluation of the deployment by the head of the practice and the hospital paramedic was carried out using questionnaires. RESULTS: Within 6 weeks 58 (63%) of the 92 participants completed the online course and 17 (29%) additionally completed their traineeship. In the ICU they assisted with preparing catheter systems, medication and nursing, performed Manchester triage and initial care in the ER. After completion hospital paramedics were significantly more confident when working in a hospital, catheterization and tracheostoma care (p < 0.05). Of the supervisors 94% deemed the deployment as useful and 100% of the participants were prepared to be available at short notice in their areas as compensation for the COVID-19-pandemic in the event of a staff shortage. Through the provision of additional intensive care ventilators and monitoring units in the period from March to the beginning of May 2020 and the personnel management that was carried out, the EvKB was in a position to increase the number of previously provided ventilator beds by potentially >40 ventilation places. CONCLUSION: Blended learning concepts, such as hospital paramedics, can quickly qualify medical personnel for use in system-relevant settings, relieve nursing staff and thus create an expansion of intensive care capacities. Existing or pending pandemic and contingency plans should be complemented by such blended learning training so that they are immediately available in case of a second pandemic wave, future pandemics or other crisis situations.

Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

Electrode Afterload: A Valuable Technique in a Case of Short Electrode Insertion.

Introduction. The location of the electrode inside the cochlea is important for speech performance. However, many variables, including array length, insertion depth, and individual anatomy, may affect the intracochlear position of the electrode. Insertion deeper than 20 mm and revision surgery are critical situations in which residual hearing and electrode integrity may be at risk. This case report challenges this hypothesis and raises the following question: is it possible to achieve a better speech understanding with an electrode afterload without compromising residual hearing? Case Report. A 73-year-old female patient showed up for evaluation of hearing loss. The patient was operated four times in an external hospital due to cholesteatoma formation in the right ear. Related to a poor aided speech understanding, a CI-surgery was performed. 5 months after the surgery, the subject returned with poor speech understanding. A revision surgery was performed, where the first white marker of the electrode was seen in the round window (20 mm). The electrode was inserted 4 mm deeper into the cochlea. After six and twelve months, the results of the Freiburger monosyllabic speech test improved till 25% and 45%, respectively. Discussion. Hearing preservation is possible with a revisional deeper insertion from 20 mm to 24 mm. In this case, a partial obliteration of an open cavity made the electrode surgically easily accessible. This allowed the deeper insertion during the revision surgery. In a regular surgical field with a posterior tympanotomy, the revision surgery is more challenging and brings the electrode into the risk of an iatrogenic destruction. Conclusion. This case of an electrode afterload after having inserted the electrode initially to mm, demonstrates that hearing can be preserved and speech perception can improve after performing this maneuver.

NF1 mutations in conjunctival melanoma.

BACKGROUND: Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood. METHODS: A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis. RESULTS: Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS). CONCLUSIONS: Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma.

Species-specific developmental toxicity in rats and rabbits: Generation of a reference compound list for development of alternative testing approaches.

For regulatory information requirements, developmental toxicity testing is often conducted in two mammalian species. In order to provide a set of reference compounds that could be used to explore alternative approaches to supersede testing in a second species, a retrospective data analysis was conducted. The aim was to identify compounds for which species sensitivity differences between rats and rabbits are not caused by maternal toxicity or toxicokinetic differences. A total of 330 compounds were analysed and classified according to their species-specific differences. A lack of concordance between rat and rabbit was observed in 24% of the compounds, of which 10% were found to be selective developmental toxicants in one of the species. In contrast to previously published analyses the presented comparison is based entirely on publically data allowing validating and comparing alternative approaches for developmental toxicity testing. Furthermore, this list could be useful to identify mechanisms leading to species differences.

An ecotoxicological view on neurotoxicity assessment.

The numbers of potential neurotoxicants in the environment are raising and pose a great risk for humans and the environment. Currently neurotoxicity assessment is mostly performed to predict and prevent harm to human populations. Despite all the efforts invested in the last years in developing novel in vitro or in silico test systems, in vivo tests with rodents are still the only accepted test for neurotoxicity risk assessment in Europe. Despite an increasing number of reports of species showing altered behaviour, neurotoxicity assessment for species in the environment is not required and therefore mostly not performed. Considering the increasing numbers of environmental contaminants with potential neurotoxic potential, eco-neurotoxicity should be also considered in risk assessment. In order to do so novel test systems are needed that can cope with species differences within ecosystems. In the field, online-biomonitoring systems using behavioural information could be used to detect neurotoxic effects and effect-directed analyses could be applied to identify the neurotoxicants causing the effect. Additionally, toxic pressure calculations in combination with mixture modelling could use environmental chemical monitoring data to predict adverse effects and prioritize pollutants for laboratory testing. Cheminformatics based on computational toxicological data from in vitro and in vivo studies could help to identify potential neurotoxicants. An array of in vitro assays covering different modes of action could be applied to screen compounds for neurotoxicity. The selection of in vitro assays could be guided by AOPs relevant for eco-neurotoxicity. In order to be able to perform risk assessment for eco-neurotoxicity, methods need to focus on the most sensitive species in an ecosystem. A test battery using species from different trophic levels might be the best approach. To implement eco-neurotoxicity assessment into European risk assessment, cheminformatics and in vitro screening tests could be used as first approach to identify eco-neurotoxic pollutants. In a second step, a small species test battery could be applied to assess the risks of ecosystems.

[Ocular graft versus host disease : Corneal complications]. / Okuläre Graft-versus-Host-Disease : Korneale Komplikationen.

BACKGROUND: Ocular graft-versus-host disease (GvHD) following allogeneic blood stem cell transplantation leads to immunologically induced alterations in many ocular tissues, particularly at the ocular surface. Within the framework of the main topic, this article focuses primarily on corneal complications in chronic ocular GvHD. OBJECTIVE: This article aims to promote understanding of the influencing factors, diagnostics, and therapeutic options pertaining to corneal complications in ocular GvHD. Furthermore, the possibilities for prevention are discussed. MATERIALS AND METHODS: This analysis is based on a literature review as well as on data from the Ophthalmology Clinic at the University Hospital Essen. RESULTS: Corneal complications often occur secondarily in ocular GvHD, as a consequence of severe inflammatory alterations of the conjunctiva or eyelid. Spontaneous corneal perforations associated with only mild symptoms are less common during the course of disease. From the ophthalmologist's perspective, it is important that the inflammatory activity of all the different ocular tissues is considered. Treatment may follow a stepwise scheme that includes substitution, immunosuppression, and surgical rehabilitation. CONCLUSION: Systematic diagnosis of ocular GvHD helps to prevent corneal complications or support early therapeutic intervention. An interdisciplinary approach to diagnosis and treatment planning is recommended, in order to optimize local and systemic immunosuppressive therapy.

Genome-wide estimate of the heritability of Multiple System Atrophy.

INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants.

[Long-term results of autologous transplantation of limbal epithelium cultivated ex vivo for limbal stem cell deficiency]. / Langzeitergebnisse zur autologen Transplantation von ex vivo kultiviertem Limbusepithel bei limbaler Stammzellinsuffizienz.

OBJECTIVE: This study reports the long-term clinical outcome of autologous limbal epithelial cells cultivated ex vivo on intact amniotic membranes (AM) for ocular surface reconstruction in limbal stem cell deficiency (LSCD). PATIENTS AND METHODS: A total of 61 eyes from 57 patients (46 males and 11 females) with LSCD were treated by transplantation of autologous limbal epithelial cells cultivated on intact AM. The etiology of the LSCD was chemical and thermal burns (n = 34), recurrent or primary large-sized pterygium (n = 12), mitomycin C and tumor excision-induced LSCD (n = 9), severe infectious keratitis (n = 3), perforating injury, epidermolysis bullosa and contact lens-associated keratopathy (each n = 1). Only eyes with a follow-up time of at least 12 months were included in the analysis. The main outcome end points were restoration of ocular surface integrity and improvement of visual acuity (VA). RESULTS: The mean follow-up time was 50.8 ± 32.7 months. An entirely stable corneal surface was reconstructed in 46 (75.4%) eyes. Visual acuity significantly increased in 40 (65.6 %) eyes, was stable in 12 (19.7%) eyes and decreased in 9 eyes (14.8%). The mean visual acuity significantly increased (p < 0.0001) from 1.4 ± 0.91 LogMAR preoperatively to 0.8± 0.67 LogMAR postoperatively. CONCLUSION: Transplantation of limbal epithelium cultivated ex vivo on intact AM leads to restoration of a stable corneal surface and resulted in a significant increase of visual acuity in most cases of LSCD. Autologous transplantation of cultivated limbal epithelium showed an excellent prognosis and outcome after long-term follow-up.

Optical properties of strain-compensated CdSe/ZnSe/(Zn,Mg)Se quantum well microdisks.

Strain-compensated CdSe/ZnSe/(Zn,Mg)Se quantum well structures that were grown on (In,Ga)As allow for efficient room-temperature photoluminescence and spectral tuning over the whole visible range. We fabricated microdisk cavities from these samples by making use of a challenging chemical structuring technique for selective and homogeneous removal of the (In,Ga)As sacrificial layer below the quantum structure. The observed whispering gallery modes in our microdisks are mainly visible up to photon energies of ~ 2.3 eV due to strong self-absorption. As extinction coefficients and effective refractive indices are dominated by the quantum well material CdSe, thick quantum wells (> 3 monolayer) are necessary to observe resonances in the corresponding quantum well emission.

[Operative therapy and irradiation of conjunctival melanoma]. / Operative Therapie und Bestrahlung konjunktivaler Melanome.

BACKGROUND: Radiotherapy of conjunctival melanoma has gained in importance in recent years compared to less invasive therapeutic approaches. This is due to the high recurrence rates achieved by omitting adjuvant therapy and to the increasing availability of suitable radiotherapeutic methods, so that tumors formerly not amenable to organ-preserving therapy can now be treated. OBJECTIVE: This article presents the current radiotherapeutic options for conjunctival melanoma. The aim is to describe the diagnostic and therapeutic strategies and the course of therapy of malignant conjunctival melanoma. It is the authors' intention to justify the necessity of the adjuvant therapy of conjunctival melanoma and to emphasize the need for interdisciplinary cooperation during the course of tumor therapy. METHODS: The article is based on results published in the literature as well as on data collected and experience gained in our centre.

The role of chemical speciation, chemical fractionation and calcium disruption in manganese-induced developmental toxicity in zebrafish (Danio rerio) embryos.

Manganese (Mn) is an essential nutrient that can be toxic in excess concentrations, especially during early development stages. The mechanisms of Mn toxicity is still unclear, and little information is available regarding the role of Mn speciation and fractionation in toxicology. We aimed to investigate the toxic effects of several chemical forms of Mn in embryos of Danio rerio exposed during different development stages, between 2 and 122h post fertilization. We found a stage-specific increase of lethality associated with hatching and removal of the chorion. Mn(II), ([Mn(H2O)6](2+)) appeared to be the most toxic species to embryos exposed for 48h, and Mn(II) citrate was most toxic to embryos exposed for 72 and/or 120h. Manganese toxicity was associated with calcium disruption, manganese speciation and metal fractionation, including bioaccumulation in tissue, granule fractions, organelles and denaturated proteins.

Filtration effects of zebra mussels on pathogens and total bacterial burden in the Odra Lagoon (South Baltic).

As a result of their mode of filter feeding, zebra mussels (Dreissena polymorpha Pall.) have been observed to purify natural water bodies and in vitro. Therefore, the possibility of using zebra mussels for water purification was investigated in a slightly brackish water body of a large lagoon. In this study, water samples were taken above, near and at distance from zebra mussel beds (MB) in the Odra Lagoon in North East Germany. Near typical bacterial species like Aeromonas spp. pathogenic bacteria with potential relation to hospital wastewater pollution (Burkholderia cepacia, Staphylococcus aureus, Weeksella spp.) were detected. There were no correlations found between either total bacteria or pathogens and distance to MB and no antimicrobial effect of the mussels could be deduced. For bioremediation in larger water bodies like lagoons, natural zebra MB do not seem to play a major antimicrobial role and the effect of artificial mussel grids especially against hospital pathogens should be investigated.

[Short-term and long-term complications after transplantation of cultivated limbal epithelium]. / Kurz- und Langzeitkomplikationen nach Transplantation von kultiviertem Limbusepithel.

Recent advances in tissue engineering have facilitated the development of new strategies in ocular surface reconstruction. Limitations and possibilities of ex vivo cultivation and limbal epithelium cell culture techniques as well as the short and long-term complications after transplantation of ex vivo expansion of cultivated limbal epithelium for the treatment of limbal stem cell deficiency are summarized in this review.

TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours.

BACKGROUND: Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations. METHODS: The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas. RESULTS: Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma. CONCLUSION: Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.