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- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (5)
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- Zentraleinheit Klinische Massenspektrometrie (3)
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Three novel tetracationic bis‐triarylboranes with 3,4‐ethylenedioxythiophene (EDOT) linkers, and their neutral precursors, showed significant red‐shifted absorption and emission compared to their thiophene‐containing analogues, with one of the EDOT‐derivatives emitting in the NIR region. Only the EDOT‐linked trixylylborane tetracation was stable in aqueous solution, indicating that direct attachment of a thiophene or even 3‐methylthiophene to the boron atom is insufficient to provide hydrolytic stability in aqueous solution. Further comparative analysis of the EDOT‐linked trixylylborane tetracation and its bis‐thiophene analogue revealed efficient photo‐induced singlet oxygen production, with the consequent biological implications. Thus, both analogues bind strongly to ds‐DNA and BSA, very efficiently enter living human cells, accumulate in several different cytoplasmic organelles with no toxic effect but, under intense visible light irradiation, they exhibit almost instantaneous and very strong cytotoxic effects, presumably attributed to singlet oxygen production. Thus, both compounds are intriguing theranostic agents, whose intracellular and probably intra‐tissue location can be monitored by strong fluorescence, allowing switching on of the strong bioactivity by well‐focused visible light.
The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline‐type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate‐based nanogels may also be of great importance for clinical translation.
Background and purpose
Impaired kidney function is associated with an increased risk of vascular events in acute stroke patients, when assessed by single measurements of estimated glomerular filtration rate (eGFR). It is unknown whether repeated measurements provide additional information for risk prediction.
Methods
The MonDAFIS (Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke) study randomly assigned 3465 acute ischemic stroke patients to either standard procedures or an additive Holter electrocardiogram. Baseline eGFR (CKD‐EPI formula) were dichotomized into values of < versus ≥60 ml/min/1.73 m\(^{2}\). eGFR dynamics were classified based on two in‐hospital values as “stable normal” (≥60 ml/min/1.73 m\(^{2}\)), “increasing” (by at least 15% from baseline, second value ≥ 60 ml/min/1.73 m\(^{2}\)), “decreasing” (by at least 15% from baseline of ≥60 ml/min/1.73 m\(^{2}\)), and “stable decreased” (<60 ml/min/1.73 m\(^{2}\)). The composite endpoint (stroke, major bleeding, myocardial infarction, all‐cause death) was assessed after 24 months. We estimated hazard ratios in confounder‐adjusted models.
Results
Estimated glomerular filtration rate at baseline was available in 2947 and a second value in 1623 patients. After adjusting for age, stroke severity, cardiovascular risk factors, and randomization, eGFR < 60 ml/min/1.73 m\(^{2}\) at baseline (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.40–3.54) as well as decreasing (HR = 1.79, 95% CI = 1.07–2.99) and stable decreased eGFR (HR = 1.64, 95% CI = 1.20–2.24) were independently associated with the composite endpoint. In addition, eGFR < 60 ml/min/1.732 at baseline (HR = 3.02, 95% CI = 1.51–6.10) and decreasing eGFR were associated with all‐cause death (HR = 3.12, 95% CI = 1.63–5.98).
Conclusions
In addition to patients with low eGFR levels at baseline, also those with decreasing eGFR have increased risk for vascular events and death; hence, repeated estimates of eGFR might add relevant information to risk prediction.
Digital platforms, such as Amazon, represent the major beneficiaries of the Covid‐19 crisis. This study examines the role of digital platforms and their engagement in digitalisation initiatives targeting (small) brick‐and‐mortar retailers in Germany, thereby contributing to a better understanding of how digital platforms augment, substitute or reorganise physical retail spaces. This study applies a mixed‐method approach based on qualitative interviews, participant observation as well as media analysis. First, the study illustrates the controversial role of digital platforms by positioning themselves as supporting partners of the (offline) retailers, while simultaneously shifting power towards the platforms themselves. Second, digital platforms have established themselves not only as infrastructure providers but also as actors within these infrastructures, framing digital as well as physical retail spaces, inter alia due to their role as publicly legitimised retail advisers. Third, while institutions want to help retailers to survive, they simultaneously enhance retailers' dependency on digital platforms.
Although inclusion is the declared goal, the transition from a system based on special schools to an inclusive school system has only been progressing very slowly in individual countries. In an evolving school system, the existing special schools keep struggling to justify their existence. This study investigates the regional distribution effects based on official school data and shows the influence of a pull effect on special schools as a distance effect of special schools affecting the placement of students. For this purpose, official school statistics including all students at special and regular schools in the years 2010, 2015 and 2020 (N = 11 280 040) are evaluated in a spatiotemporal comparison using Educational Data Mining. In a hierarchical regression model on school placement in inclusive schools, the distance between primary and special schools has the highest influence (β = 0.48) on the inclusion rate (i.e., the proportion of students with special needs who are educated in regular schools in relation to all students with disabilities), along with the size (β = −0.14) and the density of special schools in a district (β = −0.12). The effects differ according to the population density of the region and are stronger in large cities. When the proportion of students with and without SEN in regular schools is considered (support rate), the density of special schools has the greatest impact on school placement (ß = 43.44). Self‐preservation of schools, traditional funding systems and regional differences between urban and rural areas are discussed as possible reasons.
Aims
To investigate Epstein‐Barr virus (EBV) latency types in 19 cases of EBV‐positive nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL), as such information is currently incomplete.
Methods and results
Immunohistochemistry (IHC) for CD20, CD79a, PAX5, OCT2, CD30, CD15, CD3 and programmed cell death protein 1 was performed. For EBV detection, in‐situ hybridisation (ISH) for EBV‐encoded RNA (EBER) was employed combined with IHC for EBV‐encoded latent membrane protein (LMP)‐1, EBV‐encoded nuclear antigen (EBNA)‐2, and EBV‐encoded BZLF1. In 95% of the cases, neoplastic cells with features of Hodgkin and Reed–Sternberg (HRS) cells were present, mostly showing expression of CD30. In all cases, the B‐cell phenotype was largely intact, and delineation from classic Hodgkin lymphoma (CHL) was further supported by myocyte enhancer factor 2B (MEF2B) detection. All tumour cells were EBER‐positive except in two cases. EBV latency type II was most frequent (89%) and type I was rare. Cases with latency type I were CD30‐negative. Five cases contained some BZLF1‐positive and/or EBNA‐2‐positive bystander lymphocytes.
Conclusions
As HRS morphology of neoplastic cells and CD30 expression are frequent features of EBV‐positive NLPHL, preservation of the B‐cell transcription programme, MEF2B expression combined with NLPHL‐typical architecture and background composition facilitate distinction from CHL. EBER ISH is the method of choice to identify these cases. The majority present with EBV latency type II, and only rare cases present with latency type I, which can be associated with missing CD30 expression. The presence of occasional bystander lymphocytes expressing BZLF1 and/or EBNA‐2 and the partial EBV infection of neoplastic cells in some cases could indicate that EBV is either not primarily involved or is only a transient driver in the pathogenesis of EBV‐positive NLPHL.
The extracellular matrix (ECM) of soft tissues in vivo has remarkable biological and structural properties. Thereby, the ECM provides mechanical stability while it still can be rearranged via cellular remodeling during tissue maturation or healing processes. However, modern synthetic alternatives fail to provide these key features among basic properties. Synthetic matrices are usually completely degraded or are inert regarding cellular remodeling. Based on a refined electrospinning process, a method is developed to generate synthetic scaffolds with highly porous fibrous structures and enhanced fiber‐to‐fiber distances. Since this approach allows for cell migration, matrix remodeling, and ECM synthesis, the scaffold provides an ideal platform for the generation of soft tissue equivalents. Using this matrix, an electrospun‐based multilayered skin equivalent composed of a stratified epidermis, a dermal compartment, and a subcutis is able to be generated without the use of animal matrix components. The extension of classical dense electrospun scaffolds with high porosities and motile fibers generates a fully synthetic and defined alternative to collagen‐gel‐based tissue models and is a promising system for the construction of tissue equivalents as in vitro models or in vivo implants.
Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water‐equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non‐inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off‐label to treat BML. A randomized, triple‐blind, placebo‐controlled phase III trial was conducted to assess efficacy and safety of single‐dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow‐up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single‐dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.
A starlike heterocyclic molecule containing an electron‐deficient nonaaza‐core structure and three peripheral isoquinolines locked by three tetracoordinate borons, namely isoquinoline‐nona‐starazine (QNSA), is synthesized by using readily available reactants through a rather straightforward approach. This new heteroatom‐rich QNSA possesses a quasi‐planar π‐backbone structure, and bears phenyl substituents on borons which protrude on both sides of the π‐backbones endowing it with good solubility in common organic solvents. Contrasting to its starphene analogue, QNSA shows intense fluorescence with a quantum yield (PLQY) of up to 62 % in dilute solution.
Macrocyclic Donor‐Acceptor Dyads Composed of Oligothiophene Half‐Cycles and Perylene Bisimides
(2022)
A series of donor‐acceptor (D−A) macrocyclic dyads consisting of an electron‐poor perylene bisimide (PBI) π‐scaffold bridged with electron‐rich α‐oligothiophenes bearing four, five, six and seven thiophene units between the two phenyl‐imide substituents has been synthesized and characterized by steady‐state UV/Vis absorption and fluorescence spectroscopy, cyclic and differential pulse voltammetry as well as transient absorption spectroscopy. Tying the oligothiophene strands in a conformationally fixed macrocyclic arrangement leads to a more rigid π‐scaffold with vibronic fine structure in the respective absorption spectra. Electrochemical analysis disclosed charged state properties in solution which are strongly dependent on the degree of rigidification within the individual macrocycle. Investigation of the excited state dynamics revealed an oligothiophene bridge size‐dependent fast charge transfer process for the macrocyclic dyads upon PBI subunit excitation.