Refine
Year of publication
Document Type
- Article (31801)
- Part of Periodical (11989)
- Book (8348)
- Doctoral Thesis (5772)
- Part of a Book (3973)
- Working Paper (3404)
- Review (2949)
- Preprint (2420)
- Contribution to a Periodical (2399)
- Conference Proceeding (1776)
Language
- German (43471)
- English (30837)
- French (1071)
- Portuguese (843)
- Multiple languages (320)
- Spanish (309)
- Croatian (302)
- Italian (198)
- mis (174)
- Turkish (168)
Keywords
- Deutsch (1086)
- Literatur (880)
- taxonomy (774)
- Deutschland (553)
- Rezension (516)
- new species (459)
- Rezeption (354)
- Frankfurt <Main> / Universität (341)
- Übersetzung (330)
- Geschichte (302)
Institute
- Medizin (7883)
- Präsidium (5281)
- Physik (4999)
- Extern (2742)
- Wirtschaftswissenschaften (2738)
- Gesellschaftswissenschaften (2383)
- Biowissenschaften (2213)
- Biochemie und Chemie (1985)
- Frankfurt Institute for Advanced Studies (FIAS) (1897)
- Informatik (1738)
Highlights
• Pediatric patients with RASopathies exhibit an increased heart mass.
• Cardiomyocyte size and volume are reduced in pediatric patients with RASopathies.
• Cardiomyocyte numbers per heart are increased in pediatric RASopathy patients.
• Cardiomyocytes in juvenile RASopathy have an immature state.
• Elevated LV mass in RASopathy patients is mainly due to cardiomyocyte hyperplasia.
Abstract
Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart.
Methods and results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4–10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected.
Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).
Objective: This study presents data from the admission trial to show the feasibility, safety and effectiveness of the Nit-Occlud® Lê VSD in the treatment of perimembranous ventricular septal defects with an aneurysmal configuration and a diameter up to 8 mm.
Background: The majority of ventricular septal defects (VSD) are still closed surgically, while a less invasive transcatheter treatment by closure devices is available. Device-based closure is reported to be associated with the risk of complete atrio-ventricular block, especially with double-disc devices in perimembranous defects.
Methods: In six tertiary centers in Germany and Israel, an interventional closure of a periembranous VSD was attempted in 88 patients using the Nit-Occlud® Lê VSD.
Results: The interventional VSD closure was performed in 85 patients. Patients had a median age of 8.0 (2–65) years and a median body weight of 26.7 (10–109) kg. A complete closure of the defects was achieved in 85.4% 2 weeks after device implantation, in 88.9% after three months and in 98.6% at the 5-year follow-up. There was no incidence of death during the study nor did any patient suffer of permanent atrio-ventricular block of higher degree. Serious adverse events, by definition, are potentially life-threatening or require surgery to correct, while major serious events require medical or transcatheter intervention to correct. The study results exhibit a serious adverse event rate of 3.5% (3/85 patients) and a major adverse event rate of 5.9% (5/85 patients).
Conclusion: The Nit-Occlud® Lê VSD coil offers the possibility of an effective and safe approach in patients with aneurysmal perimembranous ventricular septal defects.
Background: Newborns with hypoplastic left heart (HLH) are usually palliated with the Norwood procedure or a hybrid stage I procedure. Hybrid is our preferred approach. Given the critical relationship between stage I, interstage, and comprehensive stage II or advanced biventricular repair, we hypothesized that appropriate drug treatment is a significant therapeutic cornerstone, especially for the management of the high-risk interstage.
Methods: We report a single-center observational study addressing the cardiovascular effects of, in particular, oral β-blockers and the additional use of angiotensin-converting enzyme (ACE) and mineralocorticoid inhibitors.
Results: In total, 51 newborns—30 with HLH syndrome (HLHS) and 21 with HLH complex (HLHC)—with a median bodyweight of 3.0 kg (range 1.9–4.4; nine with bodyweight ≤ 2500 g) underwent an uneventful “Giessen hybrid approach” using a newly approved duct stent. All patients were discharged home with a single, double or triple therapy consisting of ß-blockers, ACE and mineralocorticoid inhibitors; 90% of the patients received bisoprolol, 10% received propranolol, 72% received lisinopril, and 78% received spironolactone. Resting heart rate decreased from 138 bpm (range 112–172; n = 51) at admission to 123 bpm (range 99–139; n = 51) at discharge and 110 bpm before stage II/biventricular repair/heart transplantation (range 90–140; n = 37) accompanied by favorable bodyweight gain. No side effects were evident.
Conclusion: In view of drug risk/benefit profiles, as well as the variable morphology and hemodynamics, the highly selective β1-adrenoceptor blocker bisoprolol is our preferred drug for treatment of HLHS/HLHC in the interstage. We avoid using ACE inhibitor monotherapy and exclude potential risks for coronary and cerebral perfusion pressure beforehand.
Arterial duct stenting, pioneered in the early 1990s for newborns with a duct-dependent pulmonary and systemic circulation, has evolved significantly over the past decades. This progressive technique has led to the development of novel therapeutic strategies, including the Hybrid approach introduced three decades ago, and more recently, a complete transcatheter approach for treating newborns with hypoplastic left heart syndrome (HLHS). Subsequently, the transcatheter method has been extended to bi-ventricular lesions and patients with pulmonary hypertension, establishing a reverse Potts-shunt pathophysiology. Considering current experiences, this review aims to assess the strengths, weaknesses, and complications associated with ductal stenting, which represents a critical component of these complex treatment strategies. Despite advancements, the mortality rate of Norwood and Hybrid stage-1 procedures has plateaued, underscoring the importance of enhancing the quality of life of affected patients as the primary therapeutic goal. The prerequisite is a gentle, almost atraumatic medicine, particularly during the newborn period. It is essential to recognize that both the Hybrid and total transcatheter approaches demand comparable experience to Norwood surgery. Successful outcomes hinge on much more than merely inserting a stent into the duct; they require meticulous attention to detail and comprehensive management strategies.
Given the heterogenous etiology of pediatric heart failure (pHF), evidence-based studies improving pHF are unlikely. A paradigm shift towards updated medicine-based evidence is therefore necessary. In view of the life expectancy of children, cardiac regeneration strategies are required. Therefore, age- and disease-related differences in myocardial (receptor) physiology require individualized precision medicine. First-line diuretic therapy, adopted from the treatment of adults with HF with no chance for recovery, should be questioned in the treatment of pHF with potential for recovery. Inadequate use of diuretics is a common reason for additional stimulation of the neurohumoral axis. Consecutive intravascular volume depletion led to an inadequate treatment with β-blocker and renin–angiotensin–aldosterone antagonists. Given the age-related catecholamine-driven cardiovascular (patho-) physiology, highly selective β1-blockers (bisoprolol) protect against β1-(noradrenaline)-related myocytic apoptosis and necrosis, but allow β2-receptor-mediated myocardial regeneration. Based on its high safety–efficacy profile with rarely seen adverse effects but easily monitorable efficacy by the surrogate of heart rate (reduction), bisoprolol is our first-line drug in infancy. Reduced heart rate economizes the heart and full body oxygen consumption and extends the diastolic filling and coronary perfusion time. Based on our many years of institutional experience, physicians should be encouraged to use β1-selected blockers in infants with dilated cardiomyopathy and hypoplastic left heart syndrome after stage-1 procedure, but also to treat ventricular septal defects with a significant left-to-right shunt. In summary, individualized pHF therapy is the prerequisite for a causal treatment to improve HF symptoms, but above all for the most functional regeneration possible.
The hypoplasia of left-sided heart structures shows great variability and complexity. What the many variants have in common is that their heart structures are neither fully developed before nor after birth. Fetuses and newborns require an individual therapy depending on anatomy and function of the heart. Fetal interventions focus on improving left heart structures by catheter-based interventions and maternal hyperoxygenation which promotes growth as the left ventricular preload and blood flow within the cavity increase. Stage-I management of newborns with single ventricle physiology is usually based on the Norwood/Sano surgery or the Hybrid approach. Two more steps are required to ultimately achieve a Fontan circulation. Some centers also use the Hybrid approach for subsequent Norwood operation beyond the neonatal period. After the Hybrid approach, a comprehensive stage-II or corrective surgery is performed, the latter if a bi-ventricular circulation is possible. With progressively improved catheter-based interventions, particularly ductal stenting and manipulations of the atrial septum, the next advance is to develop a bespoke flow restrictor that can be easily inserted into the branches of the pulmonary artery. The main goal is to avoid complex heart operations under general anesthesia, followed by substantial intensive care in the neonatal period, especially for patients with complex heart defects. Based on the current state of the art of surgical treatment of hypoplastic left heart syndrome and variants with the Norwood surgery or the Hybrid approach, our main focus is on an alternative percutaneous transcatheter technique in the sense of a completely non-surgical stage-I approach.
Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.
We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A.Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of Atm-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).
Purpose: Soft tissue infections can be severe and life-threatening. Their treatment consists currently in radical surgical wound debridement and combined systemic antimicrobial therapy. Different side effects are possible. Local antibiotic therapy represents a new approach to reduce side effects and improve healing. The aim of this study is to assess the effectiveness of the local sprayed use of antibiotics with fibrin sealing compared with negative pressure wound therapy as an established treatment of soft-tissue infections.
Methods: In this retrospective study, patients with soft tissue infections who underwent surgical treatment were analysed. One group consists of patients, who received local fibrin-antibiotic spray (FAS) (n = 62). Patients treated by vacuum-assisted wound therapy (VAWT) as the established treatment were the control group (n = 57). Main outcomes were differences in the success of healing, the duration until healing and the number of needed operations.
Results: Clinical healing could be achieved for 55 patients (98.21%) in the FAS group vs. 47 patients (92.16%) in the VAWT group (p = 0.19). Time to require this was 10.65 ± 10.38 days in the FAS group and 22.85 ± 14.02 days in the VAWT group (p < 0.001). In the FAS group, patients underwent an average of 1.44 ± 0.72 vs.3.46 ± 1.66 operations in the VAWT group (p < 0.001).
Conclusion: Compared to vacuum-assisted wound therapy in soft tissue infections, local fibrin-antibiotic spray shows faster clinical healing and less needed operations. Leading to shorter hospital stays and more satisfied patients. The combination of sprayed fibrin and antibiotics can be seen as a promising and effective method.
Ataxia Telangiectasia (A-T) is a rare monogenetic, autosomal recessive disorder with an incidence of 1 in 40,000-100,000 live births caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The encoded serine/threonine protein kinase (ATM) plays a major role in DNA damage response as well as apoptosis, cell cycle regulation, cell survival, oxidative stress response and genomic stability. Biallelic mutations result in partial or complete loss of ATM expression and/or ATM protein activity. A-T is a disease characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency (impaired B- and T-cell development), recurrent sinopulmonary infections, radiation sensitivity, premature aging, and a predisposition to cancer. Life expectancy of these patients is highly compromised, with only around 50% expected to reach 20 years of age. Malignancies and pulmonary diseases are the two main causes of death. There is currently no therapy available for A-T patients. There are symptomatic treatments available (e.g. immunoglobulin replacement therapy, therapy with antioxidants, and the administration of growth hormone or glucocorticoids as anti- inflammatory hormones) and in some patients, allogeneic hematopoietic stem cell transplantations from matched donors were performed with improved disease outcome. Unfortunately, suitable donors are not available for most patients. An autologous hematopoietic stem cell (HSC)-directed gene therapy approach is a promising alternative, since no matching donor is needed. The patient’s own cells are used, modified ex-vivo (e.g. delivering a healthy copy of the gene with viral vectors or directly correcting the mutation with gene editing). Afterwards, modified HSCs are given back to the patient thereby repopulating the bone marrow and re-establishing the whole blood system. The aim of this project was to develop a gene transfer tool for Atm.
In the first part of this project, retroviral vectors containing the full-length murine Atm cDNA were generated. Gene transfer of Atm with retroviral vectors is challenging, as the Atm cDNA is 9.1 kb in size reaching the packaging capacity of retroviral vectors. Although the foamy viral vector is described to have superior abilities to transfer large sequences, produced titers of the foamy viral Atm vectors were low and transductions of Atm-deficient fibroblasts were inefficient. In contrast, gene transfer of Atm with gammaretroviral and lentiviral vectors was possible, and because lentiviral vectors harboring the full-length Atm coding sequence were produced with the highest viral titers, this vector was used to transduce Atm-deficient fibroblasts. Following transduction, ATM protein levels were restored (40 - 50% of wild-type level). In addition, transduced cells showed increased levels of phosphorylated ATM downstream substrates (γH2AX, pKap1 and p-p53) after irradiation, demonstrating functional reconstitution. However, efficient transduction of murine lineage marker negative cells, the target cells for an Atm gene therapy approach, was not possible and viability of these cells was highly compromised after transduction.
Therefore, a dual vector system was developed in the second part of the project to circumvent the packaging limit of retroviral vectors. Protein halves were fused with split inteins which catalyze their self-excision followed by the formation of a full-length protein in a process called protein trans-splicing. The split Atm cDNA was delivered with lentiviral vectors and sufficient viral titers were achieved for efficient double transduction of Atm-deficient fibroblasts. Whereas the reconstitution of full-length ATM protein was low in cells transduced with vectors containing Npu split inteins, the use of Rma split inteins showed superior reconstitution. When comparing reconstitution levels with two different split sites within the ATM protein, no major differences were observed. Because a proof of ATM functionality could not be shown with these vector pairs, the F2A site used to co-deliver a marker gene was replaced by an IRES element. After transduction with split intein Atm vectors containing IRES elements, the level of ATM protein reached only 10% of the wild-type level. Nevertheless, an increased amount of pKap1 and p-p53 was detected demonstrating a functional kinase activity of reconstituted ATM protein. Furthermore, a partial repair of cell cycle defects in Atm-deficient fibroblasts was demonstrated.
In parallel to the development of a gene transfer tool for Atm, preliminary experiments were performed in Atm-deficient mice to create optimal transplantation conditions for gene-corrected HSCs that could be performed in the future. Because Atm-deficient mice are highly sensitive to irradiation, conventional conditioning regimes (e.g. total body irradiation or myeloablative conditioning with chemotherapeutics) cannot be used prior to HSC transplantation. Therefore, Atm-deficient mice were pretreated with different conditioning regimens and subsequently received a bone marrow transplantation. Mice that did not receive preconditioning prior to transplantation showed no chimerism in peripheral blood, bone marrow or spleen samples, indicating that preconditioning of mice is required for donor cell engraftment. A non-myeloablative conditioning regimen with cyclophosphamide and immunosuppressive CD4 and CD8 antibodies and the application of a mobilizing agent (Plerixafor) one hour before transplantation showed the highest chimerism in recipient mice. None of the mice developed a thymic tumor, and lymphoid-biased differentiation of the donor cells was observed, as chimerism was highest in T cells in the blood, bone marrow and spleen. In addition, chimerism was higher in lymphoid progenitor cells than in myeloid progenitors. Blood counts (white blood cell and lymphocyte counts) were normal 20 weeks after transplantation (comparable to wild-type mice), making this preconditioning regime suitable for Atm-deficient mice.
Taken together, this data paves the way for using split intein-based lentiviral vectors for Atm delivery in preclinical models and opens new possibilities for developing gene therapy for A-T patients.
Within the FAIR Phase-0 programm at GSI Helmholtzzentrum für Schwerionenforschung the Coulomb dissociation of 16O into 12C and 4He was measured. A 16O primary beam with an energy of 500 AMeV was impinging on lead, carbon, and tin targets at the R3B Cave C, and the fragments were detected. The beam intensity was set to several 10^9 ions per second, which made radical changes to the standard R3B setup necessary. All detectors were produced with holes or variable gaps, in order to let unreacted beam particles pass. New detectors were built to cope with the expected high number of particles that need to be detected. All detectors are based on the detection of scintillating light.
In the Coulomb field of the target atoms the 16O ions can experience an excitation, which may lead to a breakup reaction into lighter fragments. A calorimeter around the target helps with the identification of unwanted contributions to the cross-section from excited states. The fragments pass the first set of fiber detectors and are deflected in a dipole field. The reconstruction of the particle tracks is performed with Runge-Kutta algorithms. Ultimately, this enables the determination of the excitation energy in the center-of-mass of the excited 16O nucleus. The resulting spectrum describes the cross-section of the reaction.
By comparing the experimental data with simulated events new insights into the fusion reaction, as it takes place during the helium-burning phase in stars, is possible. The analysis of the experiment is still ongoing. However, the first results show, that this experiment can provide data in an energy range never measured before. This will help to understand the cross-section and the astrophysical S-factor of this reaction.
Um die muskarinische Modulation der GABAergen Übertragung zu untersuchen, wurden mit Hilfe der Patch- Clamp- Technik an akut isolierten IC Schnitten der Ratte (P4-P14) inhibitorische postsynaptische Ströme aufgezeichnet (IPSCs). Die Aufnahmen erfolgten bei einem Haltepotential von -60mV. In allen Experimenten konnte unter der Anwesenheit von Strychnin (0,5μM, Glycinrezeptor- Antagonist) und Kynurensäure (1mM; Glutamatrezeptoren- Antagonist) spontane GABAerge IPSCs in allen untersuchten IC-Neuronen aufgezeichnet werden. Die Anwesenheit von Kynurenat blockierte auch Ströme, die möglicherweise durch nAChRen mit der Untereinheit α7 vermittelt wurden.
Die Muskarin (1μM) Applikation zeigte, eine deutliche Erhöhung der IPSCs- Frequenz (618% der Kontrolle), was uns beweist, dass die Aktivierung von mAChRen im IC zu einer Steigerung der GABAergen Übertragung führt.
Die durch Muskarin induzierten IPSCs konnten komplett durch den GABAA- Rezeptor- Antagonisten Bicucullin (10μM und 50μM) blockiert werden. Dies zeigte, dass die IPSCS durch GABAA- Rezeptoren vermittelt wurden.
4-DAMP (50nM; M3-Rezeptor Antagonist) blockierte den durch Muskarin ausgelösten Anstieg der IPSC-Frequenz. Die Muscarin-Antagonisten Telenzepin (50nM; M1-präferierend), Methoctramin (10μM; bevorzugt M2) und Himbazin (10μM; bevorzugt M4) sowie der Nikotinrezeptor-Antagonist Mecamylamin (10μM) beeinflussten die Muskarinwirkung nicht signifikant.
Diese Ergebnisse deuten darauf hin, dass die muskarinische Modulation der GABAergen Übertragung hauptsächlich durch den M3-Rezeptor vermittelt wird, während M1-, M2- und M4- sowie Nikotinrezeptoren nicht wesentlich beteiligt sind.
In Gegenwart von Tetrodotoxin (0,5μM) konnte Muscarin die IPSC-Frequenz nicht erhöhen. Dies lässt auf eine über spannungsabhängige Natriumkanäle vermittelte erhöhte Transmitterausschüttung schließen. Zudem spricht dies für eine präterminale Modulation der GABAergen Transmission durch mAChRen.
Muskarin erhöhte die Häufigkeit der GABAergen IPSCs, ohne ihre Amplituden und Zerfallskinetik zu beeinflussen, was auf einen präsynaptischen Mechanismus hindeutet.
Muskarin veränderte den Membranruhestrom und die Leitfähigkeit in den untersuchten IC-Neuronen nicht.
Der Mechanismus der durch Muscarin induzierten Verstärkung der GABAergen Übertragung im IC muss noch abgeklärt werden.
Die Behandlung von akuten und chronischen Knocheninfektionen mit begleitender Weichteilinfektion besteht derzeit in einem radikalen chirurgischen Wunddebridement. Gute Ergebnisse konnten mit der kombinierten Unterdruck-Wundtherapie (NPWT) oder dem vakuumunterstützten Verschluss (VAC) erzielt werden. Zur Behandlung und Vorbeugung von Infektionen in der Chirurgie ist eine Kombination mit einer systemischen antimikrobiellen Behandlung erforderlich, die jedoch zahlreiche Nebenwirkungen mit sich bringt. Die lokale Antibiotikatherapie stellt einen neuen Ansatz zur Verringerung der Nebenwirkungen und zur Verbesserung der Heilung dar. Ziel dieser Studie ist es, die Wirksamkeit der kombinierten Verwendung von Fibrin mit Antibiotika im Vergleich zur Unterdruck-Wundtherapie als etablierte Behandlung von Weichteilinfektionen zu bewerten.
In dieser retrospektiven Studie wurden Patienten mit Weichteilinfektionen mit oder ohne Knochenbeteiligung, die sich einer chirurgischen Behandlung unterzogen, analysiert. Eine Gruppe bestand aus Patienten, die die neuartige Fibrin-Antibiotika-Sprühung (FAS) erhielten (n=62). Die Kontrollgruppe bestand aus Patienten, die mit der etablierten vakuumunterstützten Wundtherapie (VAWT) behandelt wurden (n=57). Hauptergebnisse waren Unterschiede im Heilungserfolg, in der Dauer bis zur Heilung und in der Anzahl der notwendigen Operationen.
In der FAS-Gruppe waren 55 Patienten (98,21%) nach der letzten Operation nicht mehr infiziert, in der VAWT-Gruppe war dies bei 47 Patienten (92,16%) der Fall (p = 0,19). Die Dauer bis zur klinischen Heilung ab der ersten Operation betrug in der FAS-Gruppe 10,65 +/- 10,38 Tage und in der VAWT-Gruppe 22,85 +/- 14,02 Tage (p < 0,001). In der FAS-Gruppe benötigten 41 Patienten eine Operation (66,13%) und 17 Patienten zwei Operationen (27,42%). Die Patienten der VAWT-Gruppe benötigen mindestens zwei (n=19; 33,34%), drei (n=19; 33,34%) oder mehr Operationen.
Im Vergleich zur vakuumunterstützten Wundtherapie bei Weichteilinfektionen zeigt Fibrin-Antibiotika-Spray bessere Ergebnisse. Die Heilung setzt schneller ein und es sind weniger Operationen erforderlich, was zu einer Verkürzung des Krankenhausaufenthalts, einem geringeren Narkoserisiko und einer höheren Patientenzufriedenheit führt. Die Kombination von Fibrin und Antibiotika kann als eine vielversprechende und wirksame Methode angesehen werden.
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 19 fb−1 collected with the BESIII detector at the BEPCII collider, we search for the production of deuterons and antideuterons via e+e−→ppπ−d¯+c.c. for the first time at center-of-mass energies between 4.13 and 4.70 GeV. No significant signal is observed and the upper limit of the e+e−→ppπ−d¯+c.c. cross section is determined to be from 9.0 to 145 fb depending on the center-of-mass energy at the 90% confidence level.
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 19 fb−1 collected with the BESIII detector at the BEPCII collider, we search for the production of deuterons and antideuterons via e+e−→ppπ−d¯+c.c. for the first time at center-of-mass energies between 4.13 and 4.70 GeV. No significant signal is observed and the upper limit of the e+e−→ppπ−d¯+c.c. cross section is determined to be from 9.0 to 145 fb depending on the center-of-mass energy at the 90% confidence level.
Generation of an efficient agent-based framework for the simulation of 3D multicellular systems
(2024)
In developmental biology, the focus has shifted from mainly considering genetic and molecular aspects to considering mechanical aspects, as it has become evident in recent years that mechanical forces, tensions, and physical interactions play a significant role alongside molecular mechanisms in developmental biology. Computational models provide a useful tool for the investigation of the complex cell choreography in tissue and organ development. In particular, they allow the identification of principles governing complex behaviours and greatly contribute to understanding self-organising systems. Agent-based models act as a ”virtual laboratory”, facilitating the formulation and testing of biological hypotheses.
In this work, a mathematical model is formulated to describe the dynamics and interactions of multicellular systems. This model formulation results in a large system of coupled stochastic differential equations. Furthermore, a simulation framework is introduced to solve the system of coupled stochastic differential equations numerically. In particular, mechanical processes such as cell-cell interactions, cell growth and division, cell polarity, and active migration are considered. Firstly, a CPU-based version of the simulation framework, implemented in Python and MATLAB, is presented. This version also provides scientists with limited programming experience the abil- ity to simulate systems involving several thousand cells. Additionally, a GPU-based framework version, implemented in CUDA and C++, is introduced. This version primarily targets modellers with advanced programming knowledge. It significantly reduces simulation runtime, allows for the simulation of very large systems, and incorporates additional extensions.
The implemented CPU-based simulation framework was applied to two different biological systems. The first application concerned inner cell mass organoids (ICM organoids), which serve as an experimental model system to study early embryogenesis. In particular, ICM organoids reflect the second cell fate decision, i.e., the differentiation into embryonic tissue and yolk sac, as well as subsequent cell sorting. Using the presented simulation framework, it was demonstrated that the experimentally observed local clustering of cell types can be attributed to mechanical processes, specifically cell growth, cell division, and cell fate inheritance. These results provide evidence that molecular cell fate determination occurs within a short period during the early development of ICM organoids, and that mechanical processes and interactions predominantly characterise subsequent processes. Furthermore, it was shown that differential adhesion and undirected cell movement in a three-dimensional system are sufficient to drive the segregation of different cell types.
The second biological application focused on pancreas-derived organoids, which simulate organ development, in this case, pancreas development. These organoids exhibit high variability in their qualitative behaviour, including volume oscillations, rotation and migration, fusions, and the formation of internal structures. The presented simulation framework was applied to the volume oscillations of the organoids. It was demonstrated that these oscillations depend significantly on the cell division dynamics and size of the organoids, as well as the elasticity and adhesion strength of the cells.
Both biological applications of the framework illustrate its modular structure and, thus, its adaptability to various biological systems. They also emphasise that mechanical processes play a fundamental role in the self-organisation of complex systems. The presented framework en- ables the efficient modelling of multicellular systems and serves as an effective tool for explaining complex behaviour by coupling simple underlying mechanisms.
Using a sample of (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector, we perform the first partial wave analysis of ψ(3686)→K+K−η. In addition to the well established states, ϕ(1020), ϕ(1680), and K∗3(1780), contributions from X(1750), ρ(2150), ρ3(2250), and K∗2(1980) are also observed. The X(1750) state is determined to be a 1−− resonance. The simultaneous observation of the ϕ(1680) and X(1750) indicates that the X(1750), with previous observations in photoproduction, is distinct from the ϕ(1680). The masses, widths, branching fractions of ψ(3686)→K+K−η and the intermediate resonances are also measured.
We measured the branching fractions of the decays χcJ→Σ−Σ¯+ for the first time using the final states nn¯π+π−. The data sample exploited here is 448.1×106 ψ(3686) events collected with BESIII. We find B(χcJ→Σ−Σ¯+)=(51.3±2.4±4.1)×10−5,(5.7±1.4±0.6)×10−5,and (4.4±1.7±0.5)×10−5, for J=0,1,2, respectively, where the first uncertainties are statistical and the second systematic.
The decays J/ψ→ηΣ+Σ¯− and ψ(3686)→ηΣ+Σ¯− are observed for the first time, using (10087±44)×106 J/ψ and (448.1±2.9)×106 ψ(3686) events collected with the BESIII detector at the BEPCII collider. We determine the branching fractions of these two decays to be B(J/ψ→ηΣ+Σ¯−)=(6.34±0.21±0.37)×10−5 and B(ψ(3686)→ηΣ+Σ¯−)=(9.59±2.37±0.61)×10−6, where the first uncertainties are statistical and the second are systematic. The ratio of these two branching fractions is determined to be B(ψ(3686)→ηΣ+Σ¯−)B(J/ψ→ηΣ+Σ¯−)=(15.1±3.8)%, which is in agreement with the "12\% rule."
Utilizing the dataset corresponding to an integrated luminosity of 2.93 fb−1 at s√=3.773 GeV collected by the BESIII detector, we report the first amplitude analysis and branching fraction measurement of the D0→K−π+π0π0 decay. We investigate the sub-structures and determine the relative fractions and the phases among the different intermediate processes. Our results are used to provide an accurate detection efficiency and allow measurement of B(D0→K−π+π0π0)=(8.86±0.13(stat)±0.19(syst))%.
By analyzing an e+e− annihilation data sample with an integrated luminosity of 2.93 fb−1 taken at the center-of-mass energy of 3.773 GeV with the BESIII detector, we determine the absolute branching fractions of the hadronic decays D0→K−π+ω, D0→K0Sπ0ω, and D+→K0Sπ+ω to be (3.392±0.044stat±0.085syst)%, (0.848±0.046stat±0.031syst)%, and (0.707±0.041stat±0.029syst)%, respectively. The accuracy of the branching fraction measurement of the decay D0→K−π+ω is improved by a factor of seven compared to the world average value. The D0→K0Sπ0ω and D+→K0Sπ+ω decays are observed for the first time.
Measurement of e⁺e⁻ → π⁺π⁻D⁺D⁻ cross sections at center-of-mass energies from 4.190 to 4.946 GeV
(2022)
Using data samples collected with the BESIII detector operating at the BEPCII storage ring, we measure the cross sections of the e+e−→π+π−D+D− process at center-of-mass energies from 4.190 to 4.946 GeV with a partial reconstruction method. Two resonance structures are seen and the resonance parameters are determined from a fit to the cross section line shape. The first resonance we observe has a mass of (4373.1 ± 4.0 ± 2.2) MeV/c2 and a width of (146.5 ± 7.4 ± 1.3) MeV, in agreement with those of the Y(4390) state; the other resonance has a mass of (4706 ± 11 ± 4) MeV/c2, a width of (45 ± 28 ± 9) MeV, and a statistical significance of 4.1 standard deviations (σ). This is the first evidence for a vector state at this mass value. The spin-3 D-wave charmonium state X(3842) is searched for through the e+e−→π+π−X(3842)→π+π−D+D− process, and evidence with a significance of 4.2σ is found in the data samples with center-of-mass energies from 4.600 to 4.700 GeV.
Measurement of e⁺e⁻ → π⁺π⁻D⁺D⁻ cross sections at center-of-mass energies from 4.190 to 4.946 GeV
(2022)
Using data samples collected with the BESIII detector operating at the BEPCII storage ring, we measure the cross sections of the e+e−→π+π−D+D− process at center-of-mass energies from 4.190 to 4.946 GeV with a partial reconstruction method. Two resonance structures are seen and the resonance parameters are determined from a fit to the cross section line shape. The first resonance we observe has a mass of (4373.1 ± 4.0 ± 2.2) MeV/c2 and a width of (146.5 ± 7.4 ± 1.3) MeV, in agreement with those of the Y(4390) state; the other resonance has a mass of (4706 ± 11 ± 4) MeV/c2, a width of (45 ± 28 ± 9) MeV, and a statistical significance of 4.1 standard deviations (σ). This is the first evidence for a vector state at this mass value. The spin-3 D-wave charmonium state X(3842) is searched for through the e+e−→π+π−X(3842)→π+π−D+D− process, and evidence with a significance of 4.2σ is found in the data samples with center-of-mass energies from 4.600 to 4.700 GeV.
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Im Rahmen des BMBF-finanzierten Projekts „NaMoLi 2“ fand 2023 die dritte Befragungswelle der Bewohnenden der Lincoln-Siedlung in Darmstadt statt. Sie zeichnet sich durch die zusätzlich durchgeführte Befragung einer Vergleichsgruppe aus. Diese besteht aus Personen, die innerhalb der letzten sechs Jahre in einen anderen innenstadtnahen Darmstädter Stadtteil gezogen sind. Folglich erlaubt das Design die längsschnittartige Analyse von Veränderungen im Mobilitätsverhalten von Bewohnenden der Lincoln-Siedlung, als auch den Vergleich mit der Mobilität von Bewohnenden konventioneller Stadtviertel. Im Rahmen der Befragung in Lincoln wurden 2.114 Fragebögen verteilt und im Rahmen der Vergleichsgruppe 2.649 postalisch versendet. Aus der Lincoln-Siedlung wurden n = 293 gültige Rücksendungen erhalten, was einer Rücklaufquote von 13,9 % entspricht. Der Rücklauf der Vergleichsbefragung belief sich auf n = 659 gültige Fragebögen mit einer Rücklaufquote von 24,9 %.
Dieser Bericht stellt die Methodik der dritten Befragungswelle dar. Dazu wird zunächst das Panel-Design der Erhebung in Lincoln dargestellt, mit dem die Befragung an bisher in der Siedlung durchgeführte Erhebungen anschließt. Anschließend werden die Gemeinsamkeiten und Unterschiede zwischen dem in Lincoln verwendeten Fragebogen und jenem zur Erhebung in der Vergleichsgruppe erläutert. Es folgen die Darstellung des Vorgehens bei der Verteilung bzw. Versendung der Fragebögen in beiden Befragungsgruppen. Anschließend wird der Umgang mit dem Rücklauf dargestellt, bevor soziodemographische Parameter beider Stichproben auf Repräsentativität geprüft werden.
The study of animal behavior is essential for gaining a better understanding of the behavior, patterns, and needs of animals. A better understanding not only serves scientific progress, but also plays an important role in improving husbandry conditions in zoos, which can help to improve animal welfare (Berger, 2010; Brando and Buchanan-Smith, 2018; Walsh et al., 2019; Rose and Riley, 2021).
The behavior of large herbivores differs significantly between day and night, and most ungulates are diurnal or crepuscular (Bennie et al., 2014; Gravett et al., 2017; Davimes et al., 2018; Wu et al., 2018). In contrast, many studies examine animal behavior during the day, and unfortunately there is little information on nocturnal behavior, including sleep behavior (Berger, 2010; Rose and Robert, 2013). However, sleep behavior, especially the proportion of REM sleep, is of great importance for the well-being of an individual (Hänninen et al., 2008; Fukasawa et al., 2018; Northeast et al., 2020).
To gain more insight into the behavior of ungulates in general, studies based on large samples of different species with a long recording period are useful. This is difficult to achieve with manual data analysis, as data collection and analysis in behavioral biology is time consuming and costly. Therefore, modern methods such as automated analysis are helpful in the field of behavioral biology (Norouzzadeh et al., 2018; Beery et al., 2020; Lürig et al., 2021).
Hence, the development of a software tool for the automated assessment of nocturnal behavior of ungulates in zoos is part of this dissertation. The resulting software tool is called BOVIDS (Behavioral Observations by Videos and Images using Deep-Learning Software) and allows the automatic evaluation of video material in three steps. In the first step, object detection, the individuals on the images are recognized and cut out in order to classify the behavior in the following step, action classification. In the final step, post-processing, errors of the automated analysis are corrected and the data is prepared for further use (Hahn-Klimroth et al., 2021; Gübert et al., 2022). To create such a system, it must first be trained. Typically, two nights per individual were manually annotated, resulting in a total of 594 manually annotated nights. In addition, 224,922 images were used to evaluate whether the system was already correctly recognizing the animals' behavior. Bounding boxes were either manually drawn or evaluated on a total of 201,827 images to train the object detection network.
The software package BOVIDS was used to analyze data from a total of 196 individuals from 19 different ungulate species over a period of 101,629 hours of video material from 9,239 nights. A night is defined as the period from 7 pm to 6 am. The species studied belong to the two orders of odd-toed ungulates (Perissodactyla) and even-toed ungulates (Artiodactyla). The focus is on the behavioral categories of standing, moving, lying – head up, and lying – head down, the latter corresponding to the typical REM sleep position of ungulates. Based on the analyzed data, several biological questions were discussed in this thesis. In addition to the activity budgets and rhythms underlying the night, factors influencing behavior are also investigated. In addition, the enclosure use by the animals is evaluated.
Zebras as representatives of the Perissodactyla spend about 25% of the night lying, while the average for the Artiodactyla studied is 77%. All species studied spend an average of 8.8% of the night in REM sleep (Gübert et al., 2023a), with a typical REM sleep phase lasting between 2.2 and 7.6 minutes (Gübert et al., 2023b). Only 0.7% of time during the night is spent with movement by the animals (Gübert and Dierkes). While the number of lying phases within the Artiodactyla is very constant with an average of five phases, the number of phases in the REM sleep position varies. Age, average species size and taxonomy were found to be influencing factors (Gübert et al., 2023a). With regard to rhythmicity, it is striking that most of the species studied show an increase in lying during the night and that a strong rhythmicity of behavior can be observed. The time between two lying events is very constant and is about two hours for most animals (Gübert et al., 2023b). With regard to enclosure use, it is striking that only a small part of the enclosure is used regularly. All individuals prefer to lie down on the bedding and most individuals prefer one or two different resting places (Gübert and Dierkes).
The data created as part of this thesis can contribute to a better overall understanding of ungulate behavior. The newly developed software package BOVIDS makes it relatively easy to analyze further data on this topic. Long-term studies can now be carried out more cost-effectively, making it easier to answer many questions in the future, such as investigating other influencing factors or responses to changes in husbandry conditions.
SAFE Update September 2024
(2024)
Introduction: Multimorbidity is the simultaneous occurrence of several (chronic) diseases. Persons living with multimorbidity not only have complex care needs, but the burden of care often has a negative impact on their family lives, leisure time and professional activities. The aim of this project is to systematically review the literature to assess how multimorbidity affects the everyday lives of middle-aged persons, and to find out what abilities and resources help in the development of coping strategies to overcome the challenges of living with it.
Methods and analysis: We will systematically search for studies reporting on the everyday life experiences of middle-aged persons (30–60 years) with multimorbidity (≥2 chronic conditions) in MEDLINE, CINAHL, PsycINFO, Social Sciences Citation Index, Social Sciences Citation Index Expanded, PSYNDEX and The Cochrane Library from inception. We will include all primary studies that use quantitative, qualitative and mixed methodologies, irrespective of publication date/study setting.
Two independent reviewers will screen titles/abstracts/full texts, extract data from the selected studies and present evidence in terms of study/population characteristics, data collection method and the phenomenon of interest, that is, everyday life experiences of middle-aged persons with multimorbidity. Risk of bias will be independently assessed by two reviewers using the Mixed Methods Appraisal Tool. We will use a convergent integrated approach on qualitative/quantitative studies, whereby information will be synthesised narratively and, if possible, quantitatively.
Ethics and dissemination: Ethical approval is not required due to the nature of the proposed systematic review. Results from this research will be disseminated at relevant (inter)national conferences and via publication in peer-reviewed journals.
Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH.
Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools.
Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5–18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins.
Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.
KRAS is one of the most commonly mutated oncogenes in cancer, enabling tumor proliferation and maintenance. After various approaches to target KRAS have failed over the past decades, the first specific inhibitor of the p.G12C mutation of KRAS was recently approved by the FDA after showing promising results in adenocarcinomas of the lung and other solid tumors. Lung cancer, the most common cancer worldwide, is a promising use case for these new therapies, as adenocarcinomas in particular frequently harbor KRAS mutations. However, in squamous cell carcinoma (SCC) of the lung, KRAS mutations are rare and their impact on clinical outcome is poorly understood. In this review, we discuss the current knowledge on the prevalence and prognostic and predictive significance of KRAS mutations in the context of SCC.
The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.
Einleitung: Der Abgrenzung zwischen Totgeburt und Fehlgeburt kommt eine erhebliche Bedeutung für die ärztliche Praxis zu: Nur die Totgeburt gilt als Leiche und benötigt demzufolge eine ärztliche Leichenschau. Die Pflicht zur ärztlichen Leichenschau vor der Bestattung eines Verstorbenen ist in Deutschland in den jeweiligen „Bestattungsgesetzen“ der 16 Bundesländer und ggf. ergänzenden Verordnungen geregelt. Nach dem Grundgesetz der Bundesrepublik Deutschland (GG) liegt die Gesetzgebungsbefugnis für Todesfeststellung und Leichenschau bei den Ländern, während das Personenstandswesen in die Legitimation der Bundesgesetzgebung fällt. Die vorliegende Arbeit sollte dazu beitragen, vor dem Hintergrund der komplizierten Gefüge von Landes- und Bundesgesetzgebung sowie der Änderung des § 31 PStV vom 01.11.2018 Rechtssicherheit in der Abgrenzung von Totgeburt und Fehlgeburt für Ärztinnen und Ärzte im Rahmen der Leichenschau sowie bei der Obduktion von verstorbenen Schwangeren und Feten zu schaffen.
Material und Methoden: Alle relevanten Landesgesetze und Bundesgesetze sowie einschlägige juristische Kommentare wurden analysiert. Abfragen bezüglich der Erfordernisse bei der Meldung einer Totgeburt wurden bei Standesämtern durchgeführt, die diese Informationen online zur Verfügung gestellt hatten. Abschließend wurden die auf der aktuellen Gesetzeslage basierenden Erkenntnisse auf einen Fall vor dem Jahr 2018 hypothetisch angewandt.
Ergebnisse: In 12 der 16 Ländergesetze wird das Totgeborene – in Abgrenzung zur Fehlgeburt – nur über das Geburtsgewicht von mindestens 500 g definiert. In Hessen, Bremen und im Saarland wird zusätzlich als alternatives Kriterium die 24. Schwangerschaftswoche (SSW) genannt.
Es wurden 15 Standesämter in vier Bundesländern ermittelt. Davon forderten 10 bei Meldung einer Totgeburt die Vorlage einer ärztlichen Todesbescheinigung, dagegen 4 nicht. 14 Standesämter werteten die Totgeburt als Geburtsfall, eines gab keine Informationen dazu. 5 Standesämter werteten eine Totgeburt nicht als Sterbefall, 6 hingegen schon, und 4 stellten keine Informationen dazu zur Verfügung. 7 Standesämter gaben die aktuelle Definition einer Totgeburt an, wohingegen 5 lediglich die veraltete Definition zugrunde legten, und 3 keine Informationen diesbezüglich bereitstellten.
Diskussion: Nach den vorliegenden Ergebnissen lässt sich eine von den „Bestattungsgesetzen“ der Länder unabhängige Leichenschaupflicht für tote Leibesfrüchte ableiten, für die bezüglich der Leichendefinition die Kriterien des Personenstandsrechts gelten müssten. Demnach wäre in allen Bundesländern, unabhängig von den Kriterien in den jeweiligen „Bestattungsgesetzen“, zur Differenzierung zwischen Totgeburt und Fehlgeburt das alternative Merkmal „Erreichen der 24. SSW“ zu überprüfen, falls die tote Leibesfrucht, die keine Zeichen des Gelebthabens außerhalb des Mutterleibs aufweist, unter 500 g wiegt.
Obwohl die Abfrage bei den Standesämtern nicht als repräsentativ zu bezeichnen ist, waren dennoch die verschiedenen Vorgehensweisen unter den 15 ausgewerteten Standesämtern keine Einzelphänomene. Demzufolge erscheint zumindest die Feststellung der erheblichen Heterogenität von Standesämtern im Umgang mit Totgeburten gerechtfertigt.
Die Ausgangsfrage bei dem Fallbericht war, ob es sich bei einer aus dem Leichnam der Mutter im Rahmen einer Obduktion geborgenen toten Leibesfrucht um einen Leichnam handelt oder nicht. Es wurde damals entschieden, gemäß den gültigen Fassungen des § 31 PStV und des hessischen Friedhofs- und Bestattungsgesetzes (FBG HE), aufgrund des Unterschreitens der Gewichtsgrenze von 500 g von einer Fehlgeburt auszugehen, mit allen rechtlichen Konsequenzen. Nach der aktuellen Version des § 31 PStV wäre das Alternativkriterium „Erreichen der 24. SSW“ anwendbar gewesen.
SEDDS-loaded mucoadhesive fiber patches for advanced oromucosal delivery of poorly soluble drugs
(2022)
To date, buccal administration of lipophilic drugs is still a major challenge due to their poor solubility in saliva and limited penetration into mucosal tissues. To overcome these limitations, we developed electrospun patches combining the benefits of mucoadhesive fibers and self-emulsifying drug delivery systems (SEDDS).
The fiber system comprises a combination of mucoadhesive thiolated polyacrylic acid fibers and SEDDS-loaded fibers fabricated by parallel electrospinning. The resulting mucoadhesive electrospun SEDDS patches were systemically investigated for fiber characteristics, self-emulsification, mucoadhesion, drug penetration into porcine buccal tissue and biocompatibility.
The patches showed high encapsulation efficiency for SEDDS without causing fiber defects or leakage. SEDDS incorporation enhanced the spinning process and reduced the fiber diameter and fiber size distribution. Hydration-dependent self-emulsification provided a controlled release of curcumin being encapsulated in nano-scaled o/w emulsion for over 3 h. Due to the thiolated polyacrylic acid fibers, the buccal residence time of patches was 200-fold prolonged. Further, they promoted a significantly increased drug penetration into buccal tissue compared to fiber patches without SEDDS. Finally, biocompatibility and improved therapeutic effects of curcumin-loaded patches on human keratinocytes and fibroblasts were confirmed.
Mucoadhesive electrospun SEDDS patches represent a promising approach to overcome current challenges in the oromucosal delivery of lipophilic drugs to unlock their full therapeutic potential.
Highlights
• Self-emulsifying drug delivery systems (SEDDS) were electrospun into polymer fibers patches for oromucosal drug delivery.
• High loading capacity of the fibers with SEDDS was shown (up to 50% of polymer weight).
• 200-fold prolonged buccal patch residence time was achieved by parallel electrospinning of polyacrylic acid thiomer fibers.
• SEDDS-loaded fibers ensured prolonged release of curcumin and led to 1200-fold increase in aqueous solubility.
• In contrast to conventional fiber patches, SEDDS-loaded mucoadhesive fibers enabled deep mucosal penetration of curcumin.
Patienten/Innen (Pat.) mit Periventrikulärer Nodulärer Heterotopie (PNH) leiden häufig an pharmakoresistenter Epilepsie. Zur Identifizierung epileptogener Strukturen werden in der Forschung verschiedene Parameter als Marker für Epiletogenität untersucht. Der mittels Magnetenzephalographie (MEG) ermittelte Delta-Power-Wert ist nach der Literatur mit ischämischen und strukturellen Hirnläsionen, sowie mit wiederkehrenden epileptischen Anfällen assoziiert. Diese Studie untersuchte die Aussagekraft von durch Sensordatenanalyse ermittelte Delta-Power-Werte bei PNH Pat.. Dazu wurde eine Kohorte von 16 PNH Pat. und 16 nach Alter und Geschlecht gematchten Kontrollen mittels MEG, Magnetresonanztomographie (MRT) und neuropsychologischer Testung untersucht. Es wurden mögliche Unterschiede der Delta-Power-Werte zwischen an PNH erkrankten Epilepsiepatienten/innen und gesunden Kontrollen untersucht. Zudem wurde der Zusammenhang der Delta-Power-Werte einerseits mit Lokalisation und Volumen der Heterotopien und andererseits mit den neuropsychologischen Fähigkeiten (visuomotorischen Verarbeitungsgeschwindigkeit und exekutiven Funktion) untersucht.
Die Untersuchungen zeigten, dass das die Delta-Power-Werte sowohl global als auch lokal keine Aussagekraft über Lokalisation, Volumen oder Epileptogenität der PNHs hatten. Die exekutive Funktion und visuomotorische Verarbeitungsgeschwindigkeit waren bei den PNH Pat. signifikant schlechter als bei den gematchten Kontrollen. Zusammenfassend deuten diese Untersuchungen daraufhin, dass weder Delta-Power-Werte an sich oder Delta-Power-Werte im Sensorraum einen diagnostischen Wert bei PNH Pat. hatten. Die neuropsychologischen Tests hingegen zeigen Unterschiede der Gruppen auf und könnten daher als diagnostisches Kriterium betrachtet werden. Um feststellen zu können, ob Delta-Power-Werte an sich, oder aber Sensordaten nicht aussagekräftig in der Diagnostik von PNHs sind, müssten die MEG-Daten erneut mit veränderter Untersuchungsmethode (Quelldatenanalyse statt Sensordatenanlayse) untersucht werden.
We introduce a platform for the fabrication of customizable wound healing dressing. The platform integrates electrospun nanofibers, bioprinted hydrogels, and cellular spheroids into hierarchical, fiber-reinforced hybrid constructs. The construct leverages the mechanical strength of polycaprolactone (PCL) nanofibers and the ECM-like properties of GelMA/PEGDA hydrogel. These materials support the incorporation of bone marrow-derived mesenchymal stem cell (BM-hMSC) spheroids, which act as a supportive “cell niche,” enhancing the viability of the hMSC during and after bioprinting, and facilitating their spreading across the construct during the maturation phase. The characterization of the hybrid constructs demonstrated strong structural integrity and enhanced mechanical properties, making them well-suited for clinical wound dressing applications. In vitro assays, including live/dead staining, MTT assays, and scratch assays, revealed increased cell attachment, proliferation, and migration. The spheroids maintained their viability over extended periods, significantly contributing to wound closure in the scratch assay. This innovative approach, which combines electrospinning and light-based bioprinting, offers a promising strategy for the development of customizable wound dressings that closely adapt to the complex architecture of human skin. The bioprinting approach allows for the creation of tailored geometries for specific clinical requirements. Future research will focus on optimizing scaffold design and conducting long-term in vivo studies to validate the platform’s clinical potential.
In integrative structural biology/hybrid modeling approaches, we integrate structural models of macromolecules and experimental data to obtain faithful representations of the structures underlying the data. For example, in ensemble refinement by reweighting we first generate structural ensembles of flexible and dynamic biological macromolecules in molecular simulations. In a subsequent reweighting step, we refine the statistical weights of the structures to strike a balance between the information provided by simulations and by experimental data. For the "Bayesian inference of ensembles" approach (BioEn), we present two complementary methods to solve the underlying challenging high-dimensional optimization problem. We systematically investigate reliability, accuracy, and efficiency of these methods and integrate molecular dynamics simulations of the disordered peptide Ala-5 and NMR J-couplings. We provide an open-source library free of charge at https://github.com/bio-phys/BioEn.
In integrative structural biology/hybrid modeling approaches, we integrate structural models of macromolecules and experimental data to obtain faithful representations of the structures underlying the data. For example, in ensemble refinement by reweighting we first generate structural ensembles of flexible and dynamic biological macromolecules in molecular simulations. In a subsequent reweighting step, we refine the statistical weights of the structures to strike a balance between the information provided by simulations and by experimental data. For the "Bayesian inference of ensembles" approach (BioEn), we present two complementary methods to solve the underlying challenging high-dimensional optimization problem. We systematically investigate reliability, accuracy, and efficiency of these methods and integrate molecular dynamics simulations of the disordered peptide Ala-5 and NMR J-couplings. We provide an open-source library free of charge at https://github.com/bio-phys/BioEn.
Ensemble refinement produces structural ensembles of flexible and dynamic biomolecules by integrating experimental data and molecular simulations. Here we present two efficient numerical methods to solve the computationally challenging maximum-entropy problem arising from a Bayesian formulation of ensemble refinement. Recasting the resulting constrained weight optimization problem into an unconstrained form enables the use of gradient-based algorithms. In two complementary formulations that differ in their dimensionality, we optimize either the log-weights directly or the generalized forces appearing in the explicit analytical form of the solution. We first demonstrate the robustness, accuracy, and efficiency of the two methods using synthetic data. We then use NMR J-couplings to reweight an all-atom molecular dynamics simulation ensemble of the disordered peptide Ala-5 simulated with the AMBER99SB*-ildn-q force field. After reweighting, we find a consistent increase in the population of the polyproline-II conformations and a decrease of α-helical-like conformations. Ensemble refinement makes it possible to infer detailed structural models for biomolecules exhibiting significant dynamics, such as intrinsically disordered proteins, by combining input from experiment and simulation in a balanced manner.
Neuroendocrine neoplasms of the lung account for approximately 20% of all primary lung tumors. The most frequent entity within this group, as well as the most lethal, is small cell lung cancer (SCLC) occurring in around 15% of the cases. For this particular entity, though there have been several breakthroughs in recent years, overall understanding remains insufficient, especially when it comes to new, personalized therapeutic options. The lack of fresh tissue samples is most certainly one of the limiting factors for research. The goal of this study was to utilize archival formalin-fixed paraffin-embedded (FFPE) samples of SCLC and, more precisely, to establish and implement an efficient technique for single-cell isolation of substantial quantity and quality for translational cancer research. To establish this technique representative artificial samples and real-life samples have been carefully chosen. To generate single-cell suspensions, two different methods were suggested by current literature based on mechanical disruption (incellPREP by CellSee) and a combination of enzymatic and mechanical disruption (Miltenyi). The feasibility of these two methods was pre-evaluated by subsequent analytics such us Cytospin-PAP staining and flow cytometry to refine the protocol and apply a final selection of samples for 3′ MACE (massive analysis of cDNA ends) RNA-sequencing (GenXPro). By this, pre-analytical quality and secondary analytical output could be evaluated and implemented as a first standard guideline within the Dr. Senckenberg Institute of Pathology for ongoing projects when using archival FFPE samples. To summarize, FFPE samples are an underestimated and rarely used material for single-cell sequencing studies. Therefore, their utilization opens a possibility to apply this technique to different tumor types, especially when fresh or fresh frozen tissue samples are not available. Conducting the proper analysis of data could lead to a deeper understanding of cancer biology and to find new therapeutic vulnerabilities.
Measurement of e⁺e⁻ → ϕη′ cross sections at center-of-mass energies
between 3.508 and 4.600 GeV
(2023)
We present a measurement of the dressed cross sections for e+e−→ϕη′ at different center-of-mass energies between 3.508 and 4.600 GeV based on 15.1 fb−1 of e+e− annihilation data collected with the BESIII detector operating at the BEPCII collider. In addition, a search for the decay Y(4230)→ϕη′ is performed. No clear signal is observed and the corresponding upper limit is provided.
Cross sections for the process e+e−→K0SK0SJ/ψ at center-of-mass energies from 4.128 to 4.950 GeV are measured using data samples with a total integrated luminosity of 21.2 fb−1 collected by the BESIII detector operating at the BEPCII storage ring. The Y(4230) state is observed in the energy dependence of the e+e−→K0SK0SJ/ψ cross section for the first time with a statistical significance of 26.0σ. In addition, an enhancement around 4.710 GeV, called the Y(4710), is seen with a statistical significance of 4.2σ. There is no clear structure around 4.484 GeV. Using a fit with a coherent sum of three Breit-Wigner functions, we determine the mass and width of the Y(4230) state to be 4226.9±6.6±21.9 MeV/c2 and 71.7±16.2±31.4 MeV, respectively, and the mass and width of the Y(4710) state to be 4704.0±52.3±69.5 MeV/c2 and 183.2±114.0±90.8 MeV, respectively, where the first uncertainties are statistical and the second are systematic. In addition, the average Born cross section ratio of e+e−→K0SK0SJ/ψ to e+e−→K+K−J/ψ is measured to be 0.388+0.035−0.028±0.016, or 0.426+0.038−0.031±0.018 if three-body phase space is considered.
Cross sections for the process e+e−→K0SK0SJ/ψ at center-of-mass energies from 4.128 to 4.950 GeV are measured using data samples with a total integrated luminosity of 21.2 fb−1 collected by the BESIII detector operating at the BEPCII storage ring. The Y(4230) state is observed in the energy dependence of the e+e−→K0SK0SJ/ψ cross section for the first time with a statistical significance of 26.0σ. In addition, an enhancement around 4.710~GeV, called the Y(4710), is seen with a statistical significance of 4.2σ. There is no clear structure around 4.484 GeV. Using a fit with a coherent sum of three Breit-Wigner functions, we determine the mass and width of the Y(4230) state to be 4226.9±6.6±21.9 MeV/c2 and 71.7±16.2±31.4 MeV, respectively, and the mass and width of the Y(4710) state to be 4704.0±52.3±69.5 MeV/c2 and 183.2±114.0±90.8 MeV, respectively, where the first uncertainties are statistical and the second are systematic. In addition, the average Born cross section ratio of e+e−→K0SK0SJ/ψ to e+e−→K+K−J/ψ is measured to be 0.415+0.032−0.026±0.017, or 0.449+0.034−0.028±0.019 if three-body phase space is considered.
We report on an analysis of the decay J/ψ→γπ0η′ using a sample of (1310.6±7.0)× 106 J/ψ events collected with the BESIII detector. We search for the CP-violating process ηc→π0η′ and a dark gauge boson U′ in J/ψ→U′η′, U′→γπ0, π0→γγ. No evidence of an ηc signal is observed in the π0η′ invariant-mass spectrum and the upper limit of the branching fraction is determined to be 7.2× 10−5 at the 90\% confidence level. We also find no evidence of U′ production and set upper limits at the 90\% confidence level on the product branching fraction B(J/ψ→U′η′)×B(U′→π0γ) in the range between (0.8−6.5)×10−7 for 0.2 ≤mU′≤2.1GeV/c2. In addition, we study the process J/ψ→ωη′ with ω→γπ0. The branching fraction of J/ψ→ωη′ is found to be (1.87±0.09±0.12)×10−4, where the first uncertainty is statistical and the second is systematic, with a precision that is improved by a factor of 1.4 over the previously published BESIII measurement.
We perform for the first time an amplitude analysis of the decay D+→K0Sπ+η and report the observation of the decay D+→K0Sa0(980)+ using 2.93 fb−1 of e+e− collision data taken at a center-of-mass energy of 3.773 GeV with the BESIII detector. As the only W-annihilation free decay among D to a0(980)-pseudoscalar, D+→K0Sa0(980)+ is the ideal decay to extract the contributions of the external and internal W-emission amplitudes involving a0(980) and study the final-state interactions. The absolute branching fraction of D+→K0Sπ+η is measured to be (1.27±0.04stat.±0.03syst.)%. The product branching fractions of D+→K0Sa0(980)+ with a0(980)+→π+η and D+→π+K∗0(1430)0 with K∗0(1430)0→K0Sη are measured to be (1.33±0.05stat.±0.04syst.)% and (0.14±0.03stat.±0.01syst.)%, respectively.
Measurement of the e⁺e⁻ → ωπ⁰π⁰ cross section at center-of-mass energies from 2.0 to 3.08 GeV
(2022)
The cross section of the process e+e−→ωπ0π0 is measured at nineteen center-of-mass energies from 2.0 to 3.08 GeV using data collected with the BESIII detector at the BEPCII storage ring. A resonant structure around 2.20 GeV is observed with statistical significance larger than 5σ. Using a coherent fit to the cross section line shape, the mass and width are determined to be M=2222±7±2 MeV/c2 and Γ=59±30±6 MeV, respectively, where the first uncertainties are statistical and the second ones are systematic.
By analyzing 4.48×108 ψ(3686) events collected with the BESIII detector, we observe the decays χcJ→nK0SΛ¯+c.c. (J=0, 1, 2) for the first time, via the radiative transition ψ(3686)→γχcJ. The branching fractions are determined to be (6.67±0.26stat±0.41syst)×10−4, (1.71±0.12stat±0.12syst)×10−4, and (3.66±0.17stat±0.23syst)×10−4 for J=0, 1, and 2, respectively.
By analyzing 4.48×108 ψ(3686) events collected with the BESIII detector, we observe the decays χcJ→nK0SΛ¯+c.c. (J=0, 1, 2) for the first time, via the radiative transition ψ(3686)→γχcJ. The branching fractions are determined to be (6.67±0.26stat±0.41syst)×10−4, (1.71±0.12stat±0.12syst)×10−4, and (3.66±0.17stat±0.23syst)×10−4 for J=0, 1, and 2, respectively.
Using a data sample of ψ(3770) events collected with the BESIII detector at BEPCII corresponding to an integrated luminosity of 2.9 fb−1, we report a measurement of Λ spin polarization in e+e−→ΛΛ¯ at s√=3.773 GeV. The significance of polarization is found to be 2σ including the systematic uncertainty, which implies a zero phase between the transition amplitudes of the ΛΛ¯ helicity states. This phase can be interpreted in terms of psionic form factors, and is determined to be ΔΦΨ = ΦΨE−ΦΨM = (71+66−46 ± 5)∘. Similarly, the ratio between the form factors is found to be Rψ = |GΨE/GΨM| = 0.48+0.12−0.07 ± 0.04. The first uncertainties are statistical and the second systematic.
Objective: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA).
Methods: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16.
Results: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment.
Conclusions: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA.