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Where Does the Proton Go? Structure and Dynamics of Hydrogen‐Bond Switching in Aminophosphine Chalcogenides
No full textAminophosphates are the focus of research on prebiotic phosphorylation chemistry. Their bifunctional nature also makes them a powerful class of organocatalysts. However, the structural chemistry and dynamics of proton-binding in phosphorylation and organocatalytic mechanisms are still not fully understood. Aminophosphine chalcogenides, preserving the H2N–P+–Ch− structural motif, represent well-suited molecular models that mimic proton-binding, hydrogen-bond switching and supramolecular self-assembling behavior of catalytically and prebiotically relevant molecules. Through spectroscopic (IR, 1H DOSY, 15N NMR), molecular dynamics, and computational investigations, the dynamic proton switching capability of aminophosphate analogs was demonstrated. It was shown under which conditions the amino (NH2) or chalcogen (Ch) functions in H2N–P+–Ch− structural units are protonated. In fact, all conceivable modes of hydrogen-bonding were identified, revealing substantial differences between the oxygen derivative and the heavier congeners. Using coordinating anions, supramolecular zigzag- and cube-shaped arrangements were found in the solid-state and in solution. After break-up of the cube structure, the sulfides and selenides no longer form stable interactions with HCl molecules. In the absence of coordinating anions, protonation of the chalcogen function is preferred. In contrast to the oxygen derivative, the heavier congeners show dynamic intramolecular proton-hopping between the chalcogen and the amino function
Right Ventricular Systolic Dysfunction Predicts Recovery of Left Ventricular Systolic Function and Reduced Quality of Life in Patients With Arrhythmia‐Induced Cardiomyopathy
Get PDFIntroduction
Arrhythmia-induced cardiomyopathy (AIC) is an underrecognized condition resulting in left ventricular systolic dysfunction (LVSD) that is primarily caused by atrial fibrillation (AFib). The relationship between AIC, right ventricular (RV) function, and quality of life (QoL) has not been well studied.
Methods
We performed a post-hoc analysis of our AIC trial in which we prospectively screened for patients with tachyarrhythmia and newly diagnosed, otherwise unexplained LVSD. Following rhythm restoration, patients were followed up at 2, 4, and 6 months. Only patients with persistent sinus rhythm were analyzed. RV function was assessed via echocardiography (tricuspid annular plane systolic excursion [TASPE] and fractional area change [FAC]) and QoL by the Minnesota Living with Heart Failure Questionnaire.
Results
Of a total of 50 patients recovering from LVSD, 41 were diagnosed with AIC and 9 with non-AIC. Initially, RV function was reduced in the AIC group and recovered after rhythm restoration, whereas no relevant changes were noted in the non-AIC group. QoL was reduced in both groups and also improved after rhythm restoration. Regression analysis identified low TAPSE as a predictive parameter for AIC diagnosis and worse QoL in AIC patients.
Conclusion
We demonstrated that RV function and QoL are impaired in patients with AIC. Six months after rhythm restoration, TAPSE may serve as an early indicator of AIC while also correlating with QoL. This underscores the importance of detailed echocardiographic evaluation with a focus on RV function in patients with concomitant tachyarrhythmia and LVSD
Bundesweiter Vergleich zu heilkundlichen Maßnahmen durch Notfallsanitäterinnen und Notfallsanitäter
Get PDFHintergrund
Die heilkundliche Tätigkeit durch Notfallsanitäterinnen und Notfallsanitäter ohne notärztliche Anwesenheit basiert v. a. 1.) auf einer Delegation durch z. B. die Ärztliche Leitung Rettungsdienst oder 2.) auf eigenverantwortlicher Heilkundeausübung nach § 2a Notfallsanitätergesetz. Beide Möglichkeiten unterscheiden sich u. a. hinsichtlich der Verantwortung für die Indikationsstellung. Diese Arbeit gibt erstmals einen bundesweiten Überblick, wer welche Verantwortung im Rahmen der Behandlungsvorgaben für Notfallsanitäterinnen und Notfallsanitäter trägt.
Material und Methoden
Die Behandlungsalgorithmen zu 5 Krankheitsbildern wurden für alle Bundesländer hinsichtlich ihrer geografischen Gültigkeit, der Deklaration sowie des objektiven Charakters als Delegation der Ärztlichen Leitung Rettungsdienst oder entsprechend verantwortlicher Ärztinnen oder Ärzte (ÄLRD-Delegation) oder Heilkundeausübung (§ 2a NotSanG) und der Erstreckung auf Betäubungsmittel ausgewertet. Die Datenerhebung fand im Zeitraum von Dezember 2020 bis Juni 2022 statt.
Ergebnisse
Es wurden 112 Algorithmen mit 403 Einzelmaßnahmen analysiert. Für 11 Bundesländer wurden landesweit gültige, in 5 Ländern regional abweichende Behandlungsvorgaben gefunden. Der ÄLRD-Delegations- oder § 2a NotSanG-Status war in lediglich 40 % der einzelnen Maßnahmen explizit deklariert. Diese Deklaration zeigte in 93 % eine Übereinstimmung mit dem objektiven Charakter der Maßnahme. Eine eigenständige oder eigenverantwortliche Betäubungsmittelgabe durch NotSan ist in 6 Ländern vorgesehen.
Diskussion
In der Mehrheit der für NotSan vorgesehenen Maßnahmen ist nicht ersichtlich, ob diese in ÄLRD-Delegation oder nach § 2a NotSanG angewendet werden sollen. Eine entsprechende Deklaration durch die Ersteller könnte hier für mehr Klarheit bezüglich der Verantwortlichkeiten sorgen. Sowohl eine ÄLRD-Delegation als auch eine Betäubungsmittelgabe ohne Arztanwesenheit ist nicht in allen Bundesländern etabliert. Aufgrund der sich stetig weiterentwickelnden Rechtslage stellen sich die untersuchten Endpunkte in einzelnen Regionen mittlerweile anders dar
All-two-dimensional van der Waals heterostructures for spin injection and detection
No full textThis thesis presents all-two-dimensional van der Waals devices that facilitate efficient spin injection from a ferromagnetic Fe3GeTe2 (FGT) electrode into a conducting monolayer graphene channel. The injected spin signal is detected at a second FGT electrode. To ensure efficient spin injection, a thin hBN layer between the FGT and graphene serves as a tunnel barrier. Such a heterostructure allows for the investigation of spin transport and precession in non-local spin valve and Hanle measurements. Prior to the spin experiments, a detailed characterization of each building block is conducted. The spin injection efficiency and spin transport parameters, such as the spin lifetime and the spin diffusion constant, are determined from the Hanle experiments by fitting the experimental data to an analytical fitting function. The obtained values of the spin injection efficiency of up to P ≈ 40% demonstrate highly efficient spin injection and detection. The extracted values of the spin lifetimes and spin diffusion constants are in good agreement with those obtained in other spin transport experiments in graphene utilizing oxide tunnel barriers and conventional spin aligning electrodes. Interestingly, the extracted values of the spin diffusion constant do not match the extracted values of the charge diffusion constant in both presented spin transport samples. In order to evaluate this discrepancy, simulations were conducted using COMSOL Multiphysics. Hints of magnetic moments were found in one of the two samples, although their origin remains unknown. The results presented in this thesis successfully demonstrate efficient spin transport in all-van der Waals heterostructures, paving the way for future all-2D spintronic applications
The Elusive Ternary Intermediates of Chiral Phosphoric Acids in Ion Pair Catalysis─Structures, Conformations, and Aggregation
Get PDFIn ion-pair catalysis, the last intermediate structures prior to the stereoselective transition states are of special importance for predictive models due to the high isomerization barrier between E- and Z-substrate double bonds connecting ground and transition state energies. However, in prior experimental investigations of chiral phosphoric acids (CPA) solely the early intermediates could be investigated while the key intermediate remained elusive. In this study, the first experimental structural and conformational insights into ternary complexes with CPAs are presented using a special combination of low temperature and relaxation optimized ¹⁵N HSQC-NOESY NMR spectroscopy to enhance sensitivity. Combined NMR investigations and theoretical calculations revealed three conformers of the ternary complex, of which one also closely resembles the previously calculated transition states. In addition, a 2:1:1 ternary complex as well as an unprecedent [3:3] dimeric species consisting of two ternary complexes was revealed. Given the importance of the ground state energies for the transition state interpretation in ion pair catalysis we believe that the presented experimental insight into the structural and conformational variety of the ternary complexes is a key to the future development of predictive models in ion pair catalysis
The role of the transcriptional regulator Lmo4 in CD8+ T cell stemness, memory formation and antitumor immunity
Get PDFHigh frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8⁺ T cells. Using IFN-γ production as a proxy for CD8⁺ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8⁺ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8⁺ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8⁺ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8⁺ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8⁺ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies
The signature of topology in polar and chiral non-magnetic crystal classes
Get PDFTopology is fundamental to condensed matter physics, underlying phenomena such as the quantum Hall effect in its various forms, protected surface states and spin-valley locking. Central to this is the Berry curvature, a measure of the geometric properties of Bloch wavefunctions in crystals. Despite its established connections to space inversion and time-reversal symmetries, a comprehensive framework linking the Berry curvature to other crystal symmetries is still missing. Here, we present a theoretical model for the Jacobian matrix of the Berry curvature in the proximity of optical resonances for all non-magnetic crystal classes. The Jacobian matrix of the Berry curvature is readily derived from the second-order nonlinear optical susceptibilities of the time-invariant point groups. We show that the diagonal elements of the Jacobian matrix, which define the divergence of the Berry curvature, are non-zero only for the chiral crystal classes, pointing towards a topological origin of circular dichroism. In polar crystals, we uniquely find a non-zero curl of the Berry curvature, suggesting a topological origin of spontaneous polarization via the Maxwell-Berry equations. Our findings thus open new perspectives for the topological interpretation of textbook phenomena at the heart of condensed matter physics
Twiddler-, Reel-, and Ratchet-syndrome: an alternative approach to address the underlying mechanism of complication in cardiac implantable electronic devices
No full textThe circumstances leading to the origins of "Twiddler", "Reel", and "Ratchet" in patients with cardiac implantable electronic devices (CIED) have not yet been fully determined. This retrospective study was performed to address different mechanisms that lead to impairment of implanted leads within the context of "Twiddler", "Reel", and "Ratchet".
From 2004 and 2023, 5966 patients underwent CIED procedures at our institution. 31 patients with lead impairment by rotation were identified with evidence of pulse generator mobility, lead dislodgement with retraction and / or associated coiling of the lead(s) radiographically or intraoperatively. A review of the literature from 1963 to 2024 identified 216 cases from 165 publications.
In less than half of our patients lead retraction could be attested, and a minority of patients had clinical symptoms attributable to lead impairment by rotation. Psychiatric comorbidities and patients´ manipulation could not be ascertained.
Thorough follow-up of all patients with CIEDs appears mandatory. Precise implantation techniques from the outset may limit lead impairment by rotation
Towards a Research Programme Aiming at Causes and Consequences of Reticulate Evolution
No full textEvolution is reticulate. Reticulation increases diversity and complexity on the different levels of the evolutionary hierarchy. In addition to the tendency for diversity and complexity to increase in unchecked evolutionary systems by ongoing divergence (‘Zero-Force Evolutionary Law’, ‘Biology’s First Law’), reticulate evolution, therefore, acts as a second mechanism for the establishment of evolutionary novelty and the rise in biodiversity and biocomplexity (‘Biology’s Second Law’). This provides the raw material for subsequent diversity-confining drift and selection processes. In order to fully appreciate reticulation processes as part of an updated paradigm of evolutionary biology, a research programme on the topic should encompass the identification of the fundamental evolutionary entities as vertices and the study of the relationships among these vertices as edges in the resulting network architectures. Additionally, along with surveys on the underlying determinants, this will lead to the study of emergent boundary conditions for reticulations and for the porosity of evolutionary entities. Finally, the programme should address the question whether there are equilibrium conditions between the complete fusion and complete isolation of evolutionary entities (‘Goldilocks Zones’) that foster reticulate evolution. As tools in this research programme, machine learning and modelling approaches, along with methods in the field of network reconstruction, transcriptomics, epigenetics, and karyology, are identified
Anatomical Insights into Frontal Branch Preservation in Minimally Invasive Brow Lift Techniques: A Comparative Analysis of Anatomical Lift Prantl’s Suture Suspension (ALPS) Versus Gliding Brow Lift (GBL)
No full textThe brow region plays a crucial role in facial expression and appearance, making it a key aspect of facial rejuvenation procedures. This study focuses on minimally invasive brow lift techniques including the Anatomical Lift Prantl’s Suture Suspension (ALPS) and the Gliding Brow Lift (GBL). Based on a cadaveric dissection and a clinical case presentation, the study identifies the technical nuances of these procedures and highlights anatomical danger zones, with a particular focus on the frontal branch of the facial nerve. During both the ALPS and GBL procedures on fresh-frozen cadaveric specimens, sutures were placed and their relation to critical anatomical structures, such as the frontal branch of the facial nerve, was assessed. Results indicated that ALPS technique, which uses fewer sutures and employs a periosteal approach, reduces the risk of nerve entrapment and injury. In contrast, the GBL technique utilizes multiple percutaneous sutures for skin stabilization, which were observed to be in closer proximity to the frontal branch of the facial nerve. In clinical studies using the GBL technique, however, no nerve injuries have been observed so far, and if they do occur, they are only temporary with complete recovery. Nevertheless, this study highlights the importance of understanding anatomical relationships in the brow region to ensure safety and efficacy in brow lift procedures