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ATIP1 is a suppressor of cardiac hypertrophy and modulates AT2-dependent signaling in cardiac myocytes
No full textSo far, the molecular functions of the angiotensin-type-2 receptor (AT2) interacting protein (ATIP1) have remained unclear, although expression studies have revealed high levels of ATIP1 in the heart. To unravel its physiological function, we investigated ATIP1-KO mice. They develop a spontaneous cardiac hypertrophy with a significantly increased heart/bodyweight ratio, enlarged cardiomyocyte diameters, and augmented myocardial fibrosis. Hemodynamic measurements revealed an increased ejection fraction (EF) in untreated ATIP1-KO mice, and reduced end-systolic and end-diastolic volumes (ESV and EDV), which, in sum, reflect a compensated concentric cardiac hypertrophy. Importantly, no significant differences in blood pressure (BP) were observed. Chronic angiotensin II (AngII) infusion resulted in increases in BP and EF in ATIP1-KO and WT mice. Reductions in ESV and EDV occurred in both ATIP1-KO and WT but to a lesser extent in ATIP1-KO. Isolated cardiomyocytes exhibited a significantly increased contractility in ATIP1-KO and accelerated Ca decay. AngII treatment resulted in increased fractional shortening in WT but decreased shortening in ATIP1-KO, accompanied by accelerated cell relaxation in WT but absent effects on relaxation in ATIP1-KO cells. The AT2 agonist CGP42112A increased shortening in WT cardiomyocytes but, again, did not affect shortening in ATIP1-KO cells. Relaxation was accelerated by CGP42112A in WT but was unaffected in ATIP1-KO cells. We show that ATIP1 deficiency results in spontaneous cardiac hypertrophy in vivo and that ATIP1 is a downstream signal in the AT2 pathway regulating cell contractility. We hypothesize that the latter effect is because of a disinhibition of the AT1 pathway by impaired AT2 signaling
Insights into topochemical versus stress-induced high-pressure reactivity of azobenzene by single crystal X-ray diffraction
No full textThis study addresses azobenzene's structural compression and reactivity under hydrostatic high-pressure conditions. Synchrotron X-ray diffraction data of single crystals compressed with neon as the pressure-transmitting medium allowed the refinement of the crystal structure up to 28 GPa, at which the onset of the reaction was observed. Analysis of the pressure-dependent lattice parameters reveals a first-order isostructural phase transition at 13 GPa. We have solved the crystal structure of the high-pressure phase of azobenzene offering a key insight into the strong contribution of stress on the structural compression mechanism and crystal's reaction chemistry at elevated pressures. While the collapse of the b cell parameter, previously observed under non-hydrostatic conditions, was identified as the crucial step toward the formation of azobenzene-derived double-core nanothreads, under quasi-hydrostatic conditions the compression of the cell parameters up to 33 GPa followed a different route. The evolution of the cell parameters and the refinement of the crystal structure close to the onset of the reaction identified a topochemical polymerization path, corroborated by reaction kinetics data by infrared spectroscopy and by computed polymer structures, suggesting a complex growth process, resulting in a distinctly different material compared to that formed upon non-hydrostatic compression. These findings underscore the pivotal role of compression conditions in determining the reaction pathways of azobenzene, providing novel insights for its application in nanomaterial synthesis
Alkali metal salts of 1,2,3-benzodiazaborines: platforms for late-stage N-functionalization and metal complexation
No full textThe standard procedure for the preparation of benzoid 1,2,3-diazaborines (DABs) is the condensation of 2-formylphenyl boronic acid with a hydrazine. The choice of hydrazine derivative irreversibly predetermines the N-substituent in most cases and is additionally limited by the availability and hazardous nature of the respective hydrazines. Options to subsequently modify the N-substituent are scarce. Herein, we explore an approach to postsynthetic N-functionalization via isolable, nucleophilic DAB alkali metal amides. The structures of these metalated DABs were extensively studied, utilizing H DOSY NMR spectroscopy and XRD analysis. Subsequent reactivity studies of these unusual amides revealed an intricate, dualistic reactivity pattern. Upon treatment with mild electrophiles, the DAB amides react as N-nucleophiles, facilitating the straightforward introduction of functional groups at the N position. Due to the incorporation of the second N atom, they can moreover serve as anionic diazo ligands for the formation of μ-DAB-bridging coinage metal complexes, which bear a striking resemblance to well-studied complexes with pyrazolato (pz) ligands. Overall, this work demonstrates how BN incorporation opens new avenues in ligand design and provides a valuable tool for post-synthetic modification of aryl DABs with organic and inorganic substrates
Bispecific antibodies in the treatment of hematologic neoplasms and solid tumors
No full textDie medikamentöse Tumortherapie entwickelt sich von der klassischen zytotoxischen Chemotherapie hin zu immer gezielteren Immuntherapien. Im Gegensatz zu monoklonalen Antikörpern richten sich bispezifische Antikörper (BsAb) gegen 2 unterschiedliche Antigene und können auf diese Weise entweder Immuneffektorzellen mit Tumorzellen verbinden oder 2 unterschiedliche Signalwege in Tumorzellen blockieren. Bisher wurden mehrere BsAb zur Behandlung hämatologischer Neoplasien und ausgewählter solider Tumoren zugelassen. Die Mechanismen der Resistenz gegen BsAb sind derzeit jedoch noch nicht vollständig verstanden, und auch das neuartige Nebenwirkungsprofil bleibt eine große Herausforderung im klinischen Alltag. Zudem ist die optimale Reihenfolge der Therapie mit BsAb und anderen medikamentösen Tumortherapien, einschließlich Chimärer-Antigenrezeptor(CAR)-T-Zellen, noch nicht ausreichend definiert. Im vorliegenden Übersichtsartikel diskutieren wir die Wirk- und Resistenzmechanismen, aktuelle Studiendaten sowie zukünftige Entwicklungen von BsAb bei hämatologischen Neoplasien und soliden Tumoren.Drug-based anti-tumor therapy is evolving from classical cytotoxic chemotherapy to increasingly specific immunotherapies. Unlike monoclonal antibodies, bispecific antibodies (BsAbs) target two different antigens, allowing them to either connect immune effector cells with tumor cells or to block two distinct signaling pathways in tumor cells. Several BsAbs have already been approved for treatment of hematologic malignancies and selected solid tumors. However, the mechanisms of resistance to BsAbs are not yet fully understood, and their side effects remain a major challenge in clinical practice. Furthermore, the optimal sequencing of BsAbs and other anti-tumor therapies, including CAR-T cells, has not been defined. In this review article, we discuss mechanisms of action and resistance, current clinical data, and future developments pertaining to BsAbs in hematologic malignancies and solid tumors
Association of microstructural lesions of the corpus callosum with cognitive impairment in patients with high grade glioma
No full textPurpose
Glioblastoma is one of the most common malignant brain tumors. To ensure a treatment that does not only lengthen survival, but also improves preservation of neurocognitive functions, reliable methods to measure changes in neurocognitive abilities at an early stage are necessary. The most direct way to objectify neurocognitive properties is neuropsychological testing. Neurocognitive decline is often based on lesions of the connectome. We take the corpus callosum (CC) as a reliable structure to identify decline of white matter (WM) integrity. We hypothesized a relation between compromised structural integrity in specific regions of the CC and neurocognitive deficits in glioma patients.
Methods
We included 28 patients with high-grade glioma who underwent a neuropsychological test battery and MRI with Diffusion tensor imaging (DTI) preoperatively. MRI data was processed using the software fsl, Oxford. Neuropsychological parameters were correlated with the fractional anisotropy (FA) in three parts of the CC.
Results
Preoperatively, most of the neuropsychological parameters correlated significantly with FA of at least one of the CC volumes. Higher FA-values were associated with better focus, memory, speed and speech fluency. Different tests examined the same neuropsychological parameter and then correlated with the same region of the CC.
Conclusions
We consider the FA of the CC for an adequate parameter to examine the influence of distant lesions on neurocognitive abilities
Fever of unknown origin in B-cell depleted patients: Have you considered Neoehrlichiosis?
No full textNo abstract available
Marital status and risk of cardiovascular disease – a multi-analyst study in epidemiology
No full textIn multi-analyst studies, several analysts use the same data to independently investigate identical research questions. Multi-analyst studies have been conducted mainly in psychology, social sciences, and neuroscience, but rarely in epidemiology. Sixteen analyst groups (24 researchers) with backgrounds mainly in statistics, mathematics, and epidemiology were asked to independently perform an analysis on the influence of marital status (never married versus cohabiting married) on cardiovascular outcomes. They were asked to use data from the Survey of Health, Ageing and Retirement in Europe (SHARE), a panel study of 140,000 persons aged 50 years and above from 28 European countries and Israel, and to provide an effect estimate, a comment on their results, and the full syntax of their analyses. In additional analyses beyond the multi-analyst approach, one group selected an exemplary regression model and varied definitions of exposure and outcome and the confounder adjustment set. Each analysis was unique. The size of the 16 datasets used for the analyses ranged from 15,592 to 336,914 observations. The effect estimates (odds ratios, hazard ratios, or relative risks) ranged from 0.72 to 1.02 (reference: cohabiting married) in strictly or partly cross-sectional analyses and from 0.95 to 1.31 in strictly longitudinal analyses. The choice of regression models, adjustment sets for confounding, and variations in the precise definition of exposure and outcome, all had only small effects on the effect estimates. The range of results was mainly due to differences from cross-sectional versus longitudinal analyses rather than to single analytical decisions each of which had less influence
Click beetles (Elateridae) identify conservation units in Oriental and European beech forests
No full textBeech trees form major parts of lowland temperate forests in the Western Palearctic. To protect biodiversity, many beech forests have been designated as World Heritage Sites or established as networks of beech forest reserves. However, the insect communities within these protected forests have not been well explored. In this study, elaterids (Elateridae, Coleoptera) in 26 beech forests, from France in the west to Iran in the east, were sample to identify conservation clusters and hotspots of biodiversity. Sampling was mostly carried out using window traps and all specimens were identified to the species level. A total of 118 species were identified including one previously unreported species. Community composition analyses that focused on rare species identified five clusters comprising distinct communities: (i) the Hyrcanian Forest in Iran, (ii) the Lesser Caucasus in Türkiye, Georgia and Armenia, (iii) the Greater Caucasus in Georgia, (iv) the Pyrenees and (v) a cluster made up of forests from Central Europe, the Balkan region and the Carpathians. After controlling for sampling effort (individuals), the highest richness was found in the Caucasus region. The proportion of endemics was highest in the Oriental beech forests of the Caucasus and in Hyrcanian forests. These findings highlight the unique biodiversity of beech forests and support calls for intensified conservation actions in beech forests, particularly in the Caucasus and Hyrcanian regions, which should be prioritized for conservation efforts, due to their unique fauna.
Implications for insect conservation
Our study underscores the importance of protecting beech forests, especially in the Caucasus and Hyrcanian regions, as they host unique and endemic insect species critical for biodiversity conservation
Studying the influence of single social interactions on approach and avoidance behavior: A multimodal investigation in immersive virtual reality
No full textWhen studying spontaneous or learned emotional responses to social stimuli, research has traditionally relied on simplified stimuli repeatedly presented on a computer screen in standardized laboratory environments. While these studies have provided important insights into social perception and cognition, their restricted ecological validity may impede the extrapolation of findings to everyday social contexts. Here, we developed a novel immersive virtual reality scenario that permits the examination of social approach and avoidance behavior under naturalistic circumstances while at the same time maintaining full experimental control. Using a combination of a social conditioning procedure with a social approach–avoidance test, we conducted two experiments (both with N = 48 female participants) to investigate how individuals differing in trait social anxiety adapt their behavior after a single encounter with an either friendly or unfriendly virtual agent. In addition to overt approach and avoidance behavior, we acquired subjective ratings, eye-tracking data, and autonomic responses. Overall, we observed significant effects of the social conditioning procedure on autonomic responses and participants’ exploration behavior. After initially increased attention, participants exhibited avoidance of social threats as indicated by a higher interpersonal distance and decreased visual attention towards the negatively conditioned virtual agent in the test phase. We found no association between hypervigilance and trait social anxiety but observed higher fear ratings and enhanced avoidance of social threats in participants with elevated anxiety levels. Altogether, this study demonstrates the potential of immersive virtual environments for examining social learning processes under conditions resembling real-life social encounters
SNAPpa: A photoactivatable SNAP-tag for the spatiotemporal control of protein labeling
No full textSNAP-tag is one of the most commonly used self-labeling protein tags for cell imaging studies. To achieve selective spatiotemporal imaging of cells, we set out to engineer a photoactivatable SNAP-tag. For this, we incorporated the well-established and readily available photocaged unnatural amino acid o -nitrobenzyl- O -tyrosine (ONBY) into all three tyrosine positions of SNAP. In-gel imaging analysis and fluorescence polarization measurements revealed that placing ONBY in position Y114 of the SNAP-tag facilitates the most effective and most efficient photoactivation of the irreversible self-labeling reaction with (sulfonated) benzyl guanine substrates, which is why we dubbed this photoactivatable SNPA-tag variant “SNAPpa”. To demonstrated its potential for live-cell imaging, we further tested SNAPpa in HEK293 cells, either fused to a nuclear localization domain for intracellular imaging or fused to either a transmembrane region or the glucagon-like peptide 1 receptor for extracellular imaging. Each SNAPpa construct produced no fluorescence signal when ONBY remained in its photocaged state by keeping the cells in the dark. However, a clear fluorescence signal appeared after light-induced decaging of ONBY. Applying a localized light beam thereby highlighted the precise spatiotemporal control of cell imaging. In conclusion, SNAPpa can be used for the efficient light-induced activation of fluorescence labeling and can be easily established, readily implemented and effectively combined with the broad repertoire of substrates that is already available for SNAP