Effect of an eight-week high-intensity interval training programme on circulating sphingolipid levels in middle-aged adults at elevated cardiometabolic risk (SphingoFIT)-Protocol for a randomised controlled exercise trial.

INTRODUCTION: Evidence indicates that sphingolipid accumulation drives complex molecular alterations promoting cardiometabolic diseases. Clinically, it was shown that sphingolipids predict cardiometabolic risk independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, little is known about therapeutic modalities to lower sphingolipid levels. Exercise, a powerful means to prevent and treat cardiometabolic diseases, is a promising modality to mitigate sphingolipid levels in a cost-effective, safe, and patient-empowering manner. METHODS: This randomised controlled trial will explore whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n = 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to assess patient fitness changes. Cholesterol, triglycerides, glycated haemoglobin, the homeostatic model assessment for insulin resistance, static retinal vessel analysis, flow-mediated dilatation, and strain analysis of the heart cavities will also be assessed pre- and post-intervention. This study shall inform whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels. TRIAL REGISTRATION: The trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel MAPK11 variant in one case.

BACKGROUND: In this study we aimed to describe the morphological and pathogenetic differences between tracheal agenesis and tracheal atresia, which are not clearly distinguished from each other in the literature, and to contribute thereby to the understanding and management of these conditions. Both tracheal agenesis and tracheal atresia represent rare disorders of still unknown aetiology that cannot be detected by prenatal ultrasound. If the affected foetuses survive until birth these conditions result in respiratory failure and in futile attempts to rescue the infant's life. RESULTS: Autopsies and genetic analyses, including singleton or trio exome sequencing, were performed on five neonates/foetuses with tracheal agenesis and three foetuses with tracheal atresia. Tracheal agenesis was characterized by absence of the sublaryngeal trachea and presence of a bronchooesophageal fistula and by pulmonary isomerism and occurred as an isolated malformation complex or as part of a VACTERL association. Special findings were an additional so-called 'pig bronchus' and a first case of tracheal agenesis with sirenomelia. Tracheal atresia presenting with partial obliteration of its lumen and persistence of a fibromuscular streak resulted in CHAOS. This condition was associated with normal lung lobulation and single, non-VACTERL type malformations. Trio ES revealed a novel variant of MAPK11 in one tracheal agenesis case. Its involvement in tracheooesophageal malformation is herein discussed, but remains hypothetical. CONCLUSION: Tracheal agenesis and tracheal atresia represent different disease entities in terms of morphology, pathogenesis and accompanying anomalies due to a primary developmental and secondary disruptive possibly vascular disturbance, respectively.

Safety and efficacy of endovenous thermal ablation for treatment of symptomatic varicose veins during summertime.

Background: Traditionally, varicose vein treatment is predominately performed during the colder seasons. However, data whether higher outdoor temperatures affect the outcome and/or complication rate of endovenous thermal ablation (ETA) for treatment of symptomatic varicose veins are missing. Patients and methods: In this observational study, the medical records of all patients who had ETA of the great saphenous vein (GSV), accessory saphenous vein (ASV), or small saphenous vein (SSV) between September 2017 and October 2020 were reviewed. Results: In total 846 ETA interventions in 679 patients with 1239 treated truncal veins and an average length of 69 cm phlebectomy were included. The highest temperature recorded on and within the first 14 days after treatment was on average 19.0°C (SD±7.2°C) with a minimum and maximum of -1°C and 35.9°C. Interventions were categorized according to the recorded temperature (<25°C n=584; 25-29.9°C n=191; and ≥30°C n=71). The occlusion rates were excellent (99-100%) across groups. Despite a significantly higher proportion of patients with obesity, personal history of superficial vein thrombosis and length of phlebectomies in the high temperature groups, no significant difference regarding days of work loss, patients' satisfaction or complications including bleeding or thromboembolic events was observed. Infections were rare (0.8%), but more frequently observed in the 25-29.9°C group (2.6%; p=0.058). No infection was observed in the ≥30°C group and pain 6 weeks after the intervention was even lower (VAS 0.5±1.0 and 0.5±1.2 vs. 0.0±0.1, p=0.008). Conclusions: Given the minimal invasive nature of ETA, our results can reassure clinicians and patients that ETA varicose vein treatment is possible and safe throughout the year, even on hot summer days. A non-significant trend to more infections was observed but was not associated with other adverse outcomes such as prolonged analgetics intake or inability to work.

Brain malformations in diprosopia observed in clinical cases, museum specimens and artistic representations.

BACKGROUND: Diprosopus is a rare malformation of still unclear aetiology. It describes a laterally double faced monocephalic and single-trunk individual and has to be distinguished from the variant Janus type diprosopus. RESULTS: We examined seven double-faced foetuses, five showing true diprosopus, and one each presenting as monocephalic Janiceps and parasitic conjoined twins. Four of the foetuses presented with (cranio)rachischisis, and two had secondary hydrocephaly. Three foetuses showed cerebral duplication with concordant holoprosencephaly, Dandy-Walker cyst and/or intracranial anterior encephalocele. In the Janiceps twins, cerebral duplication was accompanied by cerebral di-symmetry. In the parasitic twins the cyclopic facial aspects were suggestive of concordant holoprosencephaly. In one of the true diprosopus cases, pregnancy was achieved after intracytoplasmic sperm injection. Whole-exome sequencing, perfomed in one case, did not reveal any possible causative variants.The comparison of our double-faced foetuses to corresponding artistic representations from the Tlatilco culture allowed retrospective assignment of hairstyles to brain malformations. CONCLUSION: Brain malformations in patients with diprosopus may not be regarded as an independent event but rather as a sequel closely related to the duplication of the notochord and neural plate and as a consequence of the cerebral and associated craniospinal structural instabilities.

Oxidant speciation and anionic ligand effects in the gold-catalyzed oxidative coupling of arenes and alkynes.

The mechanism of the gold-catalyzed oxidative cross-coupling of arenes and alkynes has been studied in detail combining stoichiometric experiments with putative reaction intermediates and DFT calculations. Our data suggest that ligand exchange between the alkyne, the Au(i)-catalyst and the hypervalent iodine reagent is responsible for the formation of both an Au(i)-acetylide complex and a more reactive "non-symmetric" I(iii) oxidant responsible for the crucial Au(i)/Au(iii) turnover. Further, the reactivity of the in situ generated Au(iii)-acetylide complex is governed by the nature of the anionic ligands transferred by the I(iii) oxidant: while halogen ligands remain unreactive, acetato ligands are efficiently displaced by the arene to yield the observed Csp2-Csp cross-coupling products through an irreversible reductive elimination step. Finally, the nature of competitive processes and catalyst deactivation pathways has also been unraveled. This detailed investigation provides insights not only on the specific features of the species involved in oxidative gold-catalyzed cross couplings but also highlights the importance of both ancillary and anionic ligands in the reactivity of the key Au(iii) intermediates.

Overview obstacle maps for obstacle-aware navigation of autonomous drones.

Achieving the autonomous deployment of aerial robots in unknown outdoor environments using only onboard computation is a challenging task. In this study, we have developed a solution to demonstrate the feasibility of autonomously deploying drones in unknown outdoor environments, with the main capability of providing an obstacle map of the area of interest in a short period of time. We focus on use cases where no obstacle maps are available beforehand, for instance, in search and rescue scenarios, and on increasing the autonomy of drones in such situations. Our vision-based mapping approach consists of two separate steps. First, the drone performs an overview flight at a safe altitude acquiring overlapping nadir images, while creating a high-quality sparse map of the environment by using a state-of-the-art photogrammetry method. Second, this map is georeferenced, densified by fitting a mesh model and converted into an Octomap obstacle map, which can be continuously updated while performing a task of interest near the ground or in the vicinity of objects. The generation of the overview obstacle map is performed in almost real time on the onboard computer of the drone, a map of size 100 m × 75 m is created in ≈ 2.75 min , therefore, with enough time remaining for the drone to execute other tasks inside the area of interest during the same flight. We evaluate quantitatively the accuracy of the acquired map and the characteristics of the planned trajectories. We further demonstrate experimentally the safe navigation of the drone in an area mapped with our proposed approach.

Cu(OH)2 and CuO Nanorod Synthesis on Piezoresistive Cantilevers for the Selective Detection of Nitrogen Dioxide.

Self-controlled active oscillating microcantilevers with a piezoresistive readout are very promising sensitive sensors, despite their small surface. In order to increase this surface and consequently their sensitivity, we nanostructured them with copper hydroxide (Cu(OH)2) or with copper oxide (CuO) nanorods. The Cu(OH)2 rods were grown, on a homogeneous copper layer previously evaporated on the top of the cantilever. The CuO nanorods were further obtained by the annealing of the copper hydroxide nanostructures. Then, these copper based nanorods were used to detect several molecules vapors. The results showed no chemical affinity (no formation of a chemical bond) between the CuO cantilevers and the tested molecules. The cantilever with Cu(OH)2 nanorods is selective to nitrogen dioxide (NO2) in presence of humidity. Indeed, among all the tested analytes, copper hydroxide has only an affinity with NO2. Despite the absence of affinity, the cantilevers could even so condensate explosives (1,3,5-trinitro-1,3,5-triazinane (RDX) and pentaerythritol tetranitrate (PETN) on their surface when the cantilever temperature was lower than the explosives source, allowing their detection. We proved that in condensation conditions, the cantilever surface material has no importance and that the nanostructuration is useless because a raw silicon cantilever detects as well as the nanostructured ones.

Gold-Catalyzed Direct Oxidative Arylation with Boron Coupling Partners.

An efficient synthesis of biaryls through a gold-catalyzed oxidative cross-coupling of arenes with strong electron-deprived aryl boronates is presented herein. Regio- and chemocontrol are achieved by the selective activation of these coupling partners by gold at different oxidation states. Under reaction conditions devoid of basic additives or directing groups, the role of acetato ligand as an internal base has been revealed as a key parameter for expanding the reaction scope in these transformations.

Quantitative phosphoproteomics of the ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia-mutated and rad3-related (ATR) dependent DNA damage response in Arabidopsis thaliana.

The reversible phosphorylation of proteins on serine, threonine, and tyrosine residues is an important biological regulatory mechanism. In the context of genome integrity, signaling cascades driven by phosphorylation are crucial for the coordination and regulation of DNA repair. The two serine/threonine protein kinases ataxia telangiectasia-mutated (ATM) and Ataxia telangiectasia-mutated and Rad3-related (ATR) are key factors in this process, each specific for different kinds of DNA lesions. They are conserved across eukaryotes, mediating the activation of cell-cycle checkpoints, chromatin modifications, and regulation of DNA repair proteins. We designed a novel mass spectrometry-based phosphoproteomics approach to study DNA damage repair in Arabidopsis thaliana. The protocol combines filter aided sample preparation, immobilized metal affinity chromatography, metal oxide affinity chromatography, and strong cation exchange chromatography for phosphopeptide generation, enrichment, and separation. Isobaric labeling employing iTRAQ (isobaric tags for relative and absolute quantitation) was used for profiling the phosphoproteome of atm atr double mutants and wild type plants under either regular growth conditions or challenged by irradiation. A total of 10,831 proteins were identified and 15,445 unique phosphopeptides were quantified, containing 134 up- and 38 down-regulated ATM/ATR dependent phosphopeptides. We identified known and novel ATM/ATR targets such as LIG4 and MRE11 (needed for resistance against ionizing radiation), PIE1 and SDG26 (implicated in chromatin remodeling), PCNA1, WAPL, and PDS5 (implicated in DNA replication), and ASK1 and HTA10 (involved in meiosis).

Microorganisms with novel dissimilatory (bi)sulfite reductase genes are widespread and part of the core microbiota in low-sulfate peatlands.

Peatlands of the Lehstenbach catchment (Germany) house as-yet-unidentified microorganisms with phylogenetically novel variants of the dissimilatory (bi)sulfite reductase genes dsrAB. These genes are characteristic of microorganisms that reduce sulfate, sulfite, or some organosulfonates for energy conservation but can also be present in anaerobic syntrophs. However, nothing is currently known regarding the abundance, community dynamics, and biogeography of these dsrAB-carrying microorganisms in peatlands. To tackle these issues, soils from a Lehstenbach catchment site (Schlöppnerbrunnen II fen) from different depths were sampled at three time points over a 6-year period to analyze the diversity and distribution of dsrAB-containing microorganisms by a newly developed functional gene microarray and quantitative PCR assays. Members of novel, uncultivated dsrAB lineages (approximately representing species-level groups) (i) dominated a temporally stable but spatially structured dsrAB community and (ii) represented "core" members (up to 1% to 1.7% relative abundance) of the autochthonous microbial community in this fen. In addition, denaturing gradient gel electrophoresis (DGGE)- and clone library-based comparisons of the dsrAB diversity in soils from a wet meadow, three bogs, and five fens of various geographic locations (distance of ∼1 to 400 km) identified that one Syntrophobacter-related and nine novel dsrAB lineages are widespread in low-sulfate peatlands. Signatures of biogeography in dsrB-based DGGE data were not correlated with geographic distance but could be explained largely by soil pH and wetland type, implying that the distribution of dsrAB-carrying microorganisms in wetlands on the scale of a few hundred kilometers is not limited by dispersal but determined by local environmental conditions.

Molecular recognition imaging using tuning fork-based transverse dynamic force microscopy.

We demonstrate simultaneous transverse dynamic force microscopy and molecular recognition imaging using tuning forks as piezoelectric sensors. Tapered aluminum-coated glass fibers were chemically functionalized with biotin and anti-lysozyme molecules and attached to one of the prongs of a 32kHz tuning fork. The lateral oscillation amplitude of the tuning fork was used as feedback signal for topographical imaging of avidin aggregates and lysozyme molecules on mica substrate. The phase difference between the excitation and detection signals of the tuning fork provided molecular recognition between avidin/biotin or lysozyme/anti-lysozyme. Aggregates of avidin and lysozyme molecules appeared as features with heights of 1-4nm in the topographic images, consistent with single molecule atomic force microscopy imaging. Recognition events between avidin/biotin or lysozyme/anti-lysozyme were detected in the phase image at high signal-to-noise ratio with phase shifts of 1-2 degrees. Because tapered glass fibers and shear-force microscopy based on tuning forks are commonly used for near-field scanning optical microscopy (NSOM), these results open the door to the exciting possibility of combining optical, topographic and biochemical recognition at the nanometer scale in a single measurement and in liquid conditions.