Simple and Effective Identification of Local 6π- and Global [4n + 2] Aromaticity of Macrocyclic Conjugated Hydrocarbons by 1H/13C Chemical Shifts and the Corresponding Ring Current Effect.

Structures, 1H/13C chemical shifts, and the ring current effects (spatial magnetic properties: through-space NMR shieldings [TSNMRSs]) of various π-conjugated macrocyclic hydrocarbons and the corresponding charged analogues have been calculated at the B3LYP/6-311G(d,p) theory level using the GIAO perturbation method and employing the nucleus-independent chemical shift (NICS) characterization. The spatial magnetic properties (TSNMRS) are visualized as iso-chemical shielding surfaces (ICSSs) of various size and direction and together with especially the δ(1H)/ppm chemical shifts employed to unequivocally qualify and quantify local 6π-aromaticity of individual benzenoid building blocks and the global ([4n + 2], n > 1) aromaticity of the macrocyclic ring.

1H and 13C NMR spectra of infinitene and the ring current effect of the aromatic molecule.

The spatial magnetic properties (through-space NMR shieldings-TSNMRSs-actually the ring current effect in 1H NMR spectroscopy) of the recently synthesized infinitene (the helically twisted [12]circulene) have been calculated using the GIAO perturbation method employing the nucleus-independent chemical shift (NICS) concept and visualized as iso-chemical-shielding surfaces (ICSS) of various size and direction. Both 1H and 13C chemical shifts of infinitene and the aromaticity of this esthetically very appealing molecule have been studied subject to the ring current effect thus obtained. This spatial magnetic response property of TSNMRSs dominates the different magnitude of 1H and 13C chemical shifts, especially in the cross-over section of infinitene, which is unequivocally classified as an aromatic molecule based on the deshielding belt of its ring current effect. Differences in aromaticity of infinitene compared with isolated benzene can also be qualified and quantified on the magnetic criterion.

40-Year Outcome of Old-School, Non-Surgical Endodontic Treatment: Practice-Based Retrospective Evaluation.

(1) Background: Non-surgical endodontic treatment has been shown to be clinically successful; however, clinical long-term data are scarce. This practice-based retrospective clinical investigation evaluated endodontic outcomes over 40 years and identified relevant clinical co-factors. (2) Methods: Two experienced dental practitioners in two different private dental practices treated 174 patients with 245 teeth from 1969 to 1993. After root canal obturation, either a new direct restoration (amalgam, resin composite, or glass-ionomer cement) or the re-cementation of a pre-existing prosthetic restoration or renewal of prosthetic restoration followed. Metal posts (operator A) or metal screws (operator B) were inserted when coronal substance loss was significant. The primary outcome (i.e., tooth survival) was achieved when the endodontically treated tooth was, in situ, painless and had full function at the end of the observation period. A secondary outcome, the impact of different prognostic factors on survival rate, was evaluated. (3) Results: The overall mean survival was 56.1% of all treated teeth after 40 years of clinical service, resulting in an annual failure rate of 1.1%. Most investigated clinical co-factors (jaw, tooth position, intracanal dressings, post/screw placement, and gender) showed no significant influence on survival. (4) Conclusions: Even with materials and techniques from the 1970s and 1980s, successful root canal treatment was achievable. Except for post-endodontic restorations, most of the evaluated factors had no significant influence on the clinical long-term survival of root canal-treated teeth.

Identification and quantification of local antiaromaticity in polycyclic aromatic hydrocarbons (PAHs) based on the magnetic criterion.

The spatial magnetic properties, through-space NMR shieldings (TSNMRSs, actually the ring current effect in 1H NMR spectroscopy), of a selection of entirely antiaromatic and aromatic polycyclic conjugated hydrocarbons (PCHs), and aromatic PCHs with antiaromatic components, have been calculated using the GIAO perturbation method employing the nucleus independent chemical shift (NICS) concept and visualized as iso-chemical-shielding surfaces (ICSSs) of various sizes and directions. Using both in-plane and above/below-plane ICSS data, polycyclic aromatic hydrocarbons can be readily distinguished from polycyclic antiaromatic ones, even when antiaromatic components are present in the polycyclic aromatic hydrocarbons (PAHs). These antiaromatic zones can also be attributed to internal components of the in-plane deshielding belt present in aromatic compounds and possible partial antiaromatic ring current effects in the same place. This makes it possible to unequivocally confirm correctly assigned or adjust incorrectly assigned antiaromaticity of individual rings in the same molecule.

Carbones (-C2--), carbenes (-C:-) and carbodications (-C2+-) on the magnetic criterion.

The spatial magnetic properties, particularly the through-space NMR shieldings (TSNMRSs, the anisotropy effect in 1H NMR spectroscopy) of carbenes, carbones and carbodication (carbo2+) compounds (with and without stabilization by NMe2 π-donation) and those of a number of carbo2+ analogues have been calculated using the GIAO perturbation method, employing the nucleus-independent chemical shift (NICS) concept, and visualized as iso-chemical-shielding surfaces (ICSS) of various sizes and directions. TSNMRSs prove the electronic structure of carbo2+ compounds to be completely different from those of carbenes and carbones, preferring both the π-electron distribution and the structure of allenes/cumulenes despite the central carbon atom being the most electrophilic centre.

Carbones - A Classification on the Magnetic Criterion.

Carbones (carbodiphosphoranes, bent allenes and chalcogen-stabilized carbones) bear the same resonance contributor X+ -C2- -Y+ (X+ , Y+ =PR3 + , CR2 + , SR2 + , SeR2 + , S+ R2 =NR) and exhibit unique bonding and donating properties at the central carbon atom. A classification is given on basis of both the geometry and the magnetic properties (13 C chemical shift of the central carbon atom and the spatial magnetic properties, through-space NMR shieldings (TS NMRSs), actually the anisotropy effect or the ring current effect of aromatic species). TS NMRS values have been calculated using the GIAO perturbation method employing the nucleus independent chemical shift (NICS) concept and the results visualized as iso-chemical-shielding surfaces (ICSS) of various size and direction. The synergy of geometry (linear or bent, orthogonal or twisted structures) and NMR characteristics (extend of the high field shift of the central carbon atom, anisotropy effect of the allene-like C=C double bonds or the ball-like anisotropy effect of carbone-like central carbon atom) provides a comprehensive picture of the dominating resonance contributor.

Natural Compounds Purified from the Leaves of Aristotelia chilensis: Makomakinol, a New Alkaloid and the Effect of Aristoteline and Hobartine on NaV Channels.

Aristotelia chilensis or "maqui" is a tree native to Chile used in the folk medicine of the Mapuche people as an anti-inflammatory agent for the treatment of digestive ailments, fever, and skin lesions. Maqui fruits are black berries which are considered a "superfruit" with notable potential health benefits, promoted to be an antioxidant, cardioprotective, and anti-inflammatory. Maqui leaves contain non-iridoid monoterpene indole alkaloids which have previously been shown to act on nicotinic acetylcholine receptors, potassium channels, and calcium channels. Here, we isolated a new alkaloid from maqui leaves, now called makomakinol, together with the known alkaloids aristoteline, hobartine, and 3-formylindole. Moreover, the polyphenols quercetine, ethyl caffeate, and the terpenes, dihydro-ß-ionone and terpin hydrate, were also obtained. In light of the reported analgesic and anti-nociceptive properties of A. chilensis, in particular a crude mixture of alkaloids containing aristoteline and hobartinol (PMID 21585384), we therefore evaluated the activity of aristoteline and hobartine on NaV1.8, a key NaV isoform involved in nociception, using automated whole-cell patch-clamp electrophysiology. Aristoteline and hobartine both inhibited Nav1.8 with an IC50 of 68 ± 3 µM and 54 ± 1 µM, respectively. Hobartine caused a hyperpolarizing shift of the voltage-dependence of the activation, whereas aristoteline did not change the voltage-dependence of the activation or inactivation. The inhibitory activity of these alkaloids on NaV channels may contribute to the reported analgesic properties of Aristotelia chilensis used by the Mapuche people.

Effect of Hyperbaric Oxygen and Inflammation on Human Gingival Mesenchymal Stem/Progenitor Cells.

The present study explores for the first time the effect of hyperbaric oxygen (HBO) on gingival mesenchymal stem cells' (G-MSCs) gene expression profile, intracellular pathway activation, pluripotency, and differentiation potential under an experimental inflammatory setup. G-MSCs were isolated from five healthy individuals (n = 5) and characterized. Single (24 h) or double (72 h) HBO stimulation (100% O2, 3 bar, 90 min) was performed under experimental inflammatory [IL-1ß (1 ng/mL)/TNF-α (10 ng/mL)/IFN-γ (100 ng/mL)] and non-inflammatory micro-environment. Next Generation Sequencing and KEGG pathway enrichment analysis, G-MSCs' pluripotency gene expression, Wnt-/ß-catenin pathway activation, proliferation, colony formation, and differentiation were investigated. G-MSCs demonstrated all mesenchymal stem/progenitor cells' characteristics. The beneficial effect of a single HBO stimulation was evident, with anti-inflammatory effects and induction of differentiation (TLL1, ID3, BHLHE40), proliferation/cell survival (BMF, ID3, TXNIP, PDK4, ABL2), migration (ABL2) and osteogenic differentiation (p < 0.05). A second HBO stimulation at 72 h had a detrimental effect, significantly increasing the inflammation-induced cellular stress and ROS accumulation through HMOX1, BHLHE40, and ARL4C amplification and pathway enrichment (p < 0.05). Results outline a positive short-term single HBO anti-inflammatory, regenerative, and differentiation stimulatory effect on G-MSCs. A second (72 h) stimulation is detrimental to the same properties. The current results could open new perspectives in the clinical application of short-termed HBO induction in G-MSCs-mediated periodontal reparative/regenerative mechanisms.

Mechanisms and consequences of weight gain after deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

Body weight gain in combination with metabolic alterations has been observed after deep brain stimulation (DBS) of subthalamic nucleus (STN) in patients with Parkinson's disease (PD), which potentially counteracts the positive effects of motor improvement. We aimed to identify stimulation-dependent effects on motor activities, body weight, body composition, energy metabolism, and metabolic blood parameters and to determine if these alterations are associated with the local impact of DBS on different STN parcellations. We assessed 14 PD patients who underwent STN DBS (PD-DBS) before as well as 6- and 12-months post-surgery. For control purposes, 18 PD patients under best medical treatment (PD-CON) and 25 healthy controls (H-CON) were also enrolled. Wrist actigraphy, body composition, hormones, and energy expenditure measurements were applied. Electrode placement in the STN was localized, and the local impact of STN DBS was estimated. We found that STN DBS improved motor function by ~ 40% (DBS ON, Med ON). Weight and fat mass increased by ~ 3 kg and ~ 3% in PD-DBS (all P ≤ 0.005). fT3 (P = 0.001) and insulin levels (P = 0.048) increased solely in PD-DBS, whereas growth hormone levels (P = 0.001), daily physical activity, and VO2 during walking were decreased in PD-DBS (all P ≤ 0.002). DBS of the limbic part of the STN was associated with changes in weight and body composition, sedentary activity, insulin levels (all P ≤ 0.040; all r ≥ 0.56), and inversely related to HOMA-IR (P = 0.033; r = - 0.62). Daily physical activity is decreased after STN DBS, which can contribute to weight gain and an unfavorable metabolic profile. We recommend actigraphy devices to provide feedback on daily activities to achieve pre-defined activity goals.

Two-screw osteosynthesis of the mandibular condylar head with different screw materials: a finite element analysis.

This study compared the biomechanical behavior of titanium, magnesium, and polylactic acid screws for two-screw osteosynthesis of mandibular condylar head fractures using finite element analysis. Von Mises stress distribution, fracture displacement, and fragment deformation were evaluated. Titanium screws performed the best in terms of carrying the highest load, resulting in the least fracture displacement and fragment deformation. Magnesium screws showed intermediate results, while PLA screws were found to be unsuitable with stress values exceeding their tensile strength. These findings suggest that magnesium alloys could be considered a suitable alternative to titanium screws in mandibular condylar head osteosynthesis.

Analysis of Single- and Double-Stranded DNA Damage in Osteoblastic Cells after Hyperbaric Oxygen Exposure.

(1) Background: Hyperbaric oxygen (HBO) exposure induces oxidative stress that may lead to DNA damage, which has been observed in human peripheral blood lymphocytes or non-human cells. Here, we investigated the impact of hyperbaric conditions on two human osteoblastic cell lines: primary human osteoblasts, HOBs, and the osteogenic tumor cell line SAOS-2. (2) Methods: Cells were exposed to HBO in an experimental hyperbaric chamber (4 ATA, 100% oxygen, 37 °C, and 4 h) or sham-exposed (1 ATA, air, 37 °C, and 4 h). DNA damage was examined before, directly after, and 24 h after exposure with an alkaline comet assay and detection of γH2AX+53BP1 colocalizing double-strand break (DSB) foci and apoptosis. The gene expression of TGFß-1, HO-1, and NQO1, involved in antioxidative functions, was measured with qRT-PCR. (3) Results: The alkaline comet assay showed significantly elevated levels of DNA damage in both cell lines after 4 h of HBO, while the DSB foci were similar to sham. γH2AX analysis indicated a slight increase in apoptosis in both cell lines. The increased expression of HO-1 in HOB and SAOS-2 directly after exposure suggested the induction of an antioxidative response in these cells. Additionally, the expression of TGF-ß1 was negatively affected in HOB cells 4 h after exposure. (4) Conclusions: in summary, this study indicates that osteoblastic cells are sensitive to the DNA-damaging effects of hyperbaric hyperoxia, with the HBO-induced DNA damage consisting largely of single-strand DNA breaks that are rapidly repaired.

Solriamfetol real world experience study (SURWEY): Initiation, titration, safety, effectiveness, and experience during follow-up for patients with narcolepsy from Germany.

BACKGROUND: Excessive daytime sleepiness (EDS) is a core narcolepsy symptom, for which solriamfetol (Sunosi®) was recently approved in the European Union. SURWEY characterises real-world strategies used by physicians when initiating solriamfetol, and patient outcomes after follow-up. METHODS: SURWEY is an ongoing retrospective chart review conducted by physicians in Germany/France/Italy. Here, data are reported from 70 German patients with EDS and narcolepsy. Eligibility included age ≥18 years, reached a stable solriamfetol dose, and completed ≥6 weeks of treatment. Patients were classified (based on existing EDS treatment) into changeover, add-on, or new-to-therapy subgroups. RESULTS: Patients' mean ± SD age was 36.9 ± 13.9 years. Changeover from prior EDS medication was the most common initiation strategy. Initial solriamfetol dose was typically 75 mg/day (69%). In 30 patients (43%), solriamfetol was titrated; 27/30 (90%) completed titration as prescribed, most within 7 days. Mean ± SD Epworth Sleepiness Scale (ESS) score was 17.6 ± 3.1 at initiation (n = 61) and 13.6 ± 3.8 at follow-up (n = 51). Slight/strong improvements in EDS were perceived for >90% of patients (patient and physician report). Sixty-two percent reported an effect duration of 6 to <10 h; 72% reported no change in perceived nighttime sleep quality. Common adverse events included headache (9%), decreased appetite (6%), and insomnia (6%); no cardiovascular events were reported. CONCLUSIONS: Most patients in this study were switched from a prior EDS medication to solriamfetol. Solriamfetol was typically initiated at 75 mg/day; titration was common. ESS scores improved after initiation, and most patients perceived improvement in EDS. Common adverse events were consistent with those reported in clinical trials. GOV REGISTRATION: N/A.

Low Concentrations of C5a Complement Receptor Antibodies Are Linked to Disease Activity and Relapse in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

OBJECTIVE: To examine concentrations of circulating antibodies targeting C3a and C5a complement receptors in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and analyze their association with disease activity. METHODS: Concentrations of antibodies against C3a and C5a complement receptors (anti-C3aR and anti-C5aR) and plasma complement fragments C3a and C5a were determined in patients with AAV (n = 110; granulomatosis with polyangiitis [GPA; n = 82] or microscopic polyangiitis [MPA; n = 28]), systemic lupus erythematosus (SLE) patients as disease controls (n = 36), and healthy donors (n = 220). C3aR and C5aR expression by circulating neutrophils, monocytes, and T cells was analyzed using flow cytometry. Clinical data were assessed at time of serum sampling and during follow-up for 60 months. RESULTS: In AAV, anti-C3aR and anti-C5aR antibodies were decreased (P = 0.0026 and P ≤ 0.0001, respectively). In remission, anti-C3aR antibody concentrations rose to values comparable to healthy donors, whereas anti-C5aR antibody concentrations did not. In GPA, anti-C5a and anti-C5aR antibody concentrations inversely correlated with each other (r = -0.6831, P = 0.0127). In newly diagnosed GPA, decreased concentrations of anti-C5aR antibodies but not anti-C3aR antibodies were associated with disease activity (P = 0.0009). Moreover, low anti-C5aR antibodies were associated with relapse in GPA (hazard ratio 3.54, P = 0.0009) and MPA (hazard ratio 4.41, P = 0.0041). The frequency of C5aR-expressing cells within T cell populations was increased in GPA (P = 0.0021 for CD4+ T cells; P = 0.0118 for CD8+ T cells), but not in MPA. CONCLUSION: Low concentrations of anti-C5aR antibodies reflect disease activity and are associated with an increased risk for relapse in AAV.

Diving ergospirometry with suspended weights: breathing- and fin-swimming style matter.

PURPOSE: Scuba diving is a complex condition including elevated ambient pressure, limited air supply, increased breathing work, and unfamiliar fin-swimming. Earlier approaches to assess diving specific data did not comprehensively address these aspects. We first present an underwater ergospirometry system and then test the hypothesis that both breathing characteristics and fin-swimming style affect the air consumption. METHODS/PARTICIPANTS: A suspended-weights ergospirometry system was mounted inside a hyperbaric chamber. Ergo group: 25 divers (24.6 ± 4.1 years); three set-ups: dry normobaric cycling (75-225 W), dry cycling at 20 m simulated depth (75-225 W), fin-swimming at 20 m (5-8 kg suspended weights). Style group: 20 other divers (24.6 ± 4.1 years): fin-swimming at 20 m (5-8 kg) with regard to ventilation ([Formula: see text]E) and fin-swimming style. RESULTS: Ergo group: linear heart rate and oxygen uptake ([Formula: see text]O2) increases with both 50 W-bicycle steps and suspended-weights ergometry (r = 0.97). During hyperbaric conditions, [Formula: see text]E was less increased versus normobaric conditions. Style group: the more efficient hip/thigh-oriented style shifted towards the knee/calf-oriented style. [Formula: see text]E and [Formula: see text]O2 were higher in beginners (< 100 dives) versus advanced divers (≥ 100 dives). Significant differences on the 5 kg-step: [Formula: see text]E: 31.5 ± 7.1 l/min vs. 23.7 ± 5.9 l/min and [Formula: see text]O2: 1.6 ± 0.3 l/min vs. 1.2 ± 0.3 l/min. A comparison is presented, in addition to illustrate the impact of differences in breathing characteristics and fin-swimming style. CONCLUSIONS: Diving ergospirometry with suspended weights in a hyperbaric chamber allows for comprehensive studies. Little diving experience in terms of breathing characteristics and fin-swimming style significantly increases [Formula: see text]E thereby increasing the risk of running-out-of-air.

Shot-to-shot two-dimensional photon intensity diagnostics within megahertz pulse-trains at the European XFEL.

Characterizing the properties of X-ray free-electron laser (XFEL) sources is a critical step for optimization of performance and experiment planning. The recent availability of MHz XFELs has opened up a range of new opportunities for novel experiments but also highlighted the need for systematic measurements of the source properties. Here, MHz-enabled beam imaging diagnostics developed for the SPB/SFX instrument at the European XFEL are exploited to measure the shot-to-shot intensity statistics of X-ray pulses. The ability to record pulse-integrated two-dimensional transverse intensity measurements at multiple planes along an XFEL beamline at MHz rates yields an improved understanding of the shot-to-shot photon beam intensity variations. These variations can play a critical role, for example, in determining the outcome of single-particle imaging experiments and other experiments that are sensitive to the transverse profile of the incident beam. It is observed that shot-to-shot variations in the statistical properties of a recorded ensemble of radiant intensity distributions are sensitive to changes in electron beam current density. These changes typically occur during pulse-distribution to the instrument and are currently not accounted for by the existing suite of imaging diagnostics. Modulations of the electron beam orbit in the accelerator are observed to induce a time-dependence in the statistics of individual pulses - this is demonstrated by applying radio-frequency trajectory tilts to electron bunch-trains delivered to the instrument. We discuss how these modifications of the beam trajectory might be used to modify the statistical properties of the source and potential future applications.

Benchmarking the Performance of Irregular Computations in AutoDock-GPU Molecular Docking.

Irregular applications can be found in different scientific fields. In computer-aided drug design, molecular docking simulations play an important role in finding promising drug candidates. AutoDock is a software application widely used for predicting molecular interactions at close distances. It is characterized by irregular computations and long execution runtimes. In recent years, a hardware-accelerated version of AutoDock, called AutoDock-GPU, has been under active development. This work benchmarks the recent code and algorithmic enhancements incorporated into AutoDock-GPU. Particularly, we analyze the impact on execution runtime of techniques based on early termination. These enable AutoDock-GPU to explore the molecular space as necessary, while safely avoiding redundant computations. Our results indicate that it is possible to achieve average runtime reductions of 50% by using these techniques. Furthermore, a comprehensive literature review is also provided, where our work is compared to relevant approaches leveraging hardware acceleration for molecular docking.

Quantification of σ-Acceptor and π-Donor Stabilization in O, S and Hal Analogues of N-Heterocyclic Carbenes (NHCs) on the Magnetic Criterion.

The spatial magnetic properties, through-space NMR shieldings (TSNMRSs), of stable O, S and Hal analogues of N-heterocyclic carbenes (NHCs) have been calculated using the GIAO perturbation method employing the nucleus-independent chemical shift (NICS) concept and the results visualized as iso-chemical-shielding surfaces (ICSSs) of various sizes and directions. The TSNMRS values (actually the anisotropy effects measurable in 1H NMR spectroscopy) are employed to qualify and quantify the position of the present mesomeric equilibria (carbenes ↔ ylides). The results are confirmed by geometry (bond angles and bond lengths), IR spectra, UV spectra, and 13C chemical shifts of the electron-deficient carbon centers.

An Updated Narrative Review on Ergometric Systems Applied to Date in Assessing Divers' Fitness.

Many recreational divers suffer medical conditions, potentially jeopardizing their safety. To scale down risks, medical examinations are mandatory and overwhelmingly performed using bicycle ergometry, which overlooks some important aspects of diving. Searching ergometric systems that better address the underwater environment, a systematic literature search was conducted using the keywords 'diving', 'fitness', 'ergometry', and 'exertion'. All presented alternative systems found convincingly describe a greatly reduced underwater physical performance. Thus, if a diver's workload in air should already be limited, he/she will suffer early from fatigue, risking a diving incident. How to assess fitness? Performance diagnostics in sports is always specific for a modality or movement. Therefore, professional scuba divers should be tested when fin-swimming underwater. For the vast number of recreational divers, the current screening can likely not be replaced. However, to prevent accidents, divers need to understand and be able to improve factors that limit their physical performance underwater. Other systems, presented here, will continue to be important tools in underwater research.

Accelerating AutoDock4 with GPUs and Gradient-Based Local Search.

AutoDock4 is a widely used program for docking small molecules to macromolecular targets. It describes ligand-receptor interactions using a physics-inspired scoring function that has been proven useful in a variety of drug discovery projects. However, compared to more modern and recent software, AutoDock4 has longer execution times, limiting its applicability to large scale dockings. To address this problem, we describe an OpenCL implementation of AutoDock4, called AutoDock-GPU, that leverages the highly parallel architecture of GPU hardware to reduce docking runtime by up to 350-fold with respect to a single-threaded process. Moreover, we introduce the gradient-based local search method ADADELTA, as well as an improved version of the Solis-Wets random optimizer from AutoDock4. These efficient local search algorithms significantly reduce the number of calls to the scoring function that are needed to produce good results. The improvements reported here, both in terms of docking throughput and search efficiency, facilitate the use of the AutoDock4 scoring function in large scale virtual screening.