Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death

Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca2+ fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation accounts for essentially the entire Ca2+ influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals and reduces cell death. ADP-ribose-loading of cells induces Ca2+ fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments and communicates via three types of chemical messengers: a nucleotide, a cation, and protein

Dentofacial and upper airway characteristics of mild and severe class II division 1 subjects

The aim of this retrospective, cross-sectional study was to assess whether mild and severe Class II division 1 subjects have craniofacial and upper airway characteristics, which relate to the severity of Class II as judged by overjet or ANB angle. The sample consisted of pre-treatment lateral cephalograms and dental casts of 131 males and 115 females (mean age 10.4 ± 1.6). Inclusion criteria were: healthy Caucasian subjects, at least ¾ Class II first molar relationship on both sides and overjet ≥ 4 mm. The cephalograms were traced and digitized. Distances and angular values were computed. Mild and severe Class II was defined by overjet (<10 mm/≥ 10 mm) or by ANB angle (<7 degrees/≥7 degrees). Statistics were performed with two-sample t-test and Pearson's correlation analysis. In the two overjet groups, significant differences were mainly found for incisor inclination while the two ANB groups differed significantly in SNA, WITS, Go-Pg, SpaSpp/MGo, SN/MGo, and Ar-Gn. The shortest airway distance between the soft palate and the posterior pharyngeal wall was significantly correlated to the NS/Ar angle. Statistical analysis revealed several significant correlations. Patients with a large overjet or ANB angle differed significantly from patients with a small overjet or ANB angle mainly in their incisor inclination. In the present sample, the overjet and to some extent also the ANB angle is determined by soft tissue or individual tooth position rather than by skeletal background. In retrognathic patients, a tendency towards smaller airway dimensions was found. However, statistical analysis did not reveal a strong connection between upper airway and dentoskeletal parameters, but a large interindividual variatio

Final Posttreatment Occlusion in Patients With Unilateral Cleft Lip and Palate

Objective: To evaluate final posttreatment occlusion in patients with complete unilateral cleft lip and palate (cUCLP) by comparing (1) 3 treatment centers, (2) males and females, (3) cleft and noncleft sides, (4) right- and left-sided clefts, and (5) orthodontic treatment with/without orthognathic surgery (OS). Design: Retrospective cohort study. Patients: Blinded posttreatment dental casts of 56 patients (19.4 ± 1.4 years) with cUCLP from 3 centers in Switzerland. Main outcome measure: Occlusal assessment using the modified Huddart/Bodenham (MHB) index. Results: Our sample comprised 35 males and 21 females, 46 with left- and 10 with right-sided clefts, of which 32 had undergone OS. The final posttreatment occlusion showed a median MHB score of 0 (interquartile range: -1.0 to 2.0) in the total sample and did not seem to depend on treatment center, sex, or OS. The MHB scores for the anterior buccal and the buccal segments were more negative on the cleft than on the noncleft side (P = .002 and P = .006, respectively). When the cleft was on the left side, the MHB score tended to be more positive in the labial (P = .046) and anterior buccal segments (P = .034). Conclusions: This study shows a very satisfactory final posttreatment occlusion in patients with cUCLP. The more constricted buccal occlusion on the cleft side emphasizes the attention that should be given in correcting the more medially positioned lesser maxillary segment. The influence of cleft-sidedness should be analyzed further on a sample including more patients with right-sided clefts. Keywords: Treatment outcome; cleft lip and palate; crossbite; dental arch relationships; dental occlusion; final post-treatment; multicentre study

Annual Variation in Atmospheric 14C between 1700 BC and 1480 BC

In 2018 Pearson et al. published a new sequence of annual radiocarbon (14C) data derived from oak (Quercus sp.) trees from Northern Ireland and bristlecone pine (Pinus longaeva) from North America across the period 1700–1500 BC. The study indicated that the more highly resolved shape of an annually based calibration dataset could improve the accuracy of 14C calibration during this period. This finding had implications for the controversial dating of the eruption of Thera in the Eastern Mediterranean. To test for interlaboratory variation and improve the robustness of the annual dataset for calibration purposes, we have generated a replicate sequence from the same Irish oaks at ETH Zürich. These data are compatible with the Irish oak 14C dataset previously produced at the University of Arizona and are used (along with additional data) to examine inter-tree and interlaboratory variation in multiyear annual 14C time-series. The results raise questions about regional 14C offsets at different scales and demonstrate the potential of annually resolved 14C for refining subdecadal and larger scale features for calibration, solar reconstruction, and multiproxy synchronization

Glutamine supplementation in cystic fibrosis: a randomized placebo-controlled trial

Rationale: Pulmonary infection and malnutrition in cystic fibrosis are associated with decreased survival. Glutamine has a possible anti-microbial effect, with a specific impact against Pseudomonas aeruginosa. We aimed to test the hypothesis that oral glutamine supplementation (21 g/day) for 8 weeks in adults with cystic fibrosis would decrease pulmonary inflammation and improve clinical status. Methods: The study design was a randomized double-blind placebo-controlled study design with an iso-nitrogenous placebo. The primary analysis was intention to treat, and the primary outcome was change in induced sputum neutrophils. Results: Thirty-nine individuals were recruited and thirty-six completed the study. Glutamine supplementation had no impact on any of the outcome measures in the intention-to-treat analysis. In the per protocol analysis, glutamine supplementation was associated with an increase in induced sputum neutrophils (P = 0.046), total cells (P = 0.03), and in Pseudomonas isolation agar colony forming units (P = 0.04) compared to placebo. Conclusions: There was no effect of glutamine supplementation on markers of pulmonary inflammation in the intention-to-treat analysis

Comparability of radiocarbon measurements in dissolved inorganic carbon of seawater produced at ETH-Zurich

Radiocarbon observations (Δ14C) in dissolved inorganic carbon (DIC) of seawater provide useful information about ocean carbon cycling and ocean circulation. To deliver high-quality observations, the Laboratory of Ion Beam Physics (LIP) at ETH-Zurich developed a new simplified method allowing the rapid analysis of radiocarbon in DIC of small seawater samples, which is continually assessed by following internal quality controls. However, a comparison with externally produced 14C measurements to better establish an equivalency between methods was still missing. Here, we make the first intercomparison with the National Ocean Sciences Accelerator Mass Spectrometry (NOSAMS) facility based on 14 duplicate seawater samples collected in 2020. We also compare with prior deep-water observations from the 1970s to 1990s. The results show a very good agreement in both comparisons. The mean Δ14C of 12 duplicate samples measured by LIP and NOSAMS were statistically identical within one sigma uncertainty while two other duplicate samples agreed within two sigma. Based on this small number of duplicate samples, LIP values appear to be slightly lower than the NOSAMS values, but more measurements will be needed for confirmation. We also comment on storage and preservation techniques used in this study, including the freezing of samples collected in foil bags