H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Quality of occlusal outcome in adult class II patients after maxillary total arch distalization with interradicular mini-screws.

BACKGROUND: The aim of the investigation was to evaluate if a Class II malocclusion in adult patients can be successfully corrected by maxillary total arch distalization with interradicular mini-screws in combination with completely customized lingual appliances (CCLA). METHODS: Two patient groups were matched for age and gender to determine differences in the quality of final treatment outcome. The treatment results of 40 adult patients with a Class I malocclusion (Group 1) were compared with those of 40 adult patients with a moderate to severe Class II malocclusion (Group 2). All patients had completed treatment with a CCLA (WIN, DW Lingual Systems, Bad Essen, Germany) without overcorrection in the individual treatment plan defined by a target set-up. To compare the treatment results of the two groups, 7 measurements using the American Board of Orthodontics Model Grading System (ABO MGS) and linear measurements for anterior-posterior (AP) and vertical dimensions were assessed at the start of lingual treatment (T1), after debonding (T2B), and compared to the individual target set-up (T2A). RESULTS: A statistically significant AP correction (mean 4.5 mm, min/max 2.1/8.6, SD 1.09) was achieved in Group 2, representing 99% of the planned amount. The planned overbite correction was fully achieved in both the Class I and Class II groups. There was a statistically significant improvement in the ABO scores in both groups (Group 1: 39.4 to 17.7, Group 2: 55.8 to 17.1), with no significant difference between the two groups at T2B. 95% of the adult patients in Group 1 and 95% in Group 2 would meet the ABO standards after maxillary total arch distalization with a CCLA and interradicular mini-screws. CONCLUSIONS: CCLAs in combination with interradicular mini-screws for maxillary total arch distalization can successfully correct moderate to severe Class II malocclusions in adult patients. The quality of the final occlusal outcome is high and the amount of the sagittal correction can be predicted by the individual target set-up.

Formation of Peroxynitrite, [O-N-O-O]-, via a Cascade of Reactions between Ozonide and Ammonia.

We report on an unexpected reaction between ammonia and potassium ozonide dissolved in liq. NH3 resulting in the formation of peroxynitrite, [ONOO]-, which exclusively happens in the presence of a specific partially fluorinated aniline-based ammonium cation. High-resolution structural data of the peroxynitrite anion in cis-conformation have been obtained. We further studied this molecule anion by single crystal Raman spectroscopy. The cis and trans isomers of peroxynitrite were analysed computationally with respect to their relative energies, the cis-trans transition barrier and their decomposition pathways to the nitrate anion. By experimentally examining cations decorated with fluorine ligands to different degrees, we demonstrate that fluorine specific interactions play a crucial role in the unexpected formation of peroxynitrite and as a conspicuously structure directing factor for the underlying crystalline solid phases, exhibiting distinct micro-separations of fluorine and hydrogen enriched regions.

Accuracy and tracing time of cephalometric analyses on a tablet or desktop computer : A prospective study.

BACKGROUND: This prospective study aimed to evaluate the influence of the computer type (tablet or desktop) on accuracy and tracing time of cephalometric analyses. METHODS: Dental students used a web-based application specifically developed for this purpose to perform cephalometric analyses on tablet and desktop computers. Landmark locations and timestamps were exported to measure the accuracy, successful detection rate and tracing time. Reference landmarks were established by six experienced orthodontists. Statistical analysis included reliability assessment, descriptive statistics, and linear mixed effect models. RESULTS: Over a period of 8 semesters a total of 277 cephalometric analyses by 161 students were included. The interrater reliability of the orthodontists establishing the reference coordinates was excellent (ICC > 0.9). For the students, the mean landmark deviation was 2.05 mm and the successful detection rate for the clinically acceptable threshold of 2 mm suggested in the literature was 68.6%, with large variations among landmarks. No effect of the computer type on accuracy and tracing time of the cephalometric analyses could be found. CONCLUSION: The use of tablet computers for cephalometric analyses can be recommended.

The Position of the Virtual Hinge Axis in Relation to the Maxilla in Digital Orthognathic Surgery Planning-A k-Means Cluster Analysis.

The aim of this study was to investigate a possible relation between skeletal phenotypes and virtual mounting data in orthognathic surgery patients. A retrospective cohort study including 323 female (26.1 ± 8.7 years) and 191 male (27.9 ± 8.3 years) orthognathic surgery patients was conducted. A k-means cluster analysis was performed on the mounting parameters: the angle α between the upper occlusal plane (uOP) and the axis orbital plane (AOP); the perpendicular distance (AxV) from the uOP to the hinge axis; and the horizontal length (AxH) of the uOP from upper incisor edge to AxV, with subsequent statistical analysis of related cepalometric values. Three clusters of mounting data were identified, representing three skeletal phenotypes: (1) balanced face with marginal skeletal class II or III and α=8∘, AxV = 36 mm and AxH = 99 mm; (2) vertical face with skeletal class II and α=11∘, AxV = 27 mm and AxH = 88 mm; (3) horizontal face with class III and α=2∘, AxV = 36 mm and AxH = 86 mm. The obtained data on the position of the hinge axis can be applied to any digital planning in orthognathic surgery using CBCT or a virtual articulator, provided that the case can be clearly assigned to one of the calculated clusters.

Non-Surgical Transversal Dentoalveolar Compensation with Completely Customized Lingual Appliances versus Surgically Assisted Rapid Palatal Expansion in Adults-Tipping or Translation in Posterior Crossbite Correction?

The aim of this study was to investigate buccolingual tooth movements (tipping/translation) in surgical and nonsurgical posterior crossbite correction. A total of 43 patients (f/m 19/24; mean age 27.6 ± 9.5 years) treated with surgically assisted rapid palatal expansion (SARPE) and 38 patients (f/m 25/13; mean age 30.4 ± 12.9 years) treated with dentoalveolar compensation using completely customized lingual appliances (DC-CCLA) were retrospectively included. Inclination was measured on digital models at canines (C), second premolars (P2), first molars (M1), and second molars (M2) before (T0) and after (T1) crossbite correction. There was no statistically significant difference (p > 0.05) in absolute buccolingual inclination change between both groups, except for the upper C (p < 0.05), which were more tipped in the surgical group. Translation, i.e., bodily tooth movements that cannot be explained by pure uncontrolled tipping, could be observed with SARPE in the maxilla and with DC-CCLA in both jaws. Dentoalveolar transversal compensation with completely customized lingual appliances does not cause greater buccolingual tipping compared to SARPE.

High-dimensional analysis of 16 SARS-CoV-2 vaccine combinations reveals lymphocyte signatures correlating with immunogenicity.

The range of vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) provides a unique opportunity to study immunization across different platforms. In a single-center cohort, we analyzed the humoral and cellular immune compartments following five coronavirus disease 2019 (COVID-19) vaccines spanning three technologies (adenoviral, mRNA and inactivated virus) administered in 16 combinations. For adenoviral and inactivated-virus vaccines, heterologous combinations were generally more immunogenic compared to homologous regimens. The mRNA vaccine as the second dose resulted in the strongest antibody response and induced the highest frequency of spike-binding memory B cells irrespective of the priming vaccine. Priming with the inactivated-virus vaccine increased the SARS-CoV-2-specific T cell response, whereas boosting did not. Distinct immune signatures were elicited by the different vaccine combinations, demonstrating that the immune response is shaped by the type of vaccines applied and the order in which they are delivered. These data provide a framework for improving future vaccine strategies against pathogens and cancer.

Direct visualization of transcription-replication conflicts reveals post-replicative DNA:RNA hybrids.

Transcription-replication collisions (TRCs) are crucial determinants of genome instability. R-loops were linked to head-on TRCs and proposed to obstruct replication fork progression. The underlying mechanisms, however, remained elusive due to the lack of direct visualization and of non-ambiguous research tools. Here, we ascertained the stability of estrogen-induced R-loops on the human genome, visualized them directly by electron microscopy (EM), and measured R-loop frequency and size at the single-molecule level. Combining EM and immuno-labeling on locus-specific head-on TRCs in bacteria, we observed the frequent accumulation of DNA:RNA hybrids behind replication forks. These post-replicative structures are linked to fork slowing and reversal across conflict regions and are distinct from physiological DNA:RNA hybrids at Okazaki fragments. Comet assays on nascent DNA revealed a marked delay in nascent DNA maturation in multiple conditions previously linked to R-loop accumulation. Altogether, our findings suggest that TRC-associated replication interference entails transactions that follow initial R-loop bypass by the replication fork.

Non-Surgical Transversal Dentoalveolar Compensation with Completely Customized Lingual Appliances versus Surgically Assisted Rapid Palatal Expansion in Adults-The Amount of Posterior Crossbite Correction.

The aim of this study was to compare the crossbite correction of a group (n = 43; f/m 19/24; mean age 27.6 ± 9.5 years) with surgically assisted rapid palatal expansion (SARPE) versus a non-surgical transversal dentoalveolar compensation (DC) group (n = 38; f/m 25/13; mean age 30.4 ± 12.9 years) with completely customized lingual appliances (CCLA). Arch width was measured on digital models at the canines (C), second premolars (P2), first molars (M1) and second molars (M2). Measurements were obtained before treatment (T0) and at the end of lingual treatment (T1) or after orthodontic alignment prior to a second surgical intervention for three-dimensional bite correction. There was no statistically significant difference (p > 0.05) in the amount of total crossbite correction between the SARPE and DC-CCLA group at C, P2, M1 and M2. Maxillary expansion was greater in the SARPE group and mandibular compression was greater in the DC-CCLA group. Crossbite correction in the DC-CCLA group was mainly a combination of maxillary expansion and mandibular compression. Dentoalveolar compensation with CCLAs as a combination of maxillary expansion and mandibular compression seems to be a clinically effective procedure to correct a transverse maxillo-mandibular discrepancy without the need for surgical assistance.

Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming.

Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.

Anion-assisted amidinium exchange and metathesis.

Dynamic covalent chemistry has become an invaluable tool for the design and preparation of adaptable yet robust molecular systems. Herein we explore the scope of a largely overlooked dynamic covalent reaction - amidinium exchange - and report on conditions that allow formal amidinium metathesis reactions.

Free-Breathing Low-Field MRI of the Lungs Detects Functional Alterations Associated With Persistent Symptoms After COVID-19 Infection.

OBJECTIVES: With the COVID-19 pandemic, repetitive lung examinations have become necessary to follow-up symptoms and associated alterations. Low-field MRI, benefiting from reduced susceptibility effects, is a promising alternative for lung imaging to limit radiations absorbed by patients during CT examinations, which also have limited capability to assess functional alterations. The aim of this investigative study was to explore the functional abnormalities that free-breathing 0.55 T MRI in combination with the phase-resolved functional lung (PREFUL) analysis could identify in patients with persistent symptoms after COVID-19 infection. MATERIALS AND METHODS: Seventy-four COVID-19 patients and 8 healthy volunteers were prospectively scanned in free-breathing with a balanced steady-state free-precession sequence optimized at 0.55 T, 5 months postinfection on average. Normalized perfusion (Q), fractional ventilation (FV), and flow-volume loop correlation (FVLc) maps were extracted with the PREFUL technique. Q, FV, and FVLc defects as well as defect overlaps between these metrics were quantified. Morphological turbo-spin-echo images were also acquired, and the extent of abnormalities was scored by a board-certified radiologist. To investigate the functional correlates of persistent symptoms, a recursive feature elimination algorithm was applied to find the most informative variables to detect the presence of persistent symptoms with a logistic regression model and a cross-validation strategy. All MRI metrics, sex, age, body mass index, and the presence of preexisting lung conditions were included. RESULTS: The most informative variables to detect persistent symptoms were the percentage of concurrent Q and FVLc defects and of areas free of those defects. A detection accuracy of 71.4% was obtained with these 2 variables when fitting the model on the entire dataset. Although none of the single variables differed between patients with and without persistent symptoms ( P > 0.05), the combined score of these 2 variables did ( P < 0.02). This score also showed a consistent increase from healthy volunteers (7.7) to patients without persistent symptoms (8.2) and with persistent symptoms (8.6). The morphological abnormality score showed poor correlation with the functional parameters. CONCLUSIONS: Functional pulmonary examinations using free-breathing 0.55 T MRI with PREFUL analysis revealed potential quantitative markers of impaired lung function in patients with persistent symptoms after COVID-19 infection, potentially complementing morphologic imaging. Future work is needed to explore the translational relevance and clinical implication of these findings.

Radical C-H Trifluoromethoxylation of (Hetero)arenes with Bis(trifluoromethyl)peroxide.

Trifluoromethoxylated (hetero)arenes are of great interest for several disciplines, especially in agro- and medicinal chemistry. Radical C-H trifluoromethoxylation of (hetero)arenes represents an attractive approach to prepare such compounds, but the high cost and low atom economy of existing . OCF3 radical sources make them unsuitable for the large-scale synthesis of trifluoromethoxylated building blocks. Herein, we introduce bis(trifluoromethyl)peroxide (BTMP, CF3 OOCF3 ) as a practical and efficient trifluoromethoxylating reagent that is easily accessible from inexpensive bulk chemicals. Using either visible light photoredox or TEMPO catalysis, trifluoromethoxylated arenes could be prepared in good yields under mild conditions directly from unactivated aromatics. Moreover, TEMPO catalysis allowed for the one-step synthesis of valuable pyridine derivatives, which have been previously prepared via multi-step approaches.

Generative adversarial networks for the design of acoustic metamaterials.

Metamaterials are attracting increasing interest in the field of acoustics due to their sound insulation effects. By periodically arranged structures, acoustic metamaterials can influence the way sound propagates in acoustic media. To date, the design of acoustic metamaterials relies primarily on the expertise of specialists since most effects are based on localized solutions and interference. This paper outlines a deep learning-based approach to extend current knowledge of metamaterial design in acoustics. We develop a design method by using conditional generative adversarial networks. The generative network proposes a cell candidate regarding a desired transmission behavior of the metamaterial. To validate our method, numerical simulations with the finite element method are performed. Our study reveals considerable insight into design strategies for sound insulation tasks. By providing design directives for acoustic metamaterials, cell candidates can be inspected and tailored to achieve desirable transmission characteristics.

Acoustics Apps: Interactive simulations for digital teaching and learning of acoustics.

This paper presents the Acoustics Apps, an e-learning platform that offers an interactive and playful environment for teaching and learning the principles of acoustics and vibration. The Acoustics Apps address the increasing demand for digitized teaching methods, which might be suitable for home schooling or as a complement to physical experiments by adding interactive simulation. The apps combine learning by experimenting, observing, and exploring using state-of-the-art scientific methods and numerical simulations. The ability to visualize and control acoustic phenomena facilitates understanding of the relevant physical principles. The apps are designed to be used intuitively and can be tailored to suit the existing knowledge of the user. As such, a wide range of users can benefit from this learning aid. It has been developed to allow barrier-free access to modern educational tools, requiring only a device with a browser and Internet access. The necessary computing power is provided by an external server using the COMSOL ServerTM technology. The Acoustics Apps are freely available for academic and teaching purposes at apps.vib.mw.tum.de.

Extreme weather events in europe and their health consequences - A systematic review.

BACKGROUND: Due to climate change, the frequency, intensity and severity of extreme weather events, such as heat waves, cold waves, storms, heavy precipitation causing wildfires, floods, and droughts are increasing, which could adversely affect human health. The purpose of this systematic review is therefore to assess the current literature about the association between these extreme weather events and their impact on the health of the European population. METHODS: Observational studies published from January 1, 2007 to May 17, 2020 on health effects of extreme weather events in Europe were searched systematically in Medline, Embase and Cochrane Central Register of Controlled Trials. The exposures of interest included extreme temperature, heat waves, cold waves, droughts, floods, storms and wildfires. The health impacts included total mortality, cardiovascular mortality and morbidity, respiratory mortality and morbidity, and mental health. We conducted the systematic review following PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis). The quality of the included studies was assessed using the NICE quality appraisal checklist (National Institute for Health and Care Excellence). RESULTS: The search yielded 1472 articles, of which 35 met the inclusion criteria and were included in our review. Studies regarding five extreme weather events (extreme heat events, extreme cold events, wildfires, floods, droughts) were found. A positive association between extreme heat/cold events and overall, cardiovascular and respiratory mortality was reported from most studies. Wildfires are likely to increase the overall and cardiovascular mortality. Floods might be associated with the deterioration of mental health instead of mortality. Depending on their length, droughts could have an influence on both respiratory and cardiovascular mortality. Contradictory evidence was found in heat-associated morbidity and wildfire-associated respiratory mortality. The associations are inconclusive due to the heterogeneous study designs, study quality, exposure and outcome assessment. CONCLUSIONS: Evidence from most of the included studies showed that extreme heat and cold events, droughts, wildfires and floods in Europe have negative impacts on human health including mental health, although some of the associations are not conclusive. Additional high-quality studies are needed to confirm our results and further studies regarding the effects of other extreme weather events in Europe are to be expected.

Conductivity and Redox Potentials of Ionic Liquid Trihalogen Monoanions [X3 ]- , [XY2 ]- , and [BrF4 ]- (X=Cl, Br, I and Y=Cl, Br).

The ionic liquid (IL) trihalogen monoanions [N2221 ][X3 ]- and [N2221 ][XY2 ]- ([N2221 ]+ =triethylmethylammonium, X=Cl, Br, I, Y=Cl, Br) were investigated electrochemically via temperature dependent conductance and cyclic voltammetry (CV) measurements. The polyhalogen monoanions were measured both as neat salts and as double salts in 1-butyl-1-methyl-pyrrolidinium trifluoromethane-sulfonate ([BMP][OTf], [X3 ]- /[XY2 ]- 0.5 M). Lighter IL trihalogen monoanions displayed higher conductivities than their heavier homologues, with [Cl3 ]- being 1.1 and 3.7 times greater than [Br3 ]- and [I3 ]- , respectively. The addition of [BMP][OTf] reduced the conductivity significantly. Within the group of polyhalogen monoanions, the oxidation potential develops in the series [Cl3 ]- >[BrCl2 ]- >[Br3 ]- >[IBr2 ]- >[ICl2 ]- >[I3 ]- . The redox potential of the interhalogen monoanions was found to be primarily determined by the central halogen, I in [ICl2 ]- and [IBr2 ]- , and Br in [BrCl2 ]- . Additionally, tetrafluorobromate(III) ([N2221 ]+ [BrF4 ]- ) was analyzed via CV in MeCN at 0 °C, yielding a single reversible redox process ([BrF2 ]- /[BrF4 ]- ).

Spatial reconstruction of the sound field in a room in the modal frequency range using Bayesian inference.

Spatial characterization of the sound field in a room is a challenging task, as it usually requires a large number of measurement points. This paper presents a probabilistic approach for sound field reconstruction in the modal frequency range for small and medium-sized rooms based on Bayesian inference. A plane wave expansion model is used to decompose the sound field in the examined domain. The posterior distribution for the amplitude of each plane wave is inferred based on a uniform prior distribution with limits based on the maximum sound pressure observed in the measurements. Two different application cases are studied, namely a numerically computed sound field in a non-rectangular two-dimensional (2D) domain and a measured sound field in a horizontal evaluation area of a lightly damped room. The proposed reconstruction method provides an accurate reconstruction for both examined cases. Further, the results of Bayesian inference are compared to the reconstruction with a deterministic compressive sensing framework. The most significant advantage of the Bayesian method over deterministic reconstruction approaches is that it provides a probability distribution of the sound pressure at every reconstruction point, and thus, allows quantifying the uncertainty of the recovered sound field.

Analysis of Structural and Functional Differences of Glucans Produced by the Natively Released Dextransucrase of Liquorilactobacillus hordei TMW 1.1822.

The properties of the glucopolymer dextran are versatile and linked to its molecular size, structure, branching, and secondary structure. However, suited strategies to control and exploit the variable structures of dextrans are scarce. The aim of this study was to delineate structural and functional differences of dextrans, which were produced in buffers at different conditions using the native dextransucrase released by Liquorilactobacillus (L.) hordei TMW 1.1822. Rheological measurements revealed that dextran produced at pH 4.0 (MW = 1.1 * 108 Da) exhibited the properties of a viscoelastic fluid up to concentrations of 10% (w/v). By contrast, dextran produced at pH 5.5 (MW = 1.86 * 108 Da) was gel-forming already at 7.5% (w/v). As both dextrans exhibited comparable molecular structures, the molecular weight primarily influenced their rheological properties. The addition of maltose to the production assays caused the formation of the trisaccharide panose instead of dextran. Moreover, pre-cultures of L. hordei TMW 1.1822 grown without sucrose were substantial for recovery of higher dextran yields, since the cells stored the constitutively expressed dextransucrase intracellularly, until sucrose became available. These findings can be exploited for the controlled recovery of functionally diverse dextrans and oligosaccharides by the use of one dextransucrase type.