Reactions of Imidazolio-Phosphides with Organotin Chlorides : Surprisingly Diverse

Reactions of primary imidazolio-phosphides ("imidazolylidene-phosphinidenes") with R2SnCl2 yield as main products spectroscopically detectable Lewis pairs which undergo base-induced dehydrochlorination in the presence of excess dichlorostannane to afford zwitterionic chloride adducts of distannylated imidazolio-phosphines. In contrast, reactions with R3SnCl proceed under dismutation to furnish mixtures containing imidazolium salts and stannylated (oligo)phosphines P(SnR3)(3) and P-7(SnR3)(3), respectively. DFT studies were used to rationalize the divergent behavior based on the presumption that the reactions proceed under thermodynamic control and the products observed represent the most stable species under the specific reaction conditions. Computational simulation of selected reaction steps provides a model mechanism for Lewis-acid promoted creation of PP-bonds, which is a prerequisite for oligophosphine formation. The computational studies further highlight parallels between reactions of imidazolio-phosphides with Lewis and Bronsted acids, and allow also to extrapolate the behavior of the P-nucleophiles towards other electrophiles than organotin chlorides.Peer reviewe

Machine Learning Nucleation Collective Variables with Graph Neural Networks

The efficient calculation of nucleation collective variables (CVs) is one of the main limitations to the application of enhanced sampling methods to the investigation of nucleation processes in realistic environments. Here we discuss the development of a graph-based model for the approximation of nucleation CVs that enables orders-of-magnitude gains in computational efficiency in the on-the-fly evaluation of nucleation CVs. By performing simulations on a nucleating colloidal system mimicking a multistep nucleation process from solution, we assess the model's efficiency in both postprocessing and on-the-fly biasing of nucleation trajectories with pulling, umbrella sampling, and metadynamics simulations. Moreover, we probe and discuss the transferability of graph-based models of nucleation CVs across systems using the model of a CV based on sixth-order Steinhardt parameters trained on a colloidal system to drive the nucleation of crystalline copper from its melt. Our approach is general and potentially transferable to more complex systems as well as to different CVs

Deducing corticotropin-releasing hormone receptor type 1 signaling networks from gene expression data by usage of genetic algorithms and graphical Gaussian models

<p>Abstract</p> <p>Background</p> <p>Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of complex and multifactorial psychiatric diseases such as anxiety and mood disorders. About 50-60% of patients with major depression show HPA axis dysfunction, i.e. hyperactivity and impaired negative feedback regulation. The neuropeptide corticotropin-releasing hormone (CRH) and its receptor type 1 (CRHR1) are key regulators of this neuroendocrine stress axis. Therefore, we analyzed CRH/CRHR1-dependent gene expression data obtained from the pituitary corticotrope cell line AtT-20, a well-established <it>in vitro </it>model for CRHR1-mediated signal transduction. To extract significantly regulated genes from a genome-wide microarray data set and to deduce underlying CRHR1-dependent signaling networks, we combined supervised and unsupervised algorithms.</p> <p>Results</p> <p>We present an efficient variable selection strategy by consecutively applying univariate as well as multivariate methods followed by graphical models. First, feature preselection was used to exclude genes not differentially regulated over time from the dataset. For multivariate variable selection a maximum likelihood (MLHD) discriminant function within GALGO, an R package based on a genetic algorithm (GA), was chosen. The topmost genes representing major nodes in the expression network were ranked to find highly separating candidate genes. By using groups of five genes (chromosome size) in the discriminant function and repeating the genetic algorithm separately four times we found eleven genes occurring at least in three of the top ranked result lists of the four repetitions. In addition, we compared the results of GA/MLHD with the alternative optimization algorithms greedy selection and simulated annealing as well as with the state-of-the-art method random forest. In every case we obtained a clear overlap of the selected genes independently confirming the results of MLHD in combination with a genetic algorithm.</p> <p>With two unsupervised algorithms, principal component analysis and graphical Gaussian models, putative interactions of the candidate genes were determined and reconstructed by literature mining. Differential regulation of six candidate genes was validated by qRT-PCR.</p> <p>Conclusions</p> <p>The combination of supervised and unsupervised algorithms in this study allowed extracting a small subset of meaningful candidate genes from the genome-wide expression data set. Thereby, variable selection using different optimization algorithms based on linear classifiers as well as the nonlinear random forest method resulted in congruent candidate genes. The calculated interacting network connecting these new target genes was bioinformatically mapped to known CRHR1-dependent signaling pathways. Additionally, the differential expression of the identified target genes was confirmed experimentally.</p

Relationship between subduction erosion and the up‐dip limit of the 2014 Mw 8.1 Iquique earthquake

The aftershock distribution of the 2014 Mw 8.1 Iquique earthquake offshore northern Chile, identified from a long‐term deployment of ocean bottom seismometers installed eight months after the mainshock, in conjunction with seismic reflection imaging, provides insights into the processes regulating the up‐dip limit of coseismic rupture propagation. Aftershocks up‐dip of the mainshock hypocenter frequently occur in the upper plate and are associated with normal faults identified from seismic reflection data. We propose that aftershock seismicity near the plate boundary documents subduction erosion that removes mass from the base of the wedge and results in normal faulting in the upper plate. The combination of very little or no sediment accretion and subduction erosion over millions of years has resulted in a very weak and aseismic frontal wedge. Our observations thus link the shallow subduction zone seismicity to subduction erosion processes that control the evolution of the overriding plate. Key Points: - We investigate structure and seismicity at the up-dip end of the 2014 Iquique earthquake rupture using amphibious seismic data. - Seismicity up-dip of the 2014 Iquique earthquake occurs over a broad range likely interpreted to be related to the basal erosion processes. - Coseismic stress changes and aftershocks activate extensional faulting of the upper plate and subduction erosion

Seismogenic up-dip limit of the 2014 Mw 8.1 Iquique earthquake links subduction erosion and upper plate deformation

The 2014 Mw 8.1 Iquique earthquake ruptured the boundary between the subducting Nazca Plate and the overriding South American Plate in the North Chilean subduction zone. The broken segment of the South American subduction zone had likely accumulated elastic strain since an M~9 earthquake in 1877 and what therefore considered a mature seismic gap. The moderate magnitude of the 2014 earthquake and its compact rupture area, which only broke the central part of the seismic gap, did not result in a significant tsunami in the Pacific Ocean. To investigate the seismo-tectonic segmentation of the North Chilean subduction zone in the region of the 2014 Iquique earthquake at the shallow seismic/aseismic transition, we combine two years of local aftershock seismicity observations from ocean bottom seismometers and long- offset seismic reflection data from the rupture area. Our study links short term deformation associated with a single seismic cycle to the permanent deformation history of an erosive convergent margin over millions of years. A high density of aftershocks following the 2014 Iquique earthquake occurred in the up-dip region of the coseismic rupture, where they form a trench parallel band. The events spread from the subducting oceanic plate across the plate boundary and into the overriding continental crust. The band of aftershock seismicity separates a pervasively fractured and likely fluid-filled marine forearc farther seaward from a less deformed section of the forearc farther landward. At the transition, active subduction erosion during the postseismic and possibly coseismic phases of the 2014 Iquique earthquake leads to basal abrasion of the upper plate and associated extensional faulting of the overlying marine forearc. Landward migration of the seismogenic up-dip limit, possibly at similar rates compared to the trench and the volcanic arc, leaves behind a heavily fractured and fluid-filled outermost forearc. This most seaward part of the subduction zone might be too weak to store sufficient elastic strain to nucleate a large megathrust earthquake

Insights into replicative senescence of human testicular peritubular cells

There is evidence for an age-related decline in male reproductive functions, yet how the human testis may age is not understood. Human testicular peritubular cells (HTPCs) transport sperm, contribute to the spermatogonial stem cell (SSC) niche and immune surveillance, and can be isolated and studied in vitro. Consequences of replicative senescence of HTPCs were evaluated to gain partial insights into human testicular aging. To this end, early and advanced HTPC passages, in which replicative senescence was indicated by increased cell size, altered nuclear morphology, enhanced beta-galactosidase activity, telomere attrition and reduced mitochondrial DNA (mtDNA), were compared. These alterations are typical for senescent cells, in general. To examine HTPC-specific changes, focused ion beam scanning electron microscopy (FIB/SEM) tomography was employed, which revealed a reduced mitochondrial network and an increased lysosome population. The results coincide with the data of a parallel proteomic analysis and indicate deranged proteostasis. The mRNA levels of typical contractility markers and growth factors, important for the SSC niche, were not significantly altered. A secretome analysis identified, however, elevated levels of macrophage migration inhibitory factor (MIF) and dipeptidyl peptidase 4 (DPP4), which may play a role in spermatogenesis. Testicular DPP4 may further represent a possible drug target

Observational constraints on methane emissions from Polish coal mines using a ground-based remote sensing network

Given its abundant coal mining activities, the Upper Silesian Coal Basin (USCB) in southern Poland is one of the largest sources of anthropogenic methane (CH$_{4}$) emissions in Europe. Here, we report on CH$_{4}$emission estimates for coal mine ventilation facilities in the USCB. Our estimates are driven by pairwise upwind–downwind observations of the column-average dry-air mole fractions of CH$_{4}$ (XCH$_{4}$) by a network of four portable, ground-based, sun-viewing Fourier transform spectrometers of the type EM27/SUN operated during the CoMet campaign in May–June 2018. The EM27/SUN instruments were deployed in the four cardinal directions around the USCB approximately 50 km from the center of the basin. We report on six case studies for which we inferred emissions by evaluating the mismatch between the observed downwind enhancements and simulations based on trajectory calculations releasing particles out of the ventilation shafts using the Lagrangian particle dispersion model FLEXPART. The latter was driven by wind fields calculated by WRF (Weather Research and Forecasting model) under assimilation of vertical wind profile measurements of three co-deployed wind lidars. For emission estimation, we use a Phillips–Tikhonov regularization scheme with the L-curve criterion. Diagnosed by the emissions averaging kernels, we find that, depending on the catchment area of the downwind measurements, our ad hoc network can resolve individual facilities or groups of ventilation facilities but that inspecting the emissions averaging kernels is essential to detect correlated estimates. Generally, our instantaneous emission estimates range between 80 and 133 kt CH$_{4}$ a$^{-1}$ for the southeastern part of the USCB and between 414 and 790 kt CH$_{4}$a$^{-1}$ for various larger parts of the basin, suggesting higher emissions than expected from the annual emissions reported by the E-PRTR (European Pollutant Release and Transfer Register). Uncertainties range between 23 % and 36 %, dominated by the error contribution from uncertain wind fields

Facilitating CAD/CAM nasoalveolar molding therapy with a novel click-in system for nasal stents ensuring a quick and user-friendly chairside nasal stent exchange

Nasoalveolar molding (NAM) aims to improve nasal symmetry with a nasal stent in cleft lip and palate (CLP) patients. When plates have to be exchanged because of dentoalveolar growth or cleft reduction, the nasal stent has to be mounted onto a new plate. This procedure elongates visiting hours for patients and parents or requires second treatment sessions. This study introduces a quick-lock additive manufacturing solution for chairside nasal stent exchange called RapidNAM. A novel taping retention pin has been designed that enables nasal stent insertion. Patients with unilateral CLP were included in this study. Plaster models were digitalized and measured by two independent observers. Two methods of CAD/CAM-molding therapies were compared: (i) conventional adhesion of a nasal stent (CAD/CAM NAM);(ii) quick-lock system in which the nasal stent was transferred to another plate (RapidNAM). CAD/CAM NAM and its refinement RapidNAM significantly increased the cleft-side nasal height and tilted the nose towards symmetry. The quick-lock system minimizes wire adaptations, since the preexisting stent can be reused. The new nasal stent development seems a feasible solution to minimize visiting hours but with clinically satisfactory results. This new nasal stent system combines traditional elements of NAM with CAD/CAM-technology

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the alpha-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD. Mitochondrial dysfunction is a contributing factor in Parkinson's disease. Here the authors carry out a multilayered omics analysis of Parkinson's disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by alpha-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients