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The growth of Vicker´s cracks during the poling of piezoelectric ceramics was studied for two PZT based compositions with different tetragonal distortion of the perovskite structure. Studies on the two compositions with different poling electric fields and similar initial crack lengths showed that crack growth was not proportional to the induced stress free longitudinal strain by 90º domain reorientation. This observation is not consistent with the previously proposed mechanism of crack growth based on a strain mismatch between the material at the crack flanks and the rest of the ceramic. This mismatch was proposed to occur because of the reduction of the electric field within the crack flanks. The reasons for the disappearance of the mismatch are discussed here, and an alternative mechanism of crack growth consistent with our results is proposed, which takes into account the electrically induced stress gradient at the crack tip, produced by the piezoelectric effect. Cracks were also found to grow during a small number of subsequent polarisation reversals, the explanation of which must be due to some other additional effect.Se ha estudiado el crecimiento de grietas Vicker durante la polarización de cerámicas piezoeléctricas para dos modificaciones del PZT con distinta distorsión tetragonal de la estructura perovskita. Los resultados en función del campo eléctrico de polarización y la longitud inicial de la grieta muestran que el crecimiento no es proporcional a la deformación libre de tensión inducida por orientación de dominios de 90º. Esta observación no es consistente con el mecanismo de crecimiento de grieta propuesto anteriormente, basado en el desajuste de deformación entre el material a los flancos de la grieta y el resto de la cerámica. Este desajuste se producía por la atenuación del campo eléctrico en los flancos de la grieta. Se discute la causa de la desaparición de este desajuste de deformación, y se propone un mecanismo alternativo de crecimiento de grieta consistente con los resultados obtenidos, que tiene en cuenta el gradiente de tensión en la punta producido por el efecto piezoeléctrico. También se ha observado crecimiento de la grieta durante un pequeño número de conmutaciones de la polarización realizadas a continuación del polarizado inicial, fenómeno que debe estar relacionado con algún otro efecto adicional.

Purpose: To propose an accurate method of measuring hip capsular thickness in patients with femoroacetabular impingement syndrome and to compare the reliability of these measurements between magnetic resonance imaging (MRI) and magnetic resonance arthrography (MRA). Methods: A previously established database of patients with femoroacetabular impingement syndrome (FAIS) was used to identify candidates with preoperative MRI or MRA from November 2018 to June 2021. Two reviewers independently examined preoperative imaging for 85 patients. Capsular thickness was measured in 12 standardized locations. Intraclass correlation coefficients (ICCs) were calculated using an absolute-agreement, 2-way random-effects model. Using the same method, 30 patients were randomly selected for repeat measurements by 1 reviewer following a washout period. Ten additional patients with preoperative MRI and MRA of the same hip were identified to compare measurements between modalities using paired samples t test. Results: ICCs for measurements on MRIs and MRAs using these proposed measurements to compare inter-rater reliability were 0.981 and 0.985. ICCs calculated using measurements by a single reviewer following a washout period for intrarater reliability were 0.998 and 0.991. When comparing MRI and MRA measurements in the same patient, t test for all pooled measurements found no difference between modality (P = .283), and breakdown of measurements by quadrant found no difference in measurements (P > .05), with the exception of the inferior aspect of the capsule on coronal sequences (P = .023). Conclusions: In patients with FAIS, both MRI and MRA have excellent reliability for quantifying hip capsular thickness. A difference in capsular thickness was found only when comparing MRI and MRA on inferior coronal aspects of the hip capsule, indicating interchangeability of these imaging modalities when measuring the clinically important aspects of the hip capsule. Level of Evidence: Level IV, diagnostic case series.

Phospholipid synthesis and fat storage as triglycerides are regulated by lipin phosphatidic acid phosphatases (PAPs), whose enzymatic PAP function requires association with cellular membranes. Using hydrogen deuterium exchange mass spectrometry, we find mouse lipin 1 binds membranes through an N-terminal amphipathic helix, the Ig-like domain and HAD phosphatase catalytic core, and a middle lipin (M-Lip) domain that is conserved in mammalian and mammalian-like lipins. Crystal structures of the M-Lip domain reveal a previously unrecognized protein fold that dimerizes. The isolated M-Lip domain binds membranes both in vitro and in cells through conserved basic and hydrophobic residues. Deletion of the M-Lip domain in lipin 1 reduces PAP activity, membrane association, and oligomerization, alters subcellular localization, diminishes acceleration of adipocyte differentiation, but does not affect transcriptional co-activation. This establishes the M-Lip domain as a dimeric protein fold that binds membranes and is critical for full functionality of mammalian lipins.

Lipin/Pah phosphatidic acid phosphatases (PAPs) generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Inactivating mutations cause rhabdomyolysis, autoinflammatory disease, and aberrant fat storage. Disease-mutations cluster within the conserved N-Lip and C-Lip regions that are separated by 500-residues in humans. To understand how the N-Lip and C-Lip combine for PAP function, we determined crystal structures of Tetrahymena thermophila Pah2 (Tt Pah2) that directly fuses the N-Lip and C-Lip. Tt Pah2 adopts a two-domain architecture where the N-Lip combines with part of the C-Lip to form an immunoglobulin-like domain and the remaining C-Lip forms a HAD-like catalytic domain. An N-Lip C-Lip fusion of mouse lipin-2 is catalytically active, which suggests mammalian lipins function with the same domain architecture as Tt Pah2. HDX-MS identifies an N-terminal amphipathic helix essential for membrane association. Disease-mutations disrupt catalysis or destabilize the protein fold. This illustrates mechanisms for lipin/Pah PAP function, membrane association, and lipin-related pathologies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC50 of ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.

The Compact Linear Collider (CLIC) is a mature option for the future of highenergy physics. It combines the benefits of the clean environment of $e^+e^-$colliders with operation at high centre-of-mass energies, allowing to probescales beyond the reach of the Large Hadron Collider (LHC) for many scenariosof new physics. This places the CLIC project at a privileged spot in betweenthe precision and energy frontiers, with capabilities that will significantlyextend knowledge on both fronts at the end of the LHC era. In this report wereview and revisit the potential of CLIC to search, directly and indirectly,for physics beyond the Standard Model.

Tripodal ligands that can encapsulate single or multiple metal sites in C3-symmetric geometric configurations constitute valuable targets for novel catalysts. Of particular interest in ligand development are efforts toward incorporating apical elements that exhibit little if any electron donicity, to enhance the electrophilic nature of a trans positioned active oxidant (e.g., metal-oxo, -nitrene). The tripodal ligand TMG3trphen-Arene has been synthesized, featuring an arene platform 1,3,5-substituted with phenylene arms possessing tetramethylguanidinyl (TMG) residues. Compound [(TMG3trphen-Arene)Cu3(μ-Cl)3] has been subsequently synthesized by extracting a Cu3(μ-Cl)3 cluster from anhydrous CuCl and shown to encapsulate a crown-shaped Cu3(μ-Cl)3 fragment, supported by Cu–NTMG bonds and modest Cu3⋯arene long-range contacts. Energy decomposition analysis (EDA) indicates that electrostatic contributions to the total interaction energy far exceed those due to orbital interactions. The latter involve orbital pairings largely associated with the NTMG stabilization of the Cu3(μ-Cl)3 cluster. The independent gradient model based on the Hirshfeld partition (IGMH) corroborates that contacts between the arene platform and the Cu3 triangle are noncovalent in nature. Catalyst [(TMG3trphen-Arene)Cu3(μ-Cl)3] enables amination of sec-benzylic and tert-C–H bonds of a panel of substrates by pre-synthesized PhINTces in solvent matrices that incorporate small amounts of HFIP. The involvement of an electrophilic aminating agent is evidenced by the better yields obtained for electron-rich benzylic sites and is further supported by Hammett analysis that reveals the development of a small positive charge during C–H bond activation. A rather modest KIE effect (2.1) is obtained from intramolecular H(D) competition in the amination of ethylbenzene, at the borderline of reported values for concerted and stepwise C–H amination systems. DFT analysis of the putative copper–nitrene oxidant indicates that the nitrene N atom is bridging between two copper sites in closely spaced triplet (ground state) and broken-symmetry singlet electronic configurations. [ABSTRACT FROM AUTHOR]

Sterylglucosidase 1 (Sgl1) is a virulence factor in Cryptococcus neoformans that modulates fungal pathogenesis and host response. Here, the authors characterize Sgl1 structurally, identify Sgl1 inhibitors, and demonstrate Sgl1 inhibition has efficacy in mouse models of infection.

Lipins need to bind cell membranes before they can function as phosphatidic acid phosphatases. Here, the authors elucidate the structural basis of lipin membrane-association and identify a lipin domain with a novel protein fold that is critical for membrane binding and full functionality of lipins.

Numerous receptor tyrosine kinases and immune receptors activate phospholipase C-γ (PLC-γ) isozymes at membranes to control diverse cellular processes including phagocytosis, migration, proliferation, and differentiation. The molecular details of this process are not well understood. Using hydrogen-deuterium exchange mass spectrometry, we show that PLC-γ1 is relatively inert to lipid vesicles that contain its substrate, phosphatidylinositol 4,5-bisphosphate (PIP2), unless first bound to the kinase domain of the fibroblast growth factor receptor (FGFR1). Exchange occurs throughout PLC-γ1 and is exaggerated in PLC-γ1 containing an oncogenic substitution (D1165H) that allosterically activates the lipase. These data support a model whereby initial complex formation shifts the conformational equilibrium of PLC-γ1 to favor activation. This receptor-induced priming of PLC-γ1 also explains the capacity of a kinase-inactive fragment of FGFR1 to modestly enhance the lipase activity of PLC-γ1 operating on lipid vesicles but not a soluble analog of PIP2 and highlights potential cooperativity between receptor engagement and membrane proximity. Priming is expected to be greatly enhanced for receptors embedded in membranes and nearly universal for the myriad of receptors and co-receptors that bind the PLC-γ isozymes.

In this article, we will discuss the history, pharmacodynamics, and neurotoxicity of psychostimulants and hallucinogens. The drugs discussed are widely used and have characteristic toxidromes and potential for neurological injuries with which the practicing clinician should be familiar. Psychostimulants are a class of drugs that includes cocaine, methamphetamine/amphetamines, and cathinones, among others, which produce a crescendoing euphoric high. Seizures, ischemic and hemorrhagic strokes, rhabdomyolysis, and a variety of movement disorders are commonly encountered in this class. Hallucinogens encompass a broad class of drugs, in which the user experiences hallucinations, altered sensorium, distorted perception, and cognitive dysfunction. The experience can be unpredictable and dysphoric, creating a profound sense of anxiety and panic in some cases. Recognizing the associated neurotoxicities and understanding the appropriate management is critical in caring for these patient populations. Several of these agents are not detectable by standard clinical laboratory analysis, making identification and diagnosis an even greater challenge. [ABSTRACT FROM AUTHOR]

Background: The acetabular sourcil is commonly interpreted as a reliable radiographic representation of the weightbearing dome of the acetabulum, despite limited modern data. Assessment of weightbearing acetabular coverage has been described using both the sourcil edge and bone edge as anatomic landmarks, leading to confusion and potential misguidance in surgical decision-making and thus compromised patient outcomes. Purpose/Hypothesis: The purpose of this study was to characterize the 3-dimensional (3D) anatomic correlates of the sourcil-edge and bone-edge radiographic measurements on false-profile radiographs. It was hypothesized that the sourcil edge would represent anterolateral coverage and the bone edge would represent anterior coverage. Study Design: Descriptive laboratory study. Methods: A total of 80 hips were grouped by large or small differences between bone-edge and sourcil-edge anterior center-edge angles, based on upper and lower quartiles of discrepancy. Three-dimensional surface mesh models and digitally reconstructed radiographs were generated from hip computed tomography scans. Sourcil-edge and bone-edge anterior center-edge angles were identified on digitally reconstructed radiographs and registered to the 3D models with fiducial markers. Intersections of bone-edge and sourcil-edge projection lines with the acetabular rim were obtained from the 3D models. Results: The bone-edge and sourcil-edge projections intersected the acetabular rim at clockface means of 2:05 ± 0:22 and 1:12 ± 0:25, respectively. The 3D models consistently demonstrated that, in both large- and small-discrepancy groups, the sourcil edge corresponded to the acetabular area just posterior to the anterior inferior iliac spine (AIIS) projection, and the bone edge corresponded to the weightbearing region inferior to the AIIS. Additionally, in large-discrepancy hips, the bone edge corresponded to more prominent acetabular coverage in the region inferomedial to the AIIS when compared with the small-discrepancy hips. Conclusion: On false-profile radiographs, the sourcil edge corresponds to superior femoral head coverage, and the bone edge corresponds to anterosuperior coverage. Radiographs with a large discrepancy between sourcil-edge and bone-edge measurements demonstrate acetabular rim prominence in the region of the AIIS. Clinical Relevance: Characterizing the anatomic weightbearing regions of the acetabulum represented on false-profile radiographs facilitates improved clinical and intraoperative decision-making in hip preservation surgery, including acetabuloplasty and periacetabular osteotomy. [ABSTRACT FROM AUTHOR]

This report summarises the physics opportunities in the search and study ofphysics beyond the Standard Model at a 100 TeV pp collider.

Lipin/Pah phosphatidic acid phosphatases generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Here authors determine structures of Tetrahymena thermophila Pah2 and identify an N-terminal amphipathic helix essential for membrane association.