Tetracycline degradation by dual-frequency ultrasound combined with peroxymonosulfate.

Tetracycline has received a great deal of interest for the harmful effects of substance abuse on ecosystems and humanity. The effects of different processes on the degradation of tetracycline were compared, with dual-frequency ultrasound (DFUS) in combination with peroxymonosulfate (PMS) being the most effective for the tetracycline degradation. Free radical scavenging experiments showed that O2∙-,SO4∙- and •OH were the main reactive radicals in the degradation of tetracycline. According to the major intermediates of tetracycline degradation identified, three possible degradation pathways were proposed, which are of significance for translational studies of tetracycline degradation. Notably, these intermediates were found to be significantly less toxicity. The number of active bubbles in the degradation vessel was calculated using a semi-empirical formula, and a higher value of 1.44 × 108 L-1s-1 of bubbles was obtained when using dual-frequency ultrasound at 20 kHz (210 W/L) and 80 kHz (85.4 W/L). Therefore, compared to 20 kHz, although the yield of strong oxidizing substances from individual active bubbles decreased slightly, a significant increment of the number of active bubbles still resulted in a higher synergistic effect, and the combination of DFUS and PMS should be effective in promoting the generation of reactive free radicals and mass transfer processes within the degradation vessel, which provides a method for efficient removal of tetracycline from wastewater.

TIMAHAC: Streamlined Tandem IMAC-HILIC Workflow for Simultaneous and High-Throughput Plant Phosphoproteomics and N-glycoproteomics.

Protein post-translational modifications (PTMs) are crucial in plant cellular processes, particularly in protein folding and signal transduction. N-glycosylation and phosphorylation are notably significant PTMs, playing essential roles in regulating plant responses to environmental stimuli. However, current sequential enrichment methods for simultaneous analysis of phosphoproteome and N-glycoproteome are labor-intensive and time-consuming, limiting their throughput. Addressing this challenge, this study introduces a novel tandem S-Trap-IMAC-HILIC (S-Trap: suspension trapping; IMAC: immobilized metal ion affinity chromatography; HILIC: hydrophilic interaction chromatography) strategy, termed TIMAHAC, for simultaneous analysis of plant phosphoproteomics and N-glycoproteomics. This approach integrates IMAC and HILIC into a tandem tip format, streamlining the enrichment process of phosphopeptides and N-glycopeptides. The key innovation lies in the use of a unified buffer system and an optimized enrichment sequence to enhance efficiency and reproducibility. The applicability of TIMAHAC was demonstrated by analyzing the Arabidopsis phosphoproteome and N-glycoproteome in response to abscisic acid (ABA) treatment. Up to 1954 N-glycopeptides and 11,255 phosphopeptides were identified from Arabidopsis, indicating its scalability for plant tissues. Notably, distinct perturbation patterns were observed in the phosphoproteome and N-glycoproteome, suggesting their unique contributions to ABA response. Our results reveal that TIMAHAC offers a comprehensive approach to studying complex regulatory mechanisms and PTM interplay in plant biology, paving the way for in-depth investigations into plant signaling networks.

Synthesis and Mechanism of 1D ZnO Based on Alkaline Dissolution-Conversion Strategy of High Stable and Soluble ɛ-Zn(OH)2.

A high soluble and stable ɛ-Zn(OH)2 precursor is synthesized at below room temperature to efficiently prepare ZnO whiskers. The experimental results indicate that the formation of ZnO whiskers is carried out mainly via two steps: the formation of ZnO seeds from ɛ-Zn(OH)2 via the in situ solid conversion, and the following growth of whiskers via dissolution-precipitation route. The decrease of temperature from 25 to 5 °C promotes the formation of ɛ-Zn(OH)2 with higher solubility and stability, which balances the conversion and dissolution rates of precursor. The Rietveld refinement, DFT calculations and MD simulations reveal that the primary reason for these characteristics is the expansion of ɛ-Zn(OH)2 lattice due to temperature, causing difficulties in the dehydration of adjacent ─OH. Simultaneously, the larger specific surface area favors the dissolution of ɛ-Zn(OH)2 . Based on this precursor, well-dispersed ZnO whiskers with 9.82 µm in length, 242.38 nm in diameter, and an average aspect ratio of 41 are successfully synthesized through a SDSN-assisted hydrothermal process at 80 °C. The process has an extremely high solid content of 2.5% (mass ratio of ZnO to solution) and an overall yield of 92%, which offers a new approach for the scaled synthesis of high aspect ratio ZnO whiskers by liquid-phase method.

Multi-mode coupled vibration analysis and radiation sound field investigation of a novel multidirectional piezoelectric ultrasonic transducer.

Nowadays, expanding the operating range and realizing multifrequency operation have emerged as focal and imperative objectives in the design of ultrasonic transducers. Due to the limitations of structure and radial sizes, conventional Langevin transducers encounter challenges in meeting the increasingly stringent requirements across diverse ultrasonic applications. Hence, this paper proposes a multidirectional piezoelectric ultrasonic transducer (MPUT) consisting of a large-dimension sandwich piezoelectric transducer (LSPT) and a metal tube in mutli-mode coupled vibration, capable of achieving wide-ranging and multifrequency acoustic radiation. Based on the analytical method, a two-dimensional electromechanical equivalent circuit model (2D-EECM) of the MPUT is established, and its frequency calculation results are validated through the finite element method (FEM) and impedance analysis experiment. The vibration testing results indicate that adjusting the radial size can control the coupled vibration intensity of the MPUT and achieve dual-frequency and multidirectional uniform radiation. The radiation sound field testing results confirm the MPUT's satisfactory three-dimensional radiation capability in water and significant improvement in acoustics operating range.

Coupled vibration of a radially polarized piezoelectric cylinder with a co-axial elastic cylinder of varying height.

The cylindrical piezoelectric transducer has the advantages of large radiation area, high electromechanical coupled coefficient, and omni-direction radiation along the radius. In this paper, a piezoelectric transducer consisting of a radially polarized piezoelectric cylinder and an outer metal cylinder of varying height is presented. The metal cylinder of varying height is approximated as the radial superposition of multiple uniform height metal cylinders, and the equivalent impedance of the transducer's coupled vibration is obtained by using the impedance matrix method, and then the resonance frequency, anti-resonance frequency, effective electromechanical coupled coefficient, and displacement amplification coefficient are obtained. In this paper, the relationship between the vibration characteristics of the cylindrical piezoelectric transducer and its geometric dimensions is studied. An experimental sample of the transducer is fabricated and assembled, and its electrical impedance curve is measured. The measured results are in good agreement with the simulation results and the theoretical calculation results. The displacement distribution of the radiation surface of the transducer at resonance frequency is measured, which verifies that the two coupled vibration modes of the transducer can be effectively excited.

Cu(II) Coordination Polymers Containing Mixed Ligands with Different Flexibilities: Structural Diversity and Iodine Adsorption.

Reactions of N,N'-bis(3-methylpyridyl)oxalamide (L1), N,N'-bis(3-methylpyridyl)adipoamide (L2) and N,N'-bis(3-methylpyridyl)sebacoamide (L3) with tricarboxylic acids and Cu(II) salts afforded {[Cu(L1)(1,3,5-HBTC)]·H2O}n (1,3,5-H3BTC = 1,3,5-benzenetricarboxylic acid), 1, {[Cu1.5(L2)1.5(1,3,5-BTC)(H2O)2]·6.5H2O}n, 2, [Cu(L2)0.5(1,3,5-HBTB)]n (1,3,5-H3BTB = 1,3,5-tri(4-carboxyphenyl)benzene), 3, [Cu4(L3)(OH)2(1,3,5-BTC)2]n, 4, {[Cu3(L3)2(1,3,5-BTB)2]·2.5MeOH·2H2O}n, 5, and {[Cu3(L3)2(1,3,5-BTB)2 ]·DMF·2H2O}n, 6, which have been structurally characterized by using single crystal X-ray crystallography. Complexes 1-4 form a 2D layer with the {44.62}-sql topology, a 2D layer with the (4.62)2(42.62.82)-bex topology, a three-fold interpenetrated 3D net with the (412·63)-pcu topology and a 3D framework with the (410·632·83)(42·6)2(43·63) topology, respectively, whereas 5 and 6 are 3D frameworks with the (63)2(64·82)(68·85·102) topology. Complex 5 shows a better iodine adsorption factor of 290.0 mg g-1 at 60 °C for 360 min than the other ones, revealing that the flexibility of the spacer ligand governs the structural diversity and the adsorption capacity.

Associations Between Polygenic Scores for Cognitive and Non-cognitive Factors of Educational Attainment and Measures of Behavior, Psychopathology, and Neuroimaging in the Adolescent Brain Cognitive Development Study.

Background: Both cognitive and non-cognitive (e.g., traits like curiosity) factors are critical for social and emotional functioning and independently predict educational attainment. These factors are heritable and genetically correlated with a range of health-relevant traits and behaviors in adulthood (e.g., risk-taking, psychopathology). However, whether these associations are present during adolescence, and to what extent these relationships diverge, could have implications for adolescent health and well-being. Methods: Using data from 5,517 youth of European ancestry from the ongoing Adolescent Brain Cognitive DevelopmentSM Study, we examined associations between polygenic scores (PGS) for cognitive and non-cognitive factors and outcomes related to cognition, socioeconomic status, risk tolerance and decision-making, substance initiation, psychopathology, and brain structure. Results: Cognitive and non-cognitive PGSs were both positively associated with cognitive performance and family income, and negatively associated with ADHD and severity of psychotic-like experiences. The cognitive PGS was also associated with greater risk-taking, delayed discounting, and anorexia, as well as lower likelihood of nicotine initiation. The cognitive PGS was further associated with cognition scores and anorexia in within-sibling analyses, suggesting these results do not solely reflect the effects of assortative mating or passive gene-environment correlations. The cognitive PGS showed significantly stronger associations with cortical volumes than the non-cognitive PGS and was associated with right hemisphere caudal anterior cingulate and pars-orbitalis in within-sibling analyses, while the non-cognitive PGS showed stronger associations with white matter fractional anisotropy and a significant within-sibling association for right superior corticostriate-frontal cortex. Conclusions: Our findings suggest that PGSs for cognitive and non-cognitive factors show similar associations with cognition and socioeconomic status as well as other psychosocial outcomes, but distinct associations with regional neural phenotypes in this adolescent sample.

PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target.

Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4-based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

Systematic design and experimental realization of a radially cascaded spherical piezoelectric transducer.

As a critical component of ultrasonic vibration systems, piezoelectric transducers play an essential role in various practical application scenarios. Recent advances in spherical transducers have been widely used in underwater sound and structural health monitoring, while the cascaded spherical piezoelectric transducer with arbitrary piezoceramic shell thickness has not been investigated. Here, we propose a radially cascaded spherical piezoelectric transducer (RCSPT) and derive its electromechanical equivalent circuit with mechanical losses, dielectric losses, and load mechanical impedances. The resulting device is composed of three concentric spherical metal shells and two radially polarized spherical piezoceramic shells. The underlying physical mechanism is the inverse piezoelectric effect, which converts electrical signals into mechanical vibrations. The effects of the spherical piezoceramic shell's thickness and location on the RCSPT are studied. We also analyze the effects of mechanical losses, dielectric losses, and load mechanical impedances on the modulus of input electric impedance of the cascaded spherical transducer. The experiments are conducted to verify the electromechanical characteristics of the resulting device, which are in good agreement with the simulated results and theoretical predictions. Our methodology will offer new possibilities for designing RCSPTs and may promote applications in various fields, such as underwater acoustic detection and structural health monitoring.

Suspension Trapping-Based Sample Preparation Workflow for In-Depth Plant Phosphoproteomics.

Plant phosphoproteomics provides a global view of phosphorylation-mediated signaling in plants; however, it demands high-throughput methods with sensitive detection and accurate quantification. Despite the widespread use of protein precipitation for removing contaminants and improving sample purity, it limits the sensitivity and throughput of plant phosphoproteomic analysis. The multiple handling steps involved in protein precipitation lead to sample loss and process variability. Herein, we developed an approach based on suspension trapping (S-Trap), termed tandem S-Trap-IMAC (immobilized metal ion affinity chromatography), by integrating an S-Trap micro-column with a Fe-IMAC tip. Compared with a precipitation-based workflow, the tandem S-Trap-IMAC method deepened the coverage of the Arabidopsis (Arabidopsis thaliana) phosphoproteome by more than 30%, with improved number of multiply phosphorylated peptides, quantification accuracy, and short sample processing time. We applied the tandem S-Trap-IMAC method for studying abscisic acid (ABA) signaling in Arabidopsis seedlings. We thus discovered that a significant proportion of the phosphopeptides induced by ABA are multiply phosphorylated peptides, indicating their importance in early ABA signaling and quantified several key phosphorylation sites on core ABA signaling components across four time points. Our results show that the optimized workflow aids high-throughput phosphoproteome profiling of low-input plant samples.

Far-UV absorption spectra of SiH2 and dibridged Si2H2 isolated in solid argon.

We employ electron bombardment during the deposition of an Ar matrix containing a small proportion of SiH4 to generate various silicon hydrides. Subsequently, the irradiation of a matrix sample at 365 nm decomposes SiH2 and dibridged Si2H2 in solid Ar, which we identify through infrared spectroscopy. We further recorded the corresponding ultraviolet absorption spectra at each experimental stage. An intense band observed in the range of 170-203 nm is largely destroyed upon 365-nm photolysis, which is assigned to the C1B2 â† X1A1 transition of SiH2. Moreover, a moderate band observed in the region of 217-236 nm is reduced slightly, which is assigned to the 31B2 â† X1A1 transition of dibridged Si2H2. These assignments are made based on the observed photolytic behavior, and the prediction of the vertical excitation energies with the corresponding oscillator strengths by using time-dependent density functional theory and equation-of-motion coupled cluster theory.

Cavitation bubble structures below a soft boundary in an ultrasonic field.

We studied the layer structure of bubbles just below water/air and water/EPE (Expand aple poly ephylene) interfaces using high-speed photography. The layer structure was generated by floating spherical clusters, the source bubbles of which were identified to come from the attachment of bubble nuclei at the interface, the floating of bubbles in the bulk liquid, or bubbles generated on the surface of the ultrasonic transducer. The boundary shape affected the layer structure, which assumed a similar profile below the water/EPE interface. We developed a simplified model composed of a bubble column and bubble chain to describe interface impacts and the interaction of bubbles in a typical branching structure. We found that the resonant frequency of the bubbles is smaller than that of an isolated single bubble. Moreover, the primary acoustic field plays an important role in the generation of the structure. A higher acoustic frequency and pressure were found to shorten the distance between the structure and the interface. A hat-like layer structure of bubbles was more likely to exist in the low-frequency (28 and 40 kHz) intense inertial cavitation field, in which bubbles oscillate violently. By contrast, structures composed of discrete spherical clusters were more likely to form in the relatively weak cavitation field at 80 kHz, in which stable and inertial cavitation coexisted. The theoretical predictions were in good agreement with the experimental observations.

Theoretical modeling and experimental verification of an improved radial composite transducer consisting of a metal ring and a radially polarized piezoelectric stack.

In the ring radial transducer, the wall thickness of the radially polarized piezoelectric ceramic is limited by the polarization technology and operating voltage, resulting in the limited power capacity and vibration ability of the transducer. Hence, an improved novel radial composite transducer (nRCT) is proposed in this paper, which consists of a radially polarized piezoelectric stack and a metal ring. Piezoelectric stack is used to enhance vibration and effectively solve the problem of difficult excitation caused by large wall thickness. A new electromechanical equivalent circuit model (EECM) of the nRCT in radial vibration is established, and the relationship between frequency characteristics of the nRCT and geometric size is analyzed. The finite element method (FEM) is used to carry out numerical modeling of the nRCT and the traditional radial composite transducer (tRCT), and preliminarily verify the calculation results of EECM. Compared with the tRCT, under the same electrical excitation, the equivalent electrical impedance of the nRCT designed in this paper decreases to 26%, and the radial vibration displacement increases to 142%. Finally, the nRCT and the tRCT are fabricated, and the experimental results have well verified the results of the theoretical analysis. The proposed radial piezoelectric stack model provides a new idea for the optimal design of radial vibration piezoelectric devices, which is expected to be further applied to the design of hydrophones, piezoelectric transformers, and medical ultrasound devices.

Acetylation-Mimic Mutation of TRIM28-Lys304 to Gln Attenuates the Interaction with KRAB-Zinc-Finger Proteins and Affects Gene Expression in Leukemic K562 Cells.

TRIM28/KAP1/TIF1ß is a crucial epigenetic modifier. Genetic ablation of trim28 is embryonic lethal, although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, several lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. Here, we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs). The TRIM28-K304Q knock-in cells were created in K562 erythroleukemia cells by CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein nuclease 9) gene editing method. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from wild-type K562 cells. The expression levels of embryonic-related globin gene and a platelet cell marker integrin-beta 3 were increased in TRIM28-K304Q mutant cells, indicating the induction of differentiation. In addition to the differentiation-related genes, many zinc-finger-proteins genes and imprinting genes were activated in TRIM28-K304Q cells; they were inhibited by wild-type TRIM28 via binding with KRAB-ZNFs. These results suggest that acetylation/deacetylation of K304 in TRIM28 constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation as demonstrated by the acetylation mimic TRIM28-K304Q.

Preparation of Hydrated TiO2 Particles by Hydrothermal Hydrolysis of Mg/Al-Bearing TiOSO4 Solution.

As the byproduct in the smelting process of vanadium titano-magnetite, titanium-bearing blast furnace slag (TBFS) can be converted to a titanyl sulfate (TiOSO4) solution containing MgSO4 and Al2(SO4)3 impurities via dissociation by concentrated H2SO4 (80-95%) at 80-200 °C, followed by leaching with H2O at 60-85 °C. In this study, hydrated TiO2 was prepared by hydrothermal hydrolysis of a Mg/Al-bearing TiOSO4 solution at 120 °C and the hydrolysis law was investigated. The experimental results indicate that MgSO4 and Al2(SO4)3 accelerated the hydrolysis and significantly affected the particle size (increasing the primary agglomerate size from 40 to 140 nm) and dispersion (reducing the aggregate size from 12.4 to 1.5 µm) of hydrated TiO2. A thermodynamic equilibrium calculation showed TiOSO4 existed as TiO2+ and SO42- in the solution, and MgSO4 and Al2(SO4)3 led to little change of [TiO2+], but an obvious decrease of [H+], which favored the hydrolysis process. At the same time, the coordination-dissociation mechanism of SO42- and Al(SO4)2- facilitated the lap bonding of Ti-O-Ti, promoting the growth of hydrated TiO2 synergistically.

Structure of bubble cluster adjacent to the water surface in the ultrasonic field.

The generation and evolution of bubble clusters in ultrasound fields were studied using high-speed photography. The transition of a spherical bubble cluster to a layer-like bubble cluster was demonstrated in detail. At a distance of half a wavelength to the water surface, the rising spherical cluster oscillated strongly and its equilibrium size grew. The speed was about 0.4 m/s and had a tendency to decrease. A jet caused by the last collapse of the spherical cluster rushed to the water surface, creating a bulge on the surface. Subsequently, due to the primary acoustic field, bubbles accumulated again below the bulge, and a layer-like bubble cluster gradually formed. The effects of acoustic frequency and intensity on the layer-like cluster were considered. It was found that the clusters located at a distance-to-wavelength ratio of about 0.08 to 0.13, very close to the water surface. The flickering bubble clusters were easy to be observed at 28 kHz and 40 kHz, while the accumulation of bubbles and their flicker were relatively weak at 80 kHz. The higher the frequency, the shorter the wavelength, the closer the structure to the water surface. However, at 80 kHz, the cavitation threshold is supposed to be higher and the resonance size of the bubbles is smaller, so the bubble oscillations and their interactions were weaker, and the phenomenon was different from the cases of 28 kHz and 40 kHz. Multiple structures mainly exist at 40 kHz. The formation and evolution of the layer-like cluster are closely dependent on the adequate supply of bubble nuclei from the water surface and the surrounding liquid. A Y-shaped bifurcation was used to model the branch streamers, which provided a path of bubbles accumulate into the clusters. The secondary Bjerknes forces between bubbles were adapted to analyze the interactions, and the results proved that it plays an important role in the appearance and evolution of the substructures.

Analysis on electric impedance-controlled active ultrasonic horn in radial vibration.

As a key component of high-powered ultrasonic vibration systems, ultrasonic horns play an important role in various practical application scenarios. Recent advances in longitudinal ultrasonic horns have enabled them to magnify the Langevin transducer's mechanical vibration and efficiently transmit the mechanical vibration to the mechanical load. However, limited research has been devoted to active radial ultrasonic horns in radial vibration. Here we propose an electric impedance-controlled active radial ultrasonic horn (ARUH) capable of tuning both resonance frequency and displacement magnification in radial vibration. The resulting device consists of a radially polarized piezoelectric ring connected with adjustable electric impedance and two metal rings with variable sections. The underlying mechanism is that the change of the converted mechanical impedance of the piezoelectric material by the external electric impedance connected to the piezoelectric material modulates the resonance frequency and displacement magnification of the ARUH. It can be found that the resonant frequency shifts to higher frequencies as the resistance increases and the resonant frequency shifts to lower frequencies as the inductance and capacitance increase, while the displacement magnification has the opposite trend to the resonance frequency. For example, the resonance frequency of the constant-section radial horn is 41130.2 Hz. When the inductance increases from -0.007 to 0.007H, the resonance frequency shifts from 41171.3 to 34606.2 Hz and the displacement magnification moves from 1.189 to 3.5. The experiments are conducted to verify the effectiveness of the resulting device, which is in good agreement with the simulated results and theoretical predictions. Our design with functionality and flexibility opens up possibilities for the design of ARUHs and may find important application prospects in diverse fields such as cold-drawn steel tubes and ultrasonic plastic welding.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.

Characterizing Alcohol Expectancies in the ABCD Study: Associations with Sociodemographic Factors, the Immediate Social Environment, and Genetic Propensities.

Alcohol expectancies (AEs) are associated with likelihood of alcohol initiation and subsequent alcohol use disorders. It is unclear whether genetic predisposition to alcohol use and/or related traits contributes to shaping how one expects to feel when drinking alcohol. We used the Adolescent Brain Cognitive Development study to examine associations between genetic propensities (i.e., polygenic risk for problematic alcohol use, depression, risk-taking), sociodemographic factors (i.e., parent income), and the immediate social environment (i.e., peer use and disapproval toward alcohol) and positive and negative AEs in alcohol-naïve children (max analytic N = 5,352). Mixed-effect regression models showed that age, parental education, importance of the child's religious beliefs, adverse childhood experiences, and peer disapproval of alcohol use were associated with positive and/or negative AEs, to varying degrees. Overall, our results suggest several familial and psychosocial predictors of AEs but little evidence of contributions from polygenic liability to problematic alcohol use or related phenotypes.