Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy-based virtual screening and machine learning evaluation.

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Covalent Bonding Between Be+ and CO2 in BeOCO+ with a Surprisingly High Antisymmetric OCO Stretching Vibration.

The cationic complex BeOCO+ is produced in a solid neon matrix. Infrared absorption spectroscopic study shows that it has a very high antisymmetric OCO stretching vibration of 2418.9 cm-1, which is about 71 cm-1 blue-shifted from that of free CO2. The quantum chemical calculations are in very good agreement with the experimental observation. Depending on the theoretical method, a linear or quasi-linear structure is predicted for the cation. The analysis of the electronic structure shows that the bonding of Be+ to one oxygen atom induces very little charge migration between the two moieties, but it causes a significant change in the σ-charge distribution that strengthens the terminal C-O bond, leading to the observed blue shift. The bonding analysis reveals that the Be+ ← OCO donation results in strong binding due to the interference of the wave function and a charge polarization within the CO2 fragment and hybridization to Be+ but only negligible charge donation.

Associations between ventilation and children's asthma and allergy in naturally ventilated Chinese homes.

Building ventilation is important for occupants' health. There are few studies of associations between home ventilation and occupant's health in China. During 2013-2016, we measured ventilation in 399 homes in Tianjin and Cangzhou, China, and surveyed the health history of children. Ventilation rates were measured using mass balance of occupant generated CO2 . The associations of home ventilation with children's asthma and allergy were analyzed in different strata of time and space. A low bedroom ventilation at night was significantly associated with an increased proportion of rhinitis among children (rhinitis current, adjusted odds ratio (AOR): 1.59; 95% confidence interval (CI): 1.01-2.49; diagnosed rhinitis, AOR: 3.02 (1.16-7.89)). Our findings suggest a dose-response relationship between ventilation rate at night in children's bedrooms and rhinitis current. The night-time ventilation rate in bedrooms has a greater association with rhinitis than the whole home ventilation rate during daytime.

Formation and Characterization of a BeOBeC Multiple Radical Featuring a Quartet Carbyne Moiety.

Through reaction of beryllium dimers with carbon monoxide, a carbonyl complex BeBeCO is formed in solid neon. Upon visible light excitation, the BeBeCO complex rearranges to a BeCOBe isomer, which further isomerizes to a low-energy BeOBeC species under UV-visible light excitation. These species are identified on the basis of infrared absorption spectroscopy with isotopic substitutions and quantum chemical studies. The BeOBeC molecule is characterized to be a multiple radical species having an electronic quintet ground state featuring an unusual quartet carbyne unit with three unpaired electrons on the carbon center. Bonding analysis indicates that the strong Pauli repulsion between carbon 2s lone pair electrons and the σ electrons of the BeOBe fragment significantly weakens the Be-C bonding and destabilizes the triplet state of the BeOBeC radical with a doublet carbyne unit. The three-center π-bonding of BeOBe is also found to play a role in stabilizing the quartet carbyne.

A Very Short Be-Be Distance but No Bond: Synthesis and Bonding Analysis of Ng-Be2 O2 -Ng' (Ng, Ng'=Ne, Ar, Kr, Xe).

Short interatomic distances below standard values for a single bond are usually identified with double or triple bonds. The synthesis and spectroscopic characterization of a molecule is reported where the distance between two beryllium atoms is shorter than a standard double bond but there is no bond. The cyclic diberyllium dioxide Be2 O2 molecule, which is coordinated by two noble gas atoms in Ng-Be2 O2 -Ng' (Ng, Ng'=Ne, Ar, Kr, Xe) was isolated and spectroscopically identified in low-temperature matrices. The complexes possess very short Be-Be distances, but the analysis of the electronic structure reveals that there is no chemical bond.

Isocyanate Formation from Reactions of Early Lanthanide Metal Atoms with NO and CO in Solid Argon.

The reactions of early lanthanide metal atoms (Ce, Pr, and Nd) with carbon monoxide and nitric oxide mixtures are studied by infrared absorption spectroscopy in solid argon. The reaction intermediates and products are identified via isotopic substitution as well as theoretical frequency calculations. The results show that the reactions proceed with the initial formation of inserted NLnO molecules, which subsequently react with CO to form the NLnO(CO) complexes on annealing. The NLnO(CO) complexes further isomerize to the more stable isocyanate OLnNCO species under UV light excitation.

Carbon Dioxide Activation by Scandium Atoms and Scandium Monoxide Molecules: Formation and Spectroscopic Characterization of ScCO3 and OCScCO3 in Solid Neon.

The reactions of carbon dioxide with scandium monoxide molecules and scandium atoms are investigated using matrix isolation infrared spectroscopy in solid neon. The species formed are identified by the effects of isotopic substitution on their infrared spectra as well as density functional calculations. The results show that the ground state ScO molecule reacts with carbon dioxide to form the carbonate complex ScCO3 spontaneously on annealing. The ground state Sc atom reacts with two carbon dioxide molecules to give the carbonate carbonyl complex OCScCO3 via the previously reported OScCO insertion intermediate on annealing. The observation of these spontaneous reactions is consistent with theoretical predictions that both the Sc + 2CO2 → OCScCO3 and ScO + CO2 → ScCO3 reactions are thermodynamically exothermic and are kinetically facile, requiring little or no activation energy.

The Oxygen-Rich Beryllium Oxides BeO4 and BeO6.

Two novel isomers of BeO4 with the structures OBeOOO and OBe(O3 ) in the electronic triplet state have been prepared as well as the known disuperoxide complex Be(O2 )2 in solid noble-gas matrices. We also report the synthesis of the oxygen-rich bis(ozonide) complex Be(O3 )2 in the triplet state which has a D2d equilibrium geometry. The molecular structures were identified by infrared absorption spectroscopy with isotopic substitutions as well as quantum chemical calculations.

Pentavalent Lanthanide Compounds: Formation and Characterization of Praseodymium(V) Oxides.

The chemistry of lanthanides (Ln=La-Lu) is dominated by the low-valent +3 or +2 oxidation state because of the chemical inertness of the valence 4f electrons. The highest known oxidation state of the whole lanthanide series is +4 for Ce, Pr, Nd, Tb, and Dy. We report the formation of the lanthanide oxide species PrO4 and PrO2 (+) complexes in the gas phase and in a solid noble-gas matrix. Combined infrared spectroscopic and advanced quantum chemistry studies show that these species have the unprecedented Pr(V) oxidation state, thus demonstrating that the pentavalent state is viable for lanthanide elements in a suitable coordination environment.

Experimental and theoretical studies of the infrared spectra and bonding properties of NgBeCO3 and a comparison with NgBeO (Ng = He, Ne, Ar, Kr, Xe).

The novel neon complex NeBeCO3 has been prepared in a low-temperature neon matrix via codeposition of laser-evaporated beryllium atoms with O2 + CO/Ne. Doping by the heavier noble gas atoms argon, krypton and xenon yielded the associated adducts NgBeCO3 (Ng = Ar, Kr, Xe). The noble gas complexes have been identified via infrared spectroscopy. Quantum chemical calculations of NgBeCO3 and NgBeO (Ng = He, Ne, Ar, Kr, Xe) using ab initio methods and density functional theory show that the Ng-BeCO3 bonds are slightly longer and weaker than the Ng-BeO bonds. The energy decomposition analysis of the Ng-Be bonds suggests that the attractive interactions come mainly from the Ng → BeCO3 and Ng → BeO σ donation.

Carbon monoxide bonding with BeO and BeCO3 : surprisingly high CO stretching frequency of OCBeCO3.

The complexes OCBeCO3 and COBeCO3 have been isolated in a low-temperature neon matrix. The more stable isomer OCBeCO3 has a very high CO stretching mode of 2263 cm(-1) , which is blue-shifted by 122 cm(-1) with respect to free CO and 79 cm(-1) higher than in OCBeO. Bonding analysis of the complexes shows that OCBeO has a stronger OCBeY bond than OCBeCO3 because it encounters stronger π backdonation. The isomers COBeCO3 and COBeO exhibit red-shifted CO stretching modes with respect to free CO. The inverse change of CO stretching frequency in OCBeY and COBeY is explained with the reversed polarization of the σ and π bonds in CO.

Formation and characterization of the boron dicarbonyl complex [B(CO)2](-).

We report the synthesis and spectroscopic characterization of the boron dicarbonyl complex [B(CO)2 ](-) . The bonding situation is analyzed and compared with the aluminum homologue [Al(CO)2 ](-) using state-of-the-art quantum chemical methods.

Infrared spectra and structures of the neutral and charged CrCO2 and Cr(CO2)2 isomers in solid neon.

The reactions from codeposition of laser-ablated chromium atoms with carbon dioxide in excess neon are studied by infrared absorption spectroscopy. The species formed are identified by the effects of isotopic substitution on their infrared spectra. Density functional calculations are performed to support the spectral assignments and to interpret the geometric and electronic structures of the experimentally observed species. Besides the previously reported insertion products OCrCO and O2Cr(CO)2, the one-to-one Cr(CO2) complex and the one-to-two Cr(CO2)2 complex as well as the CrOCrCO and OCCrCO3 complexes are also formed. The Cr(CO2) complex is characterized to be side-on η(2)-C,O-coordinated. The Cr(CO2)2 complex is identified to involve a side-on η(2)-C,O-coordinated CO2 and an end-on η(1)-O-coordinated CO2. OCCrCO3 is a carbonate carbonyl complex predicted to have a planar structure with a η(2)-O,O-coordinated carbonate ligand. The CrOCrCO complex is predicted to be linear with a high-spin ground state. Besides the neutral molecules, charged species are also produced. The Cr(CO2)(+) and Cr(CO2)2(+) cation complexes are characterized to have linear end-on η(1)-O-coordinated structures with blue-shifted antisymmetric CO2 stretching vibrational frequencies. The OCrCO(-) anion is bent with the Cr-O and CO stretching frequencies red-shifted from those of OCrCO neutral molecule.

Household indoor air quality in northeast China: On-site inspection and measurement in 399 Tianjin area residences.

There has been an increased concern on indoor air quality (IAQ) in residences since the majority of individuals' time is mainly spent indoors. We inspected and measured indoor environmental parameters in 399 homes in northeast China in order to study IAQ. We systematically measured multilevel environmental parameters (physical, chemical, and biological) in children's bedrooms during all seasons. The results indicated that the median values for indoor temperature, relative humidity, total volatile organic compounds (TVOC), and formaldehyde concentrations throughout the year were within the Chinese national standards. However, the median carbon dioxide concentrations exceeded 1000 ppm during spring, autumn, and winter. In the same seasons, the air change rate (ACR) was below the minimum required level of 0.5 h-1. Di-2-ethylhexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP) were predominantly detected in settled dust, displaying median concentrations of 126.9, 41.5, and 16.3 µg/g, respectively. Notably, phthalate concentrations were significantly higher in urban houses as compared to rural houses. Furthermore, median concentrations of Dermatophagoides farinae (Der f) and endotoxin were 689.4 ng/g and 3689.1 EU/g, respectively, trending higher in winter than summer. There was a negative correlation between ACR and chemical pollutants (TVOC, formaldehyde, and DiBP). In conclusion, northeast Chinese homes had poor indoor air quality with ubiquitous exposure to modern chemical compounds and insufficient ventilation.

Study of the molecular structure of proteins in fermented Maize-Soybean meal-based rations based on FTIR spectroscopy.

This research investigates the dynamic alterations that occur in protein molecular structure during the fermentation process of feed. Fourier transform infrared spectroscopy (FTIR), coupled with deconvolution, second derivative and curve-fitting methodologies, was employed to comparatively analyse the protein molecular structures in fermented feed. At the 48-h fermentation mark, the α-helix and ß-sheet contents reached their peaks, while the random coil and ß-turn contents were at their lowest. Simultaneously, the ß-sheet/α-helix ratio was minimized. FTIR spectroscopy emerged as a comprehensive tool, revealing the nuanced changes in molecular structure throughout the fermentation process of corn-soybean meal feed. When integrated with spectral quantitative analysis, it provides a novel perspective for evaluating the nutritional value of fermented feed.

Associations between Children's asthma and allergic symptoms and phthalates in dust in metropolitan Tianjin, China.

Prevalences of allergies and asthma have increased through the past few decades around the world, especially in countries and regions that have adopted modern lifestyles. Epidemiological studies outside of China have found a relationship between phthalates concentrations in indoor dust and symptoms of respiratory, skin and nose allergies. The aim of our study is to investigate the association between children's asthma and allergic symptoms and concentrations of different phthalates in settled dust samples collected from children's homes in metropolitan Tianjin (Tianjin and Cangzhou), China. We selected 126 cases with current allergic symptoms and 254 controls without allergic symptoms from the cohort of 7865 children. We collected dust samples from children's bedroom and analyzed them for their content of diethyl phthalate (DEP), diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP), di-2-ethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP). We found a higher concentration of DEP in rhinitis children's homes (0.33 vs. 0.27 µg/g dust) and a higher concentration of DiBP in asthma children's homes (29.04 vs. 15.66 µg/g dust). The concentration of DiBP was significantly associated with diagnosed asthma (adjusted odds ratio (AOR): 1.30; 95% confidence interval (CI): 1.07, 1.57). A dose-response relationship was found between concentrations of DiBP in dust and asthma. This study shows that some phthalates are associated with allergic and asthma symptoms in children.

A method for evaluating indoor phthalate exposure levels in collected dust.

This paper provides a method for evaluating indoor phthalate exposure levels in collected dust, including dust collection, chemical analysis and quality control. Indoor dusts were collected with a self-made equipment and pretreated by the Soxhlet extractor method. Six phthalates, i.e., diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), di-isobutyl phthalate (DiBP), benzyl butyl phthalate (BBzP), di (2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) in the dust were analyzed by gas chromatography mass spectrometry (GC-MS). •Measures were taken to avoid background contamination of phthalates during sampling and chemical analysis to accurately evaluate the indoor phthalates exposure levels.•Filter sock and self-made mouthpiece mounted on vacuum cleaner were made of nylon and aluminum respectively.•Dust from surface of plastic products was avoided. The pretreatment of vessels and analysis of blank samples were conducted to reduce "noise" from background contamination.

Prevalence of Childhood Asthma and Allergies and Their Associations with Perinatal Exposure to Home Environmental Factors: A Cross-Sectional Study in Tianjin, China.

Asthma, rhinitis, and eczema are becoming increasingly prevalent among children in China. Studies have shown that the perinatal period is critical and impacts children's health. However, research on the associations between perinatal factors and childhood allergic diseases in China are few. We investigated 7366 children of ages 0-8 years old. The childhood asthma and allergies were surveyed by distributing questionnaires, modelled after Dampness in Buildings and Health (DBH) study in Sweden and had been validated. To determine the prevalence of the allergic conditions, explore for potential confounders, and analyze the associations between the allergies and the home environmental factors, chi-square test and binary logistic regression models (enter method) were employed. The prevalence of children's doctor-diagnosed asthma, rhinitis, and eczema were 4.4%, 9.5%, and 39.1%, respectively. After adjusting for sociodemographic factors, the negative effect of dampness/humidity on children's health became more obvious, with odd ratios (aORs) of up to 1.70 (95% confidence interval (CI): 1.12-2.57) for doctor-diagnosed asthma (DDA), 2.12 (95% CI: 1.38-3.25) for doctor-diagnosed rhinitis (DDR) and 1.79 (95% CI: 1.46-2.21) for doctor-diagnosed eczema (DDE). With parental smoking, aORs of up to 4.66 (95% CI: 1.99-10.92) for DDA and 1.74 (95%: 1.00-3.02) for DDE. Renovation exhibited aORs of up to 1.67 (95% CI: 1.13-2.47) for DDR. Although they showed no significant associations with some of the health outcomes, contact with animals, in general, were risk factors for the allergic conditions. Generally, the indoor environmental factors around the perinatal period were significant risk factors for the doctor-diagnosed allergic conditions discussed in this study.

Phthalate exposure in Chinese homes and its association with household consumer products.

Phthalates are SVOCs (Semi-volatile Organic Compounds) that are widely used in industrial and daily home products. This study aimed to investigate exposure levels to phthalates in Chinese homes and to relate these to building characteristics and lifestyles. Dust in 399 homes of 410 children in urban Tianjin and rural Cangzhou was analyzed for concentrations of six target phthalates. The median concentrations were 0.31µg/g for diethyl phthalate (DEP), 16.39µg/g for di-isobutyl phthalate (DiBP), 42.60µg/g for di-n-butyl phthalate (DnBP), 0.10µg/g for benzyl butyl phthalate (BBzP), 127.11µg/g for di (2-ethylhexyl) phthalate (DEHP) and 0.28µg/g for di-isononyl phthalate (DiNP). Strong associations were found between modern flooring materials (laminated wood/wood) and concentrations of DiBP, BBzP and DiNP; modern window frame (aluminum/plastic steel) and BBzP concentration; leather polish and DEHP concentration; perfume and DEP concentration. Concentrations of phthalates were significantly higher in Tianjin urban homes than Cangzhou rural homes. Concentrations of phthalates increased significantly with increasing household income. Our study indicates that exposure to phthalates in Chinese homes increases with attributes of modern life.