Mechanism and Origins of Enantioselectivity in the Nickel-catalyzed Asymmetric Synthesis of Silicon-Stereogenic Benzosiloles.

As important π-skeletons, benzosiloles often possess unique electronic and optical properties and have been widely used in semiconductor materials. Therefore, great attention has been drawn to the area of developing novel synthetic methods for various benzosiloles. However, the synthesis of enantioenriched silicon-stereogenic benzosiloles is still at an early stage and remains to be explored. Herein, we performed systematic density functional theory studies on the recently reported nickel-catalyzed asymmetric synthesis of silicon-stereogenic benosiloles, which was enabled by an enantioselective desymmetrization of (2-alkenyl)aryl-substituted silacyclobutanes. Our computational study shows that the reaction mechanism involves ligand exchange, oxidative addition, alkene insertion, and hydrogen-transfer coupled reductive-demetalation steps. The proposed transmetalation and ß-hydride elimination mechanism was not found, which might be due to the unfavorable ring strain of the multicyclic intermediates. The novel hydrogen-transfer coupled reductive-demetalation mechanism was shown to be reasonable for the generation of the silicon-stereogenic benzosilole. Noncovalent interactions (including C-H···π and hydrogen bonding) in the rate-determining alkene insertion transition state account for the origins of the enantioselectivity. Our computational study sheds light on the detailed reaction mechanism and also provides insights for the development of novel approaches for synthesis of high-value silicon-stereogenic compounds.

Enantioselective Nickel-Catalyzed Denitrogenative Transannulation En Route to N-N Atropisomers.

Nickel-catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, it's asymmetric synthesis remains challenging because of the difficulty in controlling stereo- and regioselectivity. Herein, we report the first nickel-catalyzed asymmetric synthesis of N-N atropisomers by the denitrogenative transannulation of benzotriazones with internal alkynes. A broad range of N-N atropisomers was obtained with excellent regio- and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel-catalyzed reaction mechanism and enantioselectivity control.

Machine learning model and nomogram to predict the risk of heart failure hospitalization in peritoneal dialysis patients.

INTRODUCTION: The study presented here aimed to establish a predictive model for heart failure (HF) and all-cause mortality in peritoneal dialysis (PD) patients with machine learning (ML) algorithm. METHODS: We retrospectively included 1006 patients who initiated PD from 2010 to 2016. XGBoost, random forest (RF), and AdaBoost were used to train models for assessing risk for 1-year and 5-year HF hospitalization and mortality. The performance was validated using fivefold cross-validation. The optimal ML algorithm was used to construct the models to predictive the risk of the HF and all-cause mortality. The prediction performance of ML methods and Cox regression was compared. RESULTS: Over a median follow-up of 49 months. Two hundred and ninety-eight patients developed HF required hospitalization; 199 patients died during the follow-up. The RF model (AUC = 0.853) was the best performing model for predicting HF, and the XGBoost model (AUC = 0.871) was the best model for predicting mortality. Baseline moderate or severe renal disease, systolic blood pressure (SBP), body mass index (BMI), age, Charlson Comorbidity Index (CCI) score were strongly associated with HF hospitalization, whereas age, CCI score, creatinine, age, high-density lipoprotein cholesterol (HDL-C), total cholesterol, baseline estimated glomerular filtration rate (eGFR) were the most significant predictors of mortality. For all the above endpoints, the ML models demonstrated better discrimination than Cox regression. CONCLUSIONS: We developed and validated a novel method to predict the risk factors of HF and all-cause mortality that integrates readily available clinical, laboratory, and electrocardiographic variables to predict the risk of HF among PD patients.

Transcriptome analysis of the synergistic mechanisms between two strains of potato virus Y in Solanum tuberosum L.

Many viruses employ a process known as superinfection exclusion (SIE) to block subsequent entry or replication of the same or closely related viruses in the cells they occupy. SIE is also referred to as Cross-protection refers to the situation where a host plant infected by a mild strain of a virus or viroid gains immunity against a more severe strain closely related to the initial infectant. The mechanisms underlying cross-protection are not fully understood. In this study, we performed a comparative transcriptomic analysis of potato (Solanum tuberosum L.) leaves. The strains PVYN-Wi-HLJ-BDH-2 and PVYNTN-NW-INM-W-369-12 are henceforth designated as BDH and 369, respectively. In total, 806 differentially expressed genes (DEGs) were detected between the Control and JZ (preinfected with BDH and challenge with 369) treatment. Gene Ontology (GO) analysis showed that the response to external biological stimulation, signal transduction, kinase, immunity, redox pathways were significantly enriched. Among these pathways, we identified numerous differentially expressed metabolites related to virus infection. Moreover, our data also identified a small set of genes that likely play important roles in the establishment of cross-protection. Specifically, we observed significant differential expression of the A1-II gamma-like gene, elongation factor 1-alpha-like gene, and subtilisin-like protease StSBT1.7 gene, with StSBT1.7 being the most significant in our transcriptome data. These genes can stimulate the expression of defense plant genes, induce plant chemical defense, and participate in the induction of trauma and pathogenic bacteria. Our findings provided insights into the mechanisms underlying the ability of mild viruses to protect host plants against subsequent closely related virus infection in Solanum tuberosum L.

Prospects for the Application of Transplantation With Human Amniotic Membrane Epithelial Stem Cells in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multi-organ and systemic autoimmune disease characterized by an imbalance of humoral and cellular immunity. The efficacy and side effects of traditional glucocorticoid and immunosuppressant therapy remain controversial. Recent studies have revealed abnormalities in mesenchymal stem cells (MSCs) in SLE, leading to the application of bone marrow-derived MSCs (BM-MSCs) transplantation technique for SLE treatment. However, autologous transplantation using BM-MSCs from SLE patients has shown suboptimal efficacy due to their dysfunction, while allogeneic mesenchymal stem cell transplantation (MSCT) still faces challenges, such as donor degeneration, genetic instability, and immune rejection. Therefore, exploring new sources of stem cells is crucial for overcoming these limitations in clinical applications. Human amniotic epithelial stem cells (hAESCs), derived from the eighth-day blastocyst, possess strong characteristics including good differentiation potential, immune tolerance with low antigen-presenting ability, and unique immune properties. Hence, hAESCs hold great promise for the treatment of not only SLE but also other autoimmune diseases.

Copine proteins are required for brassinosteroid signaling in maize and Arabidopsis.

Copine proteins are highly conserved and ubiquitously found in eukaryotes, and their indispensable roles in different species were proposed. However, their exact function remains unclear. The phytohormone brassinosteroids (BRs) play vital roles in plant growth, development and environmental responses. A key event in effective BR signaling is the formation of functional BRI1-SERK receptor complex and subsequent transphosphorylation upon ligand binding. Here, we demonstrate that BONZAI (BON) proteins, which are plasma membrane-associated copine proteins, are critical components of BR signaling in both the monocot maize and the dicot Arabidopsis. Biochemical and molecular analyses reveal that BON proteins directly interact with SERK kinases, thereby ensuring effective BRI1-SERK interaction and transphosphorylation. This study advances the knowledge on BR signaling and provides an important target for optimizing valuable agronomic traits, it also opens a way to study steroid hormone signaling and copine proteins of eukaryotes in a broader perspective.

The effect of food tourism experiences on tourists' subjective well-being.

Food has become a crucial factor in attracting tourists to destinations. Providing tourists with satisfying food experiences has become a significant concern for tourist destinations. This study examines how tourists' food experiences contribute to their subjective well-being. After conducting a questionnaire survey of 360 tourists who experienced Zibo barbecue food, and analyzing the data using structural equation modeling, it was found that: tourists' food sensory experience, service experience, and environmental experience positively affect their satisfaction and subjective well-being; The effect of these experiences on tourists' satisfaction is mediated by tourist attitude; Tourist attitude and satisfaction play a chain mediating role in the effect of sensory experience, service experience, and environmental experience on tourists' subjective well-being. The research findings help to deepen the understanding of the relationship between food tourism experience and subjective well-being, enrich the theoretical research on food experience and tourists' well-being, and have insightful significance for the development and construction of other tourist destinations.

Interface-Engineered 3D porous MoS2-ReS2 in-plane heterojunction as efficient hydrogen evolution reaction electrocatalysts.

Constructing in-plane heterojunctions with high interfacial density using two-dimensional materials represents a promising yet challenging avenue for enhancing the hydrogen evolution reaction (HER) in water electrolysis. In this work, we report that three-dimensional porous MoS2-ReS2 in-plane heterojunctions, fabricated via chemical vapor deposition, exhibit robust electrocatalytic activity for the water splitting reaction. The optimized MoS2-ReS2 in-plane heterojunction achieves superior HER performance across a wide pH range, requiring an overpotential of only 200 mV to reach a current density of 10 mA cm-2 in alkaline seawater. Thus, it outperforms standalone MoS2 and ReS2. Furthermore, the catalyst exhibits remarkable stability, enduring up to 200 h in alkaline seawater. Experimental results coupled with density functional theory calculations confirm that electron redistribution at the MoS2-ReS2 heterointerface is likely driven by disparities in in-plane work functions between the two phases. This leads to charge accumulation at the interface, thereby enhancing the adsorptive activity of S atoms toward H* intermediates and facilitating the dissociation of water molecules at the interface. This discovery offers valuable insights into the electrocatalytic mechanisms at the interface and provides a roadmap for designing high-performance, earth-abundant HER electrocatalysts suitable for practical applications.

A genome-wide association study identifies genes associated with cuticular wax metabolism in maize.

The plant cuticle is essential in plant defense against biotic and abiotic stresses. To systematically elucidate the genetic architecture of maize (Zea mays L.) cuticular wax metabolism, 2 cuticular wax-related traits, the chlorophyll extraction rate (CER) and water loss rate (WLR) of 389 maize inbred lines, were investigated and a genome-wide association study (GWAS) was performed using 1.25 million single nucleotide polymorphisms (SNPs). In total, 57 nonredundant quantitative trait loci (QTL) explaining 5.57% to 15.07% of the phenotypic variation for each QTL were identified. These QTLs contained 183 genes, among which 21 strong candidates were identified based on functional annotations and previous publications. Remarkably, 3 candidate genes that express differentially during cuticle development encode ß-ketoacyl-CoA synthase (KCS). While ZmKCS19 was known to be involved in cuticle wax metabolism, ZmKCS12 and ZmKCS3 functions were not reported. The association between ZmKCS12 and WLR was confirmed by resequencing 106 inbred lines, and the variation of WLR was significant between different haplotypes of ZmKCS12. In this study, the loss-of-function mutant of ZmKCS12 exhibited wrinkled leaf morphology, altered wax crystal morphology, and decreased C32 wax monomer levels, causing an increased WLR and sensitivity to drought. These results confirm that ZmKCS12 plays a vital role in maize C32 wax monomer synthesis and is critical for drought tolerance. In sum, through GWAS of 2 cuticular wax-associated traits, this study reveals comprehensively the genetic architecture in maize cuticular wax metabolism and provides a valuable reference for the genetic improvement of stress tolerance in maize.

Intracellular MicroRNA Imaging and Specific Discrimination of Prostate Cancer Circulating Tumor Cells Using Multifunctional Gold Nanoprobe-Based Thermophoretic Assay.

Circulating tumor cells (CTCs) have emerged as powerful biomarkers for diagnosis of prostate cancer. However, the effective identification and concurrently accurate imaging of CTCs for early screening of prostate cancer have been rarely explored. Herein, we reported a multifunctional gold nanoprobe-based thermophoretic assay for simultaneous specific distinguishing of prostate cancer CTCs and sensitive imaging of intracellular microRNA (miR-21), achieving the rapid and precise detection of prostate cancer. The multifunctional gold nanoprobe (GNP-DNA/Ab) was modified by two types of prostate-specific antibodies, anti-PSMA and anti-EpCAM, which could effectively recognize the targeting CTCs, and meanwhile linked double-stranded DNA for further visually imaging intracellular miR-21. Upon the specific internalization of GNP-DNA/Ab by PC-3 cells, target aberrant miR-21 could displace the signal strand to recover the fluorescence signal for sensitive detection at the single-cell level, achieving single PC-3 cell imaging benefiting from the thermophoresis-mediated signal amplification procedure. Taking advantage of the sensitive miR-21 imaging performance, GNP-DNA/Ab could be employed to discriminate the PC-3 and Jurkat cells because of the different expression levels of miR-21. Notably, PC-3 cells were efficiently recognized from white blood cells, exhibiting promising potential for the early diagnosis of prostate cancer. Furthermore, GNP-DNA/Ab possessed good biocompatibility and stability. Therefore, this work provides a great tool for aberrant miRNA-related detection and specific discrimination of CTCs, achieving the early and accurate diagnosis of prostate cancer.

The Impact of Obesity on Diabetes Onset and Neovascularization in Mouse Models of Metabolic Stress.

Animal models of metabolic disorders are essential to studying pathogenic mechanisms and developing therapies for diabetes, but the induction protocols vary, and sexual dimorphism often exists. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, blood glucose and lipid profiles were measured. The high-fat (HF) diet damaged insulin sensitivity and increased triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, and liver lipid deposition. STZ increased blood glucose and liver fibrosis with less effects on blood lipids or liver lipid deposition. The combination of DIO and STZ treatments led to significant liver lipid deposition and fibrosis. Female mice showed delayed body weight gain on HF diet and resisted STZ-induced hyperglycemia. However, once they developed DIO, which occurs around 26 weeks of HF diet, the female mice were prone to STZ-induced hyperglycemia. In hindlimb ischemia, male mice in the DIO-STZ group showed significantly worse neovascularization compared with DIO or STZ groups. The DIO-STZ females showed significantly worse recovery than the DIO-STZ males. Our observations suggest that DIO-STZ is a plausible model for studying metabolic and cardiovascular disorders in obesity and diabetes. Moreover, the findings in female animals stress the need to assess sexual dimorphism and investigate the underlying mechanisms that contribute to the worse vasculopathy manifestations in females in metabolic models.

Light-Emitting Microfibers from Lotus Root for Eco-Friendly Optical Waveguides and Biosensing.

Optical biosensors based on micro/nanofibers are highly valuable for probing and monitoring liquid environments and bioactivity. Most current optical biosensors, however, are still based on glass, semiconductors, or metallic materials, which might not be fully suitable for biologically relevant environments. Here, we introduce biocompatible and flexible microfibers from lotus silk as microenvironmental monitors that exhibit waveguiding of intrinsic fluorescence as well as of coupled light. These features make single-filament monitors excellent building blocks for a variety of sensing functions, including pH probing and detection of bacterial activity. These results pave the way for the development of new and entirely eco-friendly, potentially multiplexed biosensing platforms.

Toll-Like Receptor 4 Deficiency Ameliorates Propofol-Induced Impairments of Cognitive Function and Synaptic Plasticity in Young Mice.

Propofol is one of the most used intravenous anesthetic agents, which is widely used in clinical anesthesia induction and maintenance of pediatric patients. Exposure of the developing brain to propofol has been reported to lead to adverse brain changes, which in turn can induce persistent behavioral abnormalities in adulthood. However, the mechanisms by which propofol exposure in the developing brain induces cognitive impairment remain unclear. Here we report that repeated propofol exposure during the second postnatal week impairs spatial learning and memory in young mice. The reduced excitatory synaptic function and synaptogenesis in hippocampal CA1 neurons underlie this cognitive impairment. Propofol exposure specifically activates Toll-like receptor 4 (TLR4)-myeloid differentiation primary response protein 88 (MyD88)-NF-κB signaling pathway. TLR4 deficiency recues propofol exposure-induced synaptic function and cognitive deficits in young mice. Thus, we provide evidence that the activation of the TLR4-mediated pathway by propofol exposure may serve as a crucial trigger for the cognitive impairment in young adulthood caused by repeated exposure to propofol in the developing brain.

Trends in bronchopulmonary dysplasia and respiratory support among extremely preterm infants in China over a decade.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is one of the most serious complications affecting extremely preterm infants. We aimed to evaluate temporal trends in BPD and administration of respiratory support among extremely preterm infants in China over a decade. METHODS: This was a retrospective study using data from a multicenter database, which included infants born less than 28 weeks' gestation discharged from 68 tertiary neonatal care centers in China between 2010 and 2019. Changes in rates and severity of BPD, as well as modalities and duration of respiratory support, were evaluated. RESULTS: Among 4808 eligible infants with gestational age (GA) of 21+6/7  to 27+6/7 weeks and a mean (SD) birth weight of 980 (177) g, no significant change of median GA was found over time. Overall, 780 (16.2%) infants died before 36 weeks' postmenstrual age, 2415 (50.2%) were classified as having no BPD, 917 (19.1%) developed Grade 1 BPD, 578 (12.0%) developed Grade 2 BPD, and 118 (2.5%) developed Grade 3 BPD. The rate of BPD increased from 20.8% in 2010 to 40.7% in 2019 (aRR for trend, 1.081; 95% confidence interval, 1.062-1.099), especially for Grade 1 and Grade 2. Although survival to discharge improved over the decade, the overall survival without BPD did not change during the study period. The use of invasive mechanical ventilation (IMV) remained unchanged. However, the use of noninvasive ventilation (NIV) increased from 71.5% in 2010 to 89.8% in 2019. Moreover, the median duration of NIV increased over time, from 17.0 (4.8, 34.0) days in 2010 to 33.0 (21.0, 44.0) days in 2019, without significant change in the duration of IMV. CONCLUSIONS: Although survival increased over the decade and respiratory support practices changed significantly between 2010 and 2019 in China, with increased use and duration of NIV, there was an increased rate of BPD and survival without BPD has not improved.

Multi-omic analysis revealed the therapeutic mechanisms of Alpinia oxyphylla fructus water extract against bladder overactivity in spontaneously hypertensive rats.

OBJECTIVE: Alpinia oxyphylla fructus without impurities and shells is called "Yi-Zhi-Ren" (YZR) in Chinese, and traditionally used to alleviate enuresis. The aim of this study was to investigate the effects and underlying mechanisms of YZR in the treatment of overactive bladder (OAB) in spontaneously hypertensive rats (SHR), a vascular disorder-related OAB model. METHODS: A 3-week administration of YZR water extract (p.o.) was done, followed by urodynamics to measure bladder parameters. Changes in bladder structure were observed through H&E staining and Masson's staining. An integrated approach involving network pharmacology, transcriptomics and metabolomics was employed to elucidate the potential mechanisms of YZR, and the key proteins involved in the mechanisms were validated by Western blotting. Additionally, network pharmacology was used to predict the relationship between YZR's active components and validated proteins. RESULTS: YZR treatment significantly improved the bladder storage parameters, tightened the detrusor layer, reduced inflammatory infiltration, and decreased collagen proportion in the SHR bladder. These results indicated that YZR water extract can alleviate OAB symptoms and improve bladder structure. Integrated analysis suggested that YZR may affect extracellular matrix-receptor interaction and calcium signaling pathway. Western blotting results further confirmed that the reduction in key proteins, such as TGFß1, p-SMAD3, collagen III, Gq and PLCß1, involved in collagen synthesis and calcium signaling pathways after YZR treatment. Network pharmacology predicted that sitosterol, chrysin, and nootkatone were potential components responsible for YZR's therapeutic effect on OAB. CONCLUSION: YZR's mechanisms of action in treating OAB involved the TGFß1-SMAD3 signaling pathway-related collagen synthesis and Gq-PLCß1 calcium signaling pathway, which are associated with detrusor contraction frequency and strength, respectively.

Multi-omic approaches provide insights into the molecular mechanisms of Sojae semen germinatum water extract against overactive bladder.

Sojae semen germinatum (SSG) is derived from mature soybean seeds that have been germinated and dried, typically with sprouts measuring approximately 0.5 cm in length. SSG is traditionally known for its properties in clearing heat and moisture. Nevertheless, limited information was reported on the effects and mechanisms of SSG in alleviating urinary symptoms. This study employed urodynamic parameters to investigate the therapeutic effect of SSG water extract on overactive bladder (OAB) in the rat model with benign prostatic hyperplasia. Through a combination of transcriptomic and metabolomic analyses, the pathways and key proteins of the SSG treatment for OAB were identified and validated by ELISA and Western blotting. Furthermore, network pharmacology elucidated the roles of SSG's isoflavones acting on the target which was identified by above-mentioned multi-omics analysis. Our results indicate that SSG water extract significantly mitigated OAB by down-regulating the PGE2/EP1/PLCß2/p-MLC signaling pathway. It was speculated that the active ingredient in the SSG on EP1 was genistein. This study provided valuable insights into the molecular mechanisms of SSG water extract, emphasizing the multi-target characteristics and critical pathways in improving OAB. Furthermore, this study contributes to the potential utilization of SSG as a functional food.

Germplasm characterization and SDS-PAGE analysis of caper (Capparis spinosa L.) from different provenances.

BACKGROUND: Capparis spinosa L. is a typical desert plant that is resistant to high temperatures and drought, and at the same time is rich in medicinal and food values. The objective of this study is to explore the variations in nutrient composition, morphological characteristics, and SDS-PAGE patterns of caper seeds from different provenances, aiming to provide insights for the selection of superior seed provenances. RESULTS: In this experiment, there were significant differences in the morphological characteristics and major nutritional components of caper seeds from different provenances. Seeds from the YKL (Karayagaqi Township, Yining County) and YKG (G218, KashiTown, Yining County) regions were larger in size compared to seeds from other regions. Among the four measured nutritional components, crude fat had the highest content, especially in the YKL and YKG region. The results of correlation analysis showed that crude fat was negatively correlated with soluble sugar and soluble protein but significantly positively correlated with starch content. As longitude increased from east to west, the morphological characteristics gradually increased. Based on the principal component analysis of all the parameters of the seeds, the eight provenances could be classified into three groups. HM (Hami), TGS (S202, Gaochang District, Turpan), HYW (Wubao Town, Yizhou District, Hami), TQQ (Qiquanhu Town, Turpan), and TLF (Turpan) were a group with higher soluble protein, soluble sugar, and water content. YKL and YKG were in one group, which had larger seed grains with high crude fat and starch content. AKS (Aksu) was in a separate group. The protein fractions from seeds of eight regions were extracted using Osborne fractionation method, it was found that glutelin content was the highest, while albumin content was the lowest. After these proteins were analyzed by SDS-PAGE, the electrophoretic patterns showed that the protein molecular weights were relatively small, and there were differences in protein bands among different provenances. CONCLUSION: According to the PCA results, the eight seed provenances could be divided into three groups. There were both geographically distant ones clustered into one group, and those close to each other were also divided into one group. There were differences in seed morphology, nutrient content and SDS-PAGE profiles among the different seed sources. This difference might be caused by a combination of geographic and climatic factors. In addition, YKL and YKG were roughly selected as good seed provenances, which provided a theoretical basis for the development of C. spinosa L. germplasm resources.

Weak-value amplified surface plasmon resonance sensor based on joint detection of optical activity and refractive index.

A versatile system combining surface plasmon resonance (SPR) and weak value amplification (WVA) is presented, which can measure the optical activity and refractive index of chiral/achiral molecules, ionic compounds, and their mixture in solution individually or simultaneously. The variations in output light intensity directly exhibit high sensitivity to changes in optical activity and refractive index of the aforementioned substances. Furthermore, by examining the correlation between the intensity variation trend and the optical activity of the chiral molecule, the molecule's absolute configuration can be ascertained. Utilizing this instrument, optical rotation with a resolution of 3.04 × 10-6 rad and refractive index with a resolution of 5.57 × 10-9 RIU were obtained. As an attempt at practical application, this sensor was used to detect the adulteration of glucose and fructose in pure honey. Not only can such compromised honey be distinguished from pure honey using the refractive index or optical rotation, but the difference in optical activity can also be employed to effectively differentiate between adulterated honey samples containing glucose and fructose separately.

Modeling phenotypic heterogeneity towards evolutionarily inspired osteosarcoma therapy.

Osteosarcoma is the most common bone sarcoma in children and young adults. While universally delivered, chemotherapy only benefits roughly half of patients with localized disease. Increasingly, intratumoral heterogeneity is recognized as a source of therapeutic resistance. In this study, we develop and evaluate an in vitro model of osteosarcoma heterogeneity based on phenotype and genotype. Cancer cell populations vary in their environment-specific growth rates and in their sensitivity to chemotherapy. We present the genotypic and phenotypic characterization of an osteosarcoma cell line panel with a focus on co-cultures of the most phenotypically divergent cell lines, 143B and SAOS2. Modest environmental (pH, glutamine) or chemical perturbations dramatically shift the success and composition of cell lines. We demonstrate that in nutrient rich culture conditions 143B outcompetes SAOS2. But, under nutrient deprivation or conventional chemotherapy, SAOS2 growth can be favored in spheroids. Importantly, when the simplest heterogeneity state is evaluated, a two-cell line coculture, perturbations that affect the faster growing cell line have only a modest effect on final spheroid size. Thus the only evaluated therapies to eliminate the spheroids were by switching therapies from a first strike to a second strike. This extensively characterized, widely available system, can be modeled and scaled to allow for improved strategies to anticipate resistance in osteosarcoma due to heterogeneity.

Catalytic Enantioselective Biltz Synthesis.

The Biltz synthesis establishes straightforward access to 5,5-disubstituted (thio)hydantoins by combining a 1,2-diketone and a (thio)urea. Its appealing features include inherent atom and step economy together with the potential to generate structurally diverse products. However, control of the stereochemistry of this reaction has proven to be a daunting challenge. Herein, we describe the first example of enantioselective catalytic Biltz synthesis which affords more than 40 thiohydantoins with high stereo- and regio-control, irrespective of the symmetry of thiourea structure. A one pot synthesis of corresponding hydantoins is also documented. Remarkably, experimental studies and DFT calculations establish the reaction pathway and origin of stereoselectivity.