Phenotypic and spatial heterogeneity of CD8+ tumour infiltrating lymphocytes.

CD8+ T cells are the workhorses executing adaptive anti-tumour response, and targets of various cancer immunotherapies. Latest advances have unearthed the sheer heterogeneity of CD8+ tumour infiltrating lymphocytes, and made it increasingly clear that the bulk of the endogenous and therapeutically induced tumour-suppressive momentum hinges on a particular selection of CD8+ T cells with advantageous attributes, namely the memory and stem-like exhausted subsets. A scrutiny of the contemporary perception of CD8+ T cells in cancer and the subgroups of interest along with the factors arbitrating their infiltration contextures, presented herein, may serve as the groundwork for future endeavours to probe further into the regulatory networks underlying their differentiation and migration, and optimise T cell-based immunotherapies accordingly.

Synthesis of 2,4-Disubstituted Oxazoles and Thiazoles via Brønsted Acid-Catalyzed Cyclization of α-diazoketones with Amides.

A novel method is described for the synthesis of 2,4-disubstituted oxazole and thiazole derivates via the coupling of α-diazoketones with (thio)amides or thioureas using trifluoromethanesulfonic acid (TfOH) as a catalyst. This protocol is characterized by mild reaction conditions, metal-free, and simplicity and also features good functional group tolerance, good to excellent yields, and a broad substrate scope with more than 40 examples. Experimental studies suggest a mechanism involving 2-oxo-2-phenylethyl trifluoromethanesulfonate as the key intermediate.

APIPred: An XGBoost-Based Method for Predicting Aptamer-Protein Interactions.

Aptamers are single-stranded DNA or RNA oligos that can bind to a variety of targets with high specificity and selectivity and thus are widely used in the field of biosensing and disease therapies. Aptamers are generated by SELEX, which is a time-consuming procedure. In this study, using in silico and computational tools, we attempt to predict whether an aptamer can interact with a specific protein target. We present multiple data representations of protein and aptamer pairs and multiple machine-learning-based models to predict aptamer-protein interactions with a fair degree of selectivity. One of our models showed 96.5% accuracy and 97% precision, which are significantly better than those of the previously reported models. Additionally, we used molecular docking and SPR binding assays for two aptamers and the predicted targets as examples to exhibit the robustness of the APIPred algorithm. This reported model can be used for the high throughput screening of aptamer-protein pairs for targeting cancer and rapidly evolving viral epidemics.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Characterization of benzylisoquinoline alkaloid methyltransferases in Liriodendron chinense provides insights into the phylogenic basis of angiosperm alkaloid diversity.

Benzylisoquinoline alkaloids (BIAs) are a class of plant secondary metabolites with great pharmacological value. Their biosynthetic pathways have been extensively elucidated in the species from the Ranunculales order, such as poppy and Coptis japonica, in which methylation events play central roles and are directly responsible for BIA chemodiversity. Here, we combined BIA quantitative profiling and transcriptomic analyses to identify novel BIA methyltransferases (MTs) from Liriodendron chinense, a basal angiosperm plant. We identified an N-methyltransferase (LcNMT1) and two O-methyltransferases (LcOMT1 and LcOMT3), and characterized their biochemical functions in vitro. LcNMT1 methylates (S)-coclaurine to produce mono- and dimethylated products. Mutagenesis experiments revealed that a single-residue alteration is sufficient to change its substrate selectivity. LcOMT1 methylates (S)-norcoclaurine at the C6 site and LcOMT3 methylates (S)-coclaurine at the C7 site, respectively. Two key residues of LcOMT3, A115 and T301, are identified as important contributors to its catalytic activity. Compared with Ranunculales-derived NMTs, Magnoliales-derived NMTs were less abundant and had narrower substrate specificity, indicating that NMT expansion has contributed substantially to BIA chemodiversity in angiosperms, particularly in Ranunculales species. In summary, we not only characterized three novel enzymes that could be useful in the biosynthetic production of valuable BIAs but also shed light on the molecular origin of BIAs during angiosperm evolution.

Horienoids A and B, Two Heterocoupled Sesquiterpenoid Dimers from Hedyosmum orientale.

Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A (1) and B (2) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.

Prevalence of Concomitant Coronary Artery Disease and Its Impact on Acute Kidney Injury for Chinese Adult Patients Undergoing Valvular Heart Surgery.

INTRODUCTION: Significant coronary artery disease (CAD) in patients undergoing valvular heart surgery (VHS) is an indication for combined valvular heart surgery and coronary artery bypass grafting. However, the impact of nonsignificant CAD on postoperative outcomes is not well understood. This study illustrated the epidemiological characteristics of CAD in China and investigated the impact of CAD on postoperative acute kidney injury (AKI), intensive care unit (ICU) stay, and postoperative mortality. METHODS: This study comprised an epidemiological survey followed by a case-control investigation. The epidemiological characteristics of CAD were studied in 4,172 consecutive patients who underwent coronary angiography before planned VHS at a core cardiovascular center. Then, 3,618 patients were selected for the subsequent case-control study to further analyze the associations between CAD and postoperative advanced AKI (grade 2 or 3 by KDIGO criteria), longer ICU stay (highest quartile), and increased mortality by logistic regression. RESULTS: Of the participants, 5.1 and 9.3% had moderate and significant CAD, respectively. The incidence of CAD increased after 60 years of age. Although CAD was not related to longer postoperative ICU stay in a multivariate logistic model, moderate CAD (OR 1.539 [95% CI 1.078-2.199]) and significant CAD (OR 1.798 [95% CI 1.094-2.955]) remained independent risk factors for postoperative advanced AKI after adjusting for multiple traditional risk factors. Significant CAD, but not nonsignificant CAD, was associated with postoperative mortality. CONCLUSIONS: Concomitant CAD is common in Chinese patients who undergo VHS. Moderate and significant CAD might have detrimental effects on postoperative advanced AKI.

A stoichiometric CdS interlayer for the photovoltaic performance enhancement of quantum-dot sensitized solar cells.

The CdS interlayer plays an important role as the seed layer and energy barrier in photovoltaic performance enhancement of CdSe quantum-dot sensitized solar cells (QDSCs). However, the CdS (CdS-CBD) interlayer is generally synthesized by the chemical bath deposition method (CBD) and suffers from excessive Cd2+ due to the poor controllability of interfacial chemical reactions. Here, we employed a sol-gel method to prepare a CdS interlayer (CdS-SG) with a stoichiometric ratio of Cd2+ to S2- on a TiO2 mesoporous photoanode and then fabricated CdSe QDSCs. A power conversion efficiency of 3.37% was obtained in the CdS-SG QDSCs (Cell-SG), which is higher than that of 2.64% in the CdS-CBD QDSCs (Cell-CBD) under AM 1.5G solar illumination of 100 mW cm-2. Charge extraction measurements showed that the Cell-SG contained fewer trap states than the Cell-CBD. A comprehensive study of the electron dynamics based on open-circuit voltage decay (OCVD), electrochemical impedance spectroscopy (EIS), intensity-modulated voltage spectroscopy (IMVS), and intensity-modulated photocurrent spectroscopy (IMPS) measurements revealed that the stoichiometric CdS-SG interlayer significantly reduced the charge recombination and prolonged the lifetime of photogenerated electrons in contrast to the CdS-CBD interlayer in the QDSCs.

Euphorhelipanes A and B, Triglyceride-Lowering Euphorbia Diterpenoids with a Bicyclo[4.3.0]nonane Core from Euphorbia helioscopia.

Euphorhelipanes A (1) and B (2), two Euphorbia diterpenoids with a new 4-(5,5-dimethylheptan-2-yl)-2,7-dimethylbicyclo[4.3.0]nonane skeleton, were isolated from a 95% ethanol extract of the whole plants of Euphorbia helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 represent the first examples of Euphorbia diterpenoids with a 5/6 fused carbon ring system, and their plausible biosynthetic pathways originating from jatrophanes are proposed. Compounds 1 and 2 showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells at concentrations of 1-50 µM.

High hemoglobin is associated with increased in-hospital death in patients with chronic obstructive pulmonary disease and chronic kidney disease: a retrospective multicenter population-based study.

BACKGROUND: Chronic kidney disease (CKD) is a common comorbidity of chronic obstructive pulmonary disease (COPD). Although high hemoglobin (Hb) is detrimental to CKD patients, its relationship with poor outcomes in the COPD population has not been reported. This study aimed to investigate the relationship between high Hb and in-hospital mortality and to explore reference Hb intervals in patients with COPD and CKD. METHODS: This retrospective study was multicenter population-based. A total of 47,209 patients who presented with COPD between January 2012 and December 2016 were included. The average Hb level during hospitalization was used as the Hb level. CKD and advanced CKD were defined as estimated glomerular filtration rates < 60 and < 30 ml/min/1.73 m2, respectively. The association between Hb level (measured in 1 g/dL intervals) and in-hospital mortality was analyzed in different multivariable logistic regression models by CKD stratification. RESULTS: The Hb level was decreased in the CKD subgroup. In the non-CKD group, a higher Hb level was not associated with an increased risk of in-hospital death. However, the Hb level and mortality showed a U-shaped relationship in the CKD group. After adjusting for age and Charlson Comorbidity Index, multivariable regression analysis showed that an Hb level > 17 g/dL was associated with an increased risk of death in the CKD group with an odds ratio (OR) of 2.085 (95% CI, 1.019-4.264). Hb > 14 g/dL was related to an increased risk of death in advanced CKD patients (OR, 4.579 (95% CI, 1.243-16.866)). CONCLUSIONS: High Hb is associated with an increased risk of in-hospital death in COPD patients with CKD, especially among those with advanced CKD. In this group of patients, attention should be paid to those with high Hb levels.