Explore the vast range of titles available.

In this work, the enantioselective total synthesis of (–)-quinine has been accomplished in a pot-economical manner using five reaction vessels. In the first pot, reactions involve the diphenylprolinol silyl ether-mediated Michael reaction, aza-Henry reaction, hemiaminalization, and elimination of HNO 2 (five reactions), affording a chiral tetrahydropyridine with excellent enantioselectivity. In the second pot, five reactions proceed with excellent diastereoselectivity to afford a trisubstituted piperidine with the desired stereochemistry. A further five reactions are carried out in the last one-pot sequence. Syntheses of quinine have fascinated organic chemists for over a hundred years. Here, the authors developed an organocatalyst-mediated pot-economical enantioselective total synthesis using five reaction vessels.

The failure of polycrystalline materials used in infrastructure and transportation can be catastrophic. Multiscale modeling, which requires multiscale measurements of internal stress fields, is the key to predicting the deformation and failure of alloys. We determined the three-dimensional intragranular stress tensor fields in plastically deformed bulk steel using a high-energy x-ray microbeam. We observed intragranular local stresses that deviated greatly from the grain-averaged stresses and exceeded the macroscopic tensile strength. Even under deformation smaller than the uniform elongation, the intragranular stress fields were in highly triaxial stress states, which cannot be determined from the grain-averaged stresses. The ability to determine intragranular stress tensor fields can facilitate the understanding and prediction of the deformation and failure of materials through multiscale modeling.

Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC. We evaluated somatic mutations and fragmentation of circulating tumor DNA (ctDNA) using next‐generation sequencing and droplet digital PCR in renal cell carcinoma (RCC). ctDNA can be promising tools for monitoring and predicting prognosis of RCC.

The spatial resolution in scanning-based two-dimensional microscopy is normally limited by the size of the probe, thereby a smaller probe is a prerequisite for enhancing the spatial resolution. For three-dimensional microscopy that combines translation and rotation motions of a specimen, however, complex trajectories of the probe highly overlap in the specimen, which could change the postulate above. Here, the spatial resolution achieved in scanning three-dimensional X-ray diffraction (s3DXRD) microscopy is investigated. In this method, the most appropriate orientation of the pixel in the specimen coordinate is selected by comparing the completeness of diffraction peaks with theory. Therefore, the superposed area of the beam trajectory has a strong effect on the spatial resolution, in terms of the completeness of diffraction peaks. It was found that the highly superposed area by the incident X-rays, which has the highest completeness factor in the pixel of the specimen, is much smaller than the X-ray probe size, and that sub-pixel analysis by dividing a pixel into small pieces leads to drastic improvement of the spatial resolution in s3DXRD.

Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discover potential bladder cancer (BCa) biomarkers, however urine contains numerous EVs derived from the kidney and normal urothelial epithelium, which can obfuscate information related to BCa cell‐derived EVs. In this study, we combined proteomic analysis of urinary EVs and tissue‐exudative EVs (Te‐EVs), which were isolated from culture medium of freshly resected viable BCa tissues. Urinary EVs were isolated from urine samples of 11 individuals (7 BCa patients and 4 healthy individuals), and Te‐EVs were isolated from 7 BCa tissues. We performed tandem mass tag (TMT)‐labeling liquid chromatography (LC‐MS/MS) analysis for both urinary EVs and Te‐EVs and identified 1960 proteins in urinary EVs and 1538 proteins in Te‐EVs. Most of the proteins identified in Te‐EVs were also present in urinary EVs (82.4%), with 55 of these proteins showing upregulated levels in the urine of BCa patients (fold change > 2.0; P < .1). Among them, we selected 22 membrane proteins as BCa biomarker candidates for validation using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis on urine samples from 70 individuals (40 BCa patients and 30 healthy individuals). Six urinary EV proteins (heat‐shock protein 90, syndecan‐1, myristoylated alanine‐rich C‐kinase substrate (MARCKS), MARCKS‐related protein, tight junction protein ZO‐2, and complement decay‐accelerating factor) were quantified using SRM/MRM analysis and validated as significantly upregulated in BCa patients (P < .05). In conclusion, the novel strategy that combined proteomic analysis of urinary EVs and Te‐EVs enabled selective detection of urinary BCa biomarkers. Proteomic analysis of urinary extracellular vesicles (EVs) is a powerful approach to discovering potential BCa biomarkers, however urine contains numerous EVs derived from kidney and normal urothelial epithelium that could dilute the information of cancer BCa cell‐derived EVs. In this study, we performed combined proteomic analysis of both urinary EVs and tissue‐extracted EVs (Te‐EVs) to identify reliable BCa biomarkers. This novel strategy presented here identified reliable urinary EV biomarker proteins exhibiting high levels of specificity and sensitivity for non‐invasive BCa detection.

Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non‐invasive test for detecting UTUC, but its sensitivity is low. A novel non‐invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell‐free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger‐scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non‐invasive diagnostic marker and reliable factor for tumor staging. TERT promoter and FGFR3 hotspot mutations in urinary cell‐free DNA were analyzed. In combination with urine cytology, the sensitivity was 78.6%, and specificity was 96.0% for upper tract urothelial carcinoma diagnosis.

Plastically deformed low-carbon steel has been analyzed by nondestructive three-dimensional orientation and strain mapping using scanning three-dimensional X-ray diffraction microscopy (S3DXRD). However, the application of S3DXRD is limited to single-phase alloys. In this study, we propose a modified S3DXRD analysis for dual-phase alloys, such as ferrite–pearlite carbon steel, which is composed of grains detectable as diffraction spots and a phase undetectable as diffraction spots. We performed validation experiments for ferrite–pearlite carbon steel with different pearlite fractions, in which the ferrite grains and the pearlite corresponded to the detectable grains and an undetectable phase, respectively. The regions of pearlite appeared more remarkably in orientation maps of the ferrite grains obtained from the carbon steel samples than that of the single-phase low-carbon steel and increased with the increase in the carbon concentration. The fractions of the detectable grains and the undetectable phase were determined with an uncertainty of 15%–20%. These results indicate that the proposed modified analysis is qualitatively valid for dual-phase alloys comprising detectable grains and an undetectable phase.

We have found that intestinal bacteria and their metabolites, short‐chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analyzed the gut microbiota profiles of men with suspected PCa. One hundred and fifty‐two Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: a discovery cohort (114 samples) and a test cohort (38 samples). The gut microbiota was compared between two groups, a high‐risk group (men with Grade group 2 or higher PCa) and a negative + low‐risk group (men with negative biopsy or Grade group 1 PCa), using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFA‐producing bacteria, were significantly increased in high‐risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression detected high‐risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve [AUC] = 0.85 vs 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs 0.67). The specific bacterial taxa were associated with high‐risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high‐risk PCa and could contribute to the carcinogenesis of PCa. To clarify the association between the gut microbiota and prostate cancer, we analyzed the gut microbiota profiles of 152 men undergoing prostate biopsy. The abundances of Rikenellaceae, Alistipes, and Lachnospira were significantly increased in men with high‐risk cancer. The index calculated from the abundance of 18 bacterial genera detected high‐risk cancer with higher accuracy than the prostate specific antigen test.

Bimodal behavior in the translational order of silicon’s second shell in SiO 2 liquid at high temperatures and high pressures has been recognized in theoretical studies, and the fraction of the S state with high tetrahedrality is considered as structural origin of the anomalous properties. However, it has not been well identified in experiment. Here we show experimental evidence of a bimodal behavior in the translational order of silicon’s second shell in SiO 2 glass under pressure. SiO 2 glass shows tetrahedral symmetry structure with separation between the first and second shells of silicon at low pressures, which corresponds to the S state structure reported in SiO 2 liquid. On the other hand, at high pressures, the silicon’s second shell collapses onto the first shell, and more silicon atoms locate in the first shell. These observations indicate breaking of local tetrahedral symmetry in SiO 2 glass under pressure, as well as SiO 2 liquid. Understanding the structural origin of the anomalous properties of SiO 2 liquid and glass at high pressures is fundamental in wide range of scientific fields. Here, the authors find experimental evidence of a bimodal behavior in the translational order of silicon’s second shell and breaking of local tetrahedral symmetry in SiO 2 glass under pressure.

Bladder cancer is the most common cancer of the urinary tract. Although nonmuscle-invasive bladder cancers have a good prognosis, muscle-invasive bladder cancers promote metastases and have a poor prognosis. Comprehensive analyses using RNA sequence of clinical tumor samples in bladder cancer have been reported. These reports implicated the candidate genes and pathways that play important roles in carcinogenesis and/or progression of bladder cancer. Further investigations for the function of each mutation are warranted. There is suggestive evidence for several environmental factors as risk factors of bladder cancer. Environmental factors such as cigarette smoking, exposure to chemicals and gases, bladder inflammation due to microbial and parasitic infections, diet, and nutrition could induce several genetic mutations and alter the tumor microenvironment, such as immune cells and fibroblasts. The detailed mechanism of how these environmental factors induce carcinogenesis and/or progression of bladder cancer remains unclear. To identify the relationship between the mutations and the lifestyle could be useful for prevention and treatment of bladder cancer.