Cobalt-catalyzed conformationally restricted alkylarylation enables divergent access to Csp3-rich N-heterocycles.

Due to the intrinsic spatial orientation and structural novelty, Csp3-rich N-heterocycles have been recognized as increasingly sought-after scaffolds as compared to the aromatic ring-based moieties, which have generated considerable recent attention in drug discovery. Hence, we disclose a modular cobalt-catalyzed conformationally restricted alkylarylation strategy for the divergent access to Csp3-rich N-hetero(spiro)cycles. Herein, multiple effects, including radical rebound and conformational restriction, play critical roles in the stabilization of the stereospecific alkyl-cobalt-aryl intermediate. Under simple and mild reaction conditions, cobalt catalyst combines a range of polyfunctionalized cyclenyl bromides and organozinc pivalates to rapidly and reliably forge the architecturally complex Csp3-rich N-hetero(spiro)cycles (>70 examples, >20 : 1 dr), including but not limited to the [5,5]-, [5,6]-, [5,7]-, [5,12]-bicycles, tri- and tetracyclic N-heterocycles, as well as various novel N-heterospirocyclic scaffolds in one synthetic operation. Preliminary kinetic investigations suggested that the final reductive elimination might be the rate-determining step. Moreover, ample substrate scope, good functional group compatibility and facile derivatizations to the pharmaceutically active molecules show the potential applications of this technology to organic syntheses and drug discoveries in medicinal chemistry.

Spatial patterns and the changing law of spatial and temporal factors in the economic quality of China's Silk Road Economic Belt.

It is important to quantitatively assess the level of high-quality development of the Silk Road Economic Belt and the global economy. In the past, many scholars have conducted relevant studies on high-quality economic development, but little attention has been given to China's Silk Road Economic Belt, and there is a lack of dynamic quantitative research on long time series. Based on these findings, we constructed an evaluation index system for the high-quality economic development of China's Silk Road Economic Belt based on statistical data using geographic information technology such as the Moran index and econometric methods such as the entropy weight method and the Mann-Kendall test. Then, we quantitatively depicted the spatial and temporal evolution of the high-quality economic development of China's Silk Road Economic Belt from 2007 to 2021. The results of the study showed that over time, the overall level of high-quality economic development in China's Silk Road Economic Belt and the scores of all dimensions showed a significant upwards trend from 2007 to 2021. Spatially, the level of high-quality economic development in China's Silk Road Economic Belt shows a spatial distribution pattern of being lowest in the North, followed by that in the South, and that in the Centre. Furthermore, there is a clustering distribution of high-quality economic development in China's Silk Road Economic Belt, and there is a spatial spillover effect; science and technology expenditures and the total amount of imports and exports are also crucial in promoting high-quality development of the region's economy and accelerating spatial spillovers from the Silk Road Economic Belt. The results of this study can provide an important scientific basis for the high-quality and sustainable development of the Silk Road Economic Belt in China, as well as be an important reference for related studies in other similar regions in the world.

Evaluation of pre-school pertussis booster vaccination in Shanghai, China: A cost-effectiveness analysis.

BACKGROUND: In recent years, notified pertussis cases have been increasingly documented in China. It raised a new public health concern of potential optimization in immunization strategy. This study was aimed to determine the cost-effectiveness of different immunization strategies against pertussis-containing vaccines for 6-year-old pre-school children in Shanghai. METHODS: A Markov-decision tree model was applied to evaluate two pertussis immunization strategies for 6-year-old pre-school children as following: (1) 1 dose of acellular pertussis (aP) contained vaccine (DTaP or Tdap) booster vaccinated at 6 years of age, and (2) no booster at 6 years of age regimen. Primary outcomes included quality-adjusted life years (QALYs), costs, and incremental cost-utility ratios (ICUR). Sensitivity analyses were performed. The analysis was conducted over a study period of 14 years from a societal perspective. RESULTS: Compared to no booster immunization strategy, administering 1 dose of acellular pertussis (aP) contained vaccine (DTaP or Tdap) booster at 6 years of age, resulted in an average cost reduction of CNY 814.16 (USD 116) per individual, an increase in QALYs by 0.00066, and a rise in per capita net monetary benefit (NMB) by CNY 933.51 (USD 132). The total costs over the study period were reduced by CNY 160.59 million (USD 23 million), utility increased by 130.49 QALYs, and NMB increased by CNY 184.14 million (USD 26 million). CONCLUSIONS: Implementing acellular pertussis booster immunization for 6-year-old pre-school children in Shanghai emerges as a cost-saving immunization strategy, with both cost savings and utility gains.

Genomics-based identification of a cold adapted clade in Deinococcus.

BACKGROUND: Microbes in the cold polar and alpine environments play a critical role in feedbacks that amplify the effects of climate change. Defining the cold adapted ecotype is one of the prerequisites for understanding the response of polar and alpine microbes to climate change. RESULTS: Here, we analysed 85 high-quality, de-duplicated genomes of Deinococcus, which can survive in a variety of harsh environments. By leveraging genomic and phenotypic traits with reverse ecology, we defined a cold adapted clade from eight Deinococcus strains isolated from Arctic, Antarctic and high alpine environments. Genome-wide optimization in amino acid composition and regulation and signalling enable the cold adapted clade to produce CO2 from organic matter and boost the bioavailability of mineral nitrogen. CONCLUSIONS: Based primarily on in silico genomic analysis, we defined a potential cold adapted clade in Deinococcus and provided an updated view of the genomic traits and metabolic potential of Deinococcus. Our study would facilitate the understanding of microbial processes in the cold polar and alpine environments.

Stratifin-mediated activation of AKT signaling and therapeutic targetability in hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and presents a significant threat to human health. Despite its prevalence, the underlying regulatory mechanisms of HCC remain unclear. In this study, we integrated RNA-seq datasets, proteome dataset and survival analysis and unveiled Stratifin (SFN) as a potential prognostic biomarker for HCC. SFN knockdown inhibited HCC progression in cell cultures and mouse models. Conversely, ectopic expression of Sfn in primary mouse HCC model accelerated HCC progression. Mechanistically, SFN acted as an adaptor protein, activating AKT1 signaling by fostering the interaction between PDK1 and AKT1, with the R56 and R129 sites on SFN proving to be crucial for this binding. In the syngeneic implantation model, the R56A/R129A mutant of SFN inhibited Akt signaling activation and impeded HCC growth. Additionally, peptide inhibitors designed based on the binding motif of AKT1 to SFN significantly inhibited HCC progression. In summary, our findings establish that SFN promotes HCC progression by activating AKT signaling through the R56 and R129 binding sites. This discovery opens new avenues for a promising therapeutic strategy for the treatment of HCC.

Discovery of a novel flavonol O-methyltransferase possessing sequential 4'- and 7-O-methyltransferase activity from Camptotheca acuminata Decne.

The biosynthetic route for flavonol in Camptotheca acuminata has been recently elucidated from a chemical point of view. However, the genes involved in flavonol methylation remain unclear. It is a critical step for fully uncovering the flavonol metabolism in this ancient plant. In this study, the multi-omics resource of this plant was utilized to perform flavonol O-methyltransferase-oriented mining and screening. Two genes, CaFOMT1 and CaFOMT2 are identified, and their recombinant CaFOMT proteins are purified to homogeneity. CaFOMT1 exhibits strict substrate and catalytic position specificity for quercetin, and selectively methylates only the 4'-OH group. CaFOMT2 possesses sequential O-methyltransferase activity for the 4'-OH and 7-OH of quercetin. These CaFOMT genes are enriched in the leaf and root tissues. The catalytic dyad and critical substrate-binding sites of the CaFOMTs are determined by molecular docking and further verified through site-mutation experiments. PHE181 and MET185 are designated as the critical sites for flavonol substrate selectivity. Genomic environment analysis indicates that CaFOMTs evolved independently and that their ancestral genes are different from that of the known Ca10OMT. This study provides molecular insights into the substrate-binding pockets of two new CaFOMTs responsible for flavonol metabolism in C. acuminata.

Proteomic Profiling of SGLT-2 Inhibitor Canagliflozin in a Swine Model of Chronic Myocardial Ischemia.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia. METHODS: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis. RESULTS: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change <0.5) and 250 that were upregulated (p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure. CONCLUSIONS: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.

Wearable and interactive multicolored photochromic fiber display.

Endowing flexible and adaptable fiber devices with light-emitting capabilities has the potential to revolutionize the current design philosophy of intelligent, wearable interactive devices. However, significant challenges remain in developing fiber devices when it comes to achieving uniform and customizable light effects while utilizing lightweight hardware. Here, we introduce a mass-produced, wearable, and interactive photochromic fiber that provides uniform multicolored light control. We designed independent waveguides inside the fiber to maintain total internal reflection of light as it traverses the fiber. The impact of excessive light leakage on the overall illuminance can be reduced by utilizing the saturable absorption effect of fluorescent materials to ensure light emission uniformity along the transmission direction. In addition, we coupled various fluorescent composite materials inside the fiber to achieve artificially controllable spectral radiation of multiple color systems in a single fiber. We prepared fibers on mass-produced kilometer-long using the thermal drawing method. The fibers can be directly integrated into daily wearable devices or clothing in various patterns and combined with other signal input components to control and display patterns as needed. This work provides a new perspective and inspiration to the existing field of fiber display interaction, paving the way for future human-machine integration.

Visible-light-enabled cascade cross-dehydrogenative-coupling/cyclization to construct α-chromone substituted α-amino acid derivatives.

Organophotocatalytic cascade cross-dehydrogenative-coupling/cyclization reaction of o-hydroxyarylenaminones with α-amino acid derivatives for the construction of α-chromone substituted α-amino acid derivatives was developed. Various N-arylglycine esters, amides and dipeptides underwent the cascade cyclization reaction well with o-hydroxyarylenaminones to afford the corresponding 3-aminoalkyl chromones in good to excellent yields. This approach consists of visible-light-promoted oxidation of α-amino acid derivatives, the Mannich reaction, and intramolecular nucleophilic cyclization under acidic conditions, and features a wide reaction scope, a simple operation and mild reaction conditions, which may have the potential to be used for the synthesis of bioactive molecules.

Association of the visceral adiposity index with femur bone mineral density and osteoporosis among the U.S. older adults from NHANES 2005-2020: a cross-sectional study.

Background: The visceral adiposity index (VAI) is a marker of abdominal fat distribution and adipose tissue function. However, the association between VAI and femur bone mineral density (BMD) and osteoporosis is unclear among the U.S. older adults. Methods: Cross-sectional data for adults aged 60 years and older from the 2007-2020 National Health and Nutrition Examination Survey (NHANES) were included. Multivariable linear and logistic regression were used to evaluate the association between VAI and femur BMD and osteoporosis. We used the smooth curve fitting to address nonlinearity. Moreover, a two-piecewise linear regression model was used to explain the nonlinearity further. Results: The findings of the multivariable logistic regression models showed that as the VAI value increased by one unit, the prevalence of osteoporosis decreased by 1.2% after adjusting for covariates associated with osteoporosis. The multivariable linear regression models demonstrated that VAI was positively correlated with femur BMD. Further analysis revealed an inverted L-shaped and inverted U-shaped relationship between VAI and femur BMD at different sites. Conclusions: Our findings indicated that an increased VAI is independently linked to a higher prevalence of osteoporosis among the U.S. older adults. Further analysis reveals that once VAI reaches a certain threshold, femur BMD no longer increases and may even decrease. This suggests that a moderate accumulation of visceral fat may be beneficial for bone health, while excessive visceral fat could potentially have detrimental effects.

Reduction in Nitrogen Rate and Improvement of Nitrogen Use Efficiency without Loss of Peanut Yield by Regional Mean Optimal Rate of Chemical Fertilizer Based on a Multi-Site Field Experiment in the North China Plain.

It is important to quantify nutrient requirements and optimize fertilization to improve peanut yield and fertilizer use efficiency. In this study, a multi-site field trial was conducted from 2020 to 2021 in the North China Plain to estimate nitrogen (N), phosphorus (P), and potassium (K) uptake and requirements of peanuts, and to evaluate the effects of fertilization recommendations from the regional mean optimal rate (RMOR) on dry matter, pod yield, nutrient uptake, and fertilizer use efficiency. Results show that compared with farmer practice fertilization (FP), optimal fertilization (OPT) based on the RMOR increased peanut dry matter by 6.6% and pod yield by 10.9%. The average uptake rates of N, P, and K were 214.3, 23.3, and 78.4 kg/ha, respectively, with 76.0% N harvest index, 59.8% P harvest index, and 41.4% K harvest index. The OPT treatment increased N, P, and K uptake by 19.3%, 7.3%, and 11.0% compared with FP, respectively. However, the average of yield, nutrition uptake, and harvest indexes of N, P, and K were not significantly affected by fertilization. The peanut required 42.0 kg N, 4.6 kg P, and 15.3 kg K to produce 1000 kg of pods. The OPT treatment significantly improved the N partial factor productivity and N uptake efficiency but decreased the K partial factor productivity and K uptake efficiency. The present study demonstrates that fertilizer recommendations from RMOR improve N use efficiency, and reduce N and P fertilizer application without yield loss in regions with smallholder farmers, and the corresponding estimation of nutrient requirements helps to make peanut fertilization recommendations.

A novel RNA modification prognostic signature for predicting the characteristics of the tumor microenvironment in gastric cancer.

Gastric cancer (GC) is one of the most common neoplastic malignancies, which permutes a fourth of cancer-related mortality globally. RNA modification plays a significant role in tumorigenesis, the underlying molecular mechanism of how different RNA modifications directly affect the tumor microenvironment (TME) in GC is unclear. Here, we profiled the genetic and transcriptional alterations of RNA modification genes (RMGs) in GC samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Through the unsupervised clustering algorithm, we identified three distinct RNA modification clusters and found that they participate in different biological pathways and starkly correlate with the clinicopathological characteristics, immune cell infiltration, and prognosis of GC patients. Subsequently, univariate Cox regression analysis unveiled 298 of 684 subtype-related differentially expressed genes (DEGs) are tightly interwoven to prognosis. In addition, we conducted the principal component analysis to develop the RM_Score system, which was used to quantify and predict the prognostic value of RNA modification in GC. Our analysis indicated that patients with high RM_Score were characterized by higher tumor mutational burden, mutation frequency, and microsatellite instability which were more susceptible to immunotherapy and had a favorable prognosis. Altogether, our study uncovered RNA modification signatures that may have a potential role in the TME and prediction of clinicopathological characteristics. Identification of these RNA modifications may provide a new understanding of immunotherapy strategies for gastric cancer.

Prospective assessment of pancreatic ductal adenocarcinoma diagnosis from endoscopic ultrasonography images with the assistance of deep learning.

BACKGROUND: Endosonographers are highly dependent on the diagnosis of pancreatic ductal adenocarcinoma (PDAC). The objectives of this study were to develop a deep-learning radiomics (DLR) model based on endoscopic ultrasonography (EUS) images for identifying PDAC and to explore its true clinical benefit. METHODS: A retrospective data set of EUS images that included PDAC and benign lesions was used as a training cohort (N = 368 patients) to develop the DLR model, and a prospective data set was used as a test cohort (N = 123 patients) to validate the effectiveness of the DLR model. In addition, seven endosonographers performed two rounds of reader studies on the test cohort with or without DLR assistance to further assess the clinical applicability and true benefits of the DLR model. RESULTS: In the prospective test cohort, DLR exhibited an area under the receiver operating characteristic curves of 0.936 (95% confidence interval [CI], 0.889-0.976) with a sensitivity of 0.831 (95% CI, 0.746-0.913) and 0.904 (95% CI, 0.820-0.980), respectively. With DLR assistance, the overall diagnostic performance of the seven endosonographers improved: one endosonographer achieved a significant expansion of specificity (p = .035,) and another achieved a significant increase in sensitivity (p = .038). In the junior endosonographer group, the diagnostic performance with the help of the DLR was higher than or comparable to that of the senior endosonographer group without DLR assistance. CONCLUSIONS: A prospective test cohort validated that the DLR model based on EUS images effectively identified PDAC. With the assistance of this model, the gap between endosonographers at different levels of experience narrowed, and the accuracy of endosonographers expanded.

Metabolite Profiling of Wheat Response to Cultivar Improvement and Nitrogen Fertilizer.

Both genetic improvement and the application of N fertilizer increase the quality and yields of wheat. However, the molecular kinetics that underlies the differences between them are not well understood. In this study, we performed a non-targeted metabolomic analysis on wheat cultivars from different release years to comprehensively investigate the metabolic differences between cultivar and N treatments. The results revealed that the plant height and tiller number steadily decreased with increased ears numbers, whereas the grain number and weight increased with genetic improvement. Following the addition of N fertilizer, the panicle numbers and grain weights increased in an old cultivar, whereas the panicle number and grain number per panicle increased in a modern cultivar. For the 1950s to 2010s cultivar, the yield increases due to genetic improvements ranged from -1.9% to 96.7%, whereas that of N application ranged from 19.1% to 81.6%. Based on the untargeted metabolomics approach, the findings demonstrated that genetic improvements induced 1.4 to 7.4 times more metabolic alterations than N fertilizer supply. After the addition of N, 69.6%, 29.4%, and 33.3% of the differential metabolites were upregulated in the 1950s, 1980s, and 2010s cultivars, respectively. The results of metabolic pathway analysis of the identified differential metabolites via genetic improvement indicated enrichment in 1-2 KEGG pathways, whereas the application of N fertilizer enriched 2-4 pathways. Our results provide new insights into the molecular mechanisms of wheat quality and grain yield developments.

Formulation and Characterisation of Carbamazepine Orodispersible 3D-Printed Mini-Tablets for Paediatric Use.

One of the main challenges to paediatric drug administration is swallowing difficulties, hindering the acceptability of the medicine and hence clinical outcomes. This study aims at developing a child-appropriate dosage form, the orodispersible mini-tablet (ODMT), using the model drug carbamazepine (CBZ). This dosage form was prepared and 3D-printed via a semi-solid extrusion technique. Design of Experiment methods were applied for optimising the formulation. The formulation with 40% (w/w) of SSG (superdisintegrant) and 5% (w/w) of PVP K30 (binder) was selected and loaded with CBZ. The drug-loaded tablets were characterised by a mean hardness of 18.5 N and a disintegrating time of 84 s, along with acceptable friability. The mean drug loading ratio of the tablets was tested as 90.56%, and the drug release rate in 0.1 M HCl reached 68.3% at 45 min. Excipients showed proper compatibility with the drug in physical form analysis. Taste assessment via an E-tongue was also conducted, where the drug did not show bitter taste signals at a low concentration in the taste assessment, and the sweetener also blocked bitterness signals in the testing. To this end, ODMTs were found to be potential candidates for child-appropriate dosage forms delivering CBZ.

Activity and mechanism of vanadium sulfide for organic contaminants oxidation with peroxymonosulfate.

Transition metal sulfides have been demonstrated to be effective for peroxymonosulfate (PMS) activation towards wastewater treatment. However, the activity of vanadium sulfide (VS4) and the role of the chemical state of V have not been revealed. Here, three types of VS4 with various morphologies and chemical states of V were synthesized by using methanol (M-VS4, nanosphere composed of nanosheets), ethanol (E-VS4, sea urchin like nanosphere) and ultrapure water (U-VS4, compact nanosphere) as hydrothermal solvent, respectively, and used as heterogeneous catalysts to activate PMS for the degradation of refractory organic pollutants. The effects of PMS concentration, temperature, pH, inorganic ions, and humic acid (HA) on the degradation efficiency of VS4/PMS system were investigated systematically. The results indicated that the highest specific surface area and lowest ratio of V5+ enable E-VS4/PMS system possessed the highest performance in degrading tetracycline hydrochloride (TCH), in which 100% TCH was removed after operating 10 min (0.805 min-1) under a relatively low concentration of PMS (1 mM) and catalyst (100 mg/L). It also revealed that the system exhibited a typical radical process in TCH degradation, which could be attributed to the redox cycles between V5+, V4+ and V3+ in the presence of PMS to generate various radicals. This radical process enabled the E-VS4/PMS system with a high activity in wide reaction conditions and high mineralization ratios in degrading various refractory organic pollutants within 10 min. In addition, the E-VS4/PMS system exhibited favorable reusability and stability with very less V and S ions leaching, and showed excellent performance in real water purification.

Constructing Escherichia coli co-display systems for biodegradation of polyethylene terephthalate.

BACKGROUND: The accumulation of fast-growing polyethylene terephthalate (PET) wastes has posed numerous threats to the environments and human health. Enzymatic degradation of PET is a promising approach for PET waste treatment. Currently, the efficiency of various PET biodegradation systems requires further improvements. RESULTS: In this work, we engineered whole cell systems with co-display of strong adhesive proteins and the most active PETase for PET biodegradation in E. coli cells. Adhesive proteins of cp52k and mfp-3 and Fast-PETase were simultaneously displayed on the surfaces of E. coli cells, and the resulting cells displaying mfp-3 showed 50% increase of adhesion ability compared to those without adhesive proteins. Consequently, the degradation rate of E. coli cells co-displaying mfp-3 and Fast-PETase for amorphous PET exceeded 15% within 24 h, exhibiting fast and thorough PET degradation. CONCLUSIONS: Through the engineering of co-display systems in E. coli cells, PET degradation efficiency was significantly increased compared to E. coli cells with sole display of Fast-PETase and free enzyme. This feasible E. coli co-display system could be served as a convenient tool for extending the treatment options for PET biodegradation.

Fabric computing: Concepts, opportunities, and challenges.

With the advent of the Internet of Everything, people can easily interact with their environments immersively. The idea of pervasive computing is becoming a reality, but due to the inconvenience of carrying silicon-based entities and a lack of fine-grained sensing capabilities for human-computer interaction, it is difficult to ensure comfort, esthetics, and privacy in smart spaces. Motivated by the rapid developments in intelligent fabric technology in the post-Moore era, we propose a novel computing approach that creates a paradigm shift driven by fabric computing and advocate a new concept of non-chip sensing in living spaces. We discuss the core notion and benefits of fabric computing, including its implementation, challenges, and future research opportunities.

Imperceptible, designable, and scalable braided electronic cord.

Flexible sensors, friendly interfaces, and intelligent recognition are important in the research of novel human-computer interaction and the development of smart devices. However, major challenges are still encountered in designing user-centered smart devices with natural, convenient, and efficient interfaces. Inspired by the characteristics of textile-based flexible electronic sensors, in this article, we report a braided electronic cord with a low-cost, and automated fabrication to realize imperceptible, designable, and scalable user interfaces. The braided electronic cord is in a miniaturized form, which is suitable for being integrated with various occasions in life. To achieve high-precision interaction, a multi-feature fusion algorithm is designed to recognize gestures of different positions, different contact areas, and different movements performed on a single braided electronic cord. The recognized action results are fed back to varieties of interactive terminals, which show the diversity of cord forms and applications. Our braided electronic cord with the features of user friendliness, excellent durability and rich interaction mode will greatly promote the development of human-machine integration in the future.