Exo-Selective Diels-Alder Reactions.

The Diels-Alder reaction stands as one of the most pivotal transformations in organic chemistry. Its efficiency, marked by the formation of two carbon-carbon bonds and up to four new stereocenters in a single step, underscores its versatility and indispensability in synthesizing natural products and pharmaceuticals. The most significant stereoselectivity feature is the "endo rule". While this rule underpins the predictability of the stereochemical outcomes, it also underscores the challenges in achieving the opposite diastereoselectivity, making the exo-Diels-Alder reactions often considered outliers. This review delves into recent examples of exo-Diels-Alder reactions, shedding light on the factors inverting the intrinsic tendency. We explore the roles of steric, electrostatic, and orbital interactions, as well as thermodynamic equilibriums in influencing exo/endo selectivity. Furthermore, we illustrate strategies to manipulate these factors, employing approaches such as bulky substituents, s-cis conformations, transient structural constraints, and innovative control physics. Through these analyses, our aim is to provide a comprehensive understanding of how to predict and design exo-Diels-Alder reactions, paving the way for new diastereoselective catalyst systems and expanding the chemical scope of Diels-Alder reactions.

An extracellular vesicle microRNA-initiated 3D DNAzyme motor for colorectal cancer diagnosis.

MicroRNA is regarded as a significant biomarker for cancer diagnosis, disease process evaluation and therapeutic guidance, and dual-parameter measurement may contribute to a more accurate and realistic assessment. To meet the urgent need for simultaneous detection of multiple biomarkers, we combined three-dimensional DNAzyme motors with single molecule imaging technique to construct a convenient, intuitive, and sensitive approach for the simultaneous detection of dual miRNAs in the free state or in extracellular vesicles. Quantification of target miRNAs can be realized through the detection of amplified fluorescence signals generated by the target miRNA-initiated cleavage of fluorescent substrate strands by the DNAzyme motors. The practicability was systematically validated with microRNA-21-5p and microRNA-10b-5p as targets, acquiring a satisfactory sensitivity sufficient to detect low abundance targets at 0.5 or 1 pM to 100 pM. Besides, the extracellular vesicular miRNAs can be conveniently detected without extraction. The clinical applicability was verified with a series of extracellular vesicles from clinical samples, which exhibited good distinguishability between colorectal cancer patients and healthy donors. In addition to the advantages of good specificity and high sensitivity, the system has potential to be easily adapted by minor alteration of the DNA sequences and fluorophore sets for detection of multiple miRNAs and even other types of biomarkers such as proteins. Therefore, it shows promise to be widely applied in various fields such as early diagnosis of cancer and its prognostic assessment.

Multiple Calcium Channel Types with Unique Expression Patterns Mediate Retinal Signaling at Bipolar Cell Ribbon Synapses.

Retinal bipolar cells (BCs) compose the canonical vertical excitatory pathway that conveys photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca2+ influx through voltage-gated Ca2+ (CaV) channels mediating L-type currents, the molecular identity of CaV channels in BCs is uncertain. Therefore, we combined molecular and functional analyses to determine the expression profiles of CaV α1, ß, and α2δ subunits in mouse rod bipolar (RB) cells, BCs from which the dynamics of synaptic transmission are relatively well-characterized. We found significant heterogeneity in CaV subunit expression within the RB population from mice of either sex, and significantly, we discovered that transmission from RB synapses was mediated by Ca2+ influx through P/Q-type (CaV2.1) and N-type (CaV2.2) conductances as well as the previously-described L-type (CaV1) and T-type (CaV3) conductances. Furthermore, we found both CaV1.3 and CaV1.4 proteins located near presynaptic ribbon-type active zones in RB axon terminals, indicating that the L-type conductance is mediated by multiple CaV1 subtypes. Similarly, CaV3 α1, ß, and α2δ subunits also appear to obey a "multisubtype" rule, i.e., we observed a combination of multiple subtypes, rather than a single subtype as previously thought, for each CaV subunit in individual cells.SIGNIFICANCE STATEMENT Bipolar cells (BCs) transmit photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca2+ influx through L-type voltage-gated Ca2+ (CaV) channels, the molecular identity of CaV channels in BCs is uncertain. Here, we report unexpectedly high molecular diversity of CaV subunits in BCs. Transmission from rod bipolar (RB) cell synapses can be mediated by Ca2+ influx through P/Q-type (CaV2.1) and N-type (CaV2.2) conductances as well as the previously-described L-type (CaV1) and T-type (CaV3) conductances. Furthermore, CaV1, CaV3, ß, and α2δ subunits appear to obey a "multisubtype" rule, i.e., a combination of multiple subtypes for each subunit in individual cells, rather than a single subtype as previously thought.

Adsorption Mechanism of Benzene Derivatives by Pagoda[n]arenes.

Despite the widespread use in industrial production, benzene derivatives are harmful to both human beings and the environment. The control of these substances has become an important subject of scientific research. This study introduces a new approach for adsorption and separation of benzene derivatives utilizing pagoda[n]arene based supramolecular materials. Density functional theory calculations were employed to investigate the molecular recognition mechanism of benzene derivatives by pagoda[4]arenes and pagoda[5]arenes (Pa[4]As and Pa[5]As). Results indicate that Pa[4]As and Pa[5]As can effectively accommodate benzene derivatives through non-covalent interactions, leading to the formation of stable host-guest complexes. Additionally, molecular dynamics simulations revealed that both crystalline and non-crystalline supramolecular aggregates of Pa[4]As and Pa[5]As possess the ability to adsorb benzene derivatives and maintain the stability of the adsorption. Moreover, increasing the temperature causes benzene derivatives to desorb from the adsorbing aggregates, and thus the material can be reutilized.

Improving robustness of water supply system using a multi-objective robust optimization framework.

Due to the uncertainty of rainfall and water demand, the water supply of various participants has been challenged in such a way that this challenge has accelerated the failure of water supply system. Thus, this study proposes a multi-stage Adjustable Robust Optimization integrated to the multi-objective programming framework to drive water supply system to the failure safety zone and thereby improve robustness of system under different scenarios. Indeed, Adjustable Robust Optimization framework is applied to investigate the two uncertain factors of rainfall and water demand. A real arid area of Sistan basin in southeastern Iran is considered to analyze the proposed multi-objective programming model. Next, various comparative feasibilities under different levels of uncertainty are carried out to examine the robustness status in more detail. In the following, due to the deterioration of climatic patterns in the coming years, some managerial insights are highlighted. According to the final outputs, the domestic sector has reached more optimal value compared to that of the agricultural and industrial participants in all objectives due to less water intake, and as a result, it has a significant impact on the robustness of water supply system.

Genome of the hoverfly Eupeodes corollae provides insights into the evolution of predation and pollination in insects.

BACKGROUND: Hoverflies (Diptera: Syrphidae) including Eupeodes corollae are important insects worldwide that provide dual ecosystem services including pest control and pollination. The larvae are dominant predators of aphids and can be used as biological control agents, and the adults are efficient pollinators. The different feeding habits of larvae and adults make hoverflies a valuable genetic resource for understanding the mechanisms underlying the evolution and adaptation to predation and pollination in insects. RESULTS: Here, we present a 595-Mb high-quality reference genome of the hoverfly E. corollae, which is typical of an aphid predator and a pollinator. Comparative genomic analyses of E. corollae and Coccinellidae (ladybugs, aphid predators) shed light on takeout genes (3), which are involved in circadian rhythms and feeding behavior and might regulate the feeding behavior of E. corollae in a circadian manner. Genes for sugar symporter (12) and lipid transport (7) related to energy production in E. corollae had homologs in pollinator honeybees and were absent in predatory ladybugs. A number of classical cytochrome P450 detoxification genes, mainly CYP6 subfamily members, were greatly expanded in E. corollae. Notably, comparative genomic analyses of E. corollae and other aphidophagous hoverflies highlighted three homologous trypsins (Ecor12299, Ecor12301, Ecor2966). Transcriptome analysis showed that nine trypsins, including Ecor12299, Ecor12301, and Ecor2966, are strongly expressed at the larval stage, and 10 opsin genes, which are involved in visual perception, are significantly upregulated at the adult stage of E. corollae. CONCLUSIONS: The high-quality genome assembly provided new insights into the genetic basis of predation and pollination by E. corollae and is a valuable resource for advancing studies on genetic adaptations and evolution of hoverflies and other natural enemies.

Highly Stereoselective Diels-Alder Reactions Catalyzed by Diboronate Complexes.

A highly enantioselective catalytic system for exo-Diels-Alder reactions was developed based on the newly discovered bispyrrolidine diboronates (BPDB). Activated by various Lewis or Brønsted acids, BPDB can catalyze highly stereoselective asymmetric exo-Diels-Alder reactions of monocarbonyl-based dienophiles. When 1,2-dicarbonyl-based dienophiles are used, the catalyst can sterically distinguish between the two binding sites, which leads to highly regioselective asymmetric Diels-Alder reactions. BPDB can be prepared as crystalline solids on a large scale and are stable under ambient condition. Single-crystal X-ray analysis of the structure for acid-activated BPDB indicated that its activation involves cleavage of a labile B←N bond.

Acute pulmonary embolism and severe post thrombolysis renal bleeding, two deadly complications following mini-percutaneous nephrolithotomy: a rare case report.

BACKGROUND: Acute pulmonary embolism and severe renal bleeding are two lethal postoperative complications, but there has been no report that involves both of them after mini-percutaneous nephrolithotomy. CASE PRESENTATION: A 62-year-old woman was admitted to our hospital with extremely severe hydronephrosis and multiple right renal calculi. After thorough examination, she received prone-position mini-percutaneous nephrolithotomy under spinal anaesthesia. Three days postoperatively, the patient complained of chest pain and dyspnea. Computed tomography pulmonary angiogram (CTPA) showed multiple embolisms in the left pulmonary artery and its branches. Symptoms were relieved after anticoagulant and thrombolysis therapy. On the 6th postoperative day, the patient developed shortness of breath, computed tomography angiography (CTA) showed massive hemorrhage in the right kidney, diffused contrast medium in the middle and lower part of the right kidney was seen during digital substraction angiography (DSA). Superselective right renal artery embolization (SRAE) was then applied using coil to occlude the responsible artery. The patient generally recovered under conscientious care and was approved to be discharged 26 days postoperatively. CONCLUSIONS: This is the first case that involved both acute pulmonary embolism and severe post thrombolysis renal bleeding. The importance of D-dimer in the prediction and early detection of pulmonary embolism should be noted. For post thrombolysis renal bleeding, SRAE is considered as a reliable treatment.

Asymmetric Total Synthesis of (-)-Spirochensilide A, Part 2: The Final Phase and Completion.

The final phase of the total synthesis of (-)-spirochensilide A is described. A tungsten-mediated cyclopropene-based Pauson-Khand reaction was developed to form the spiral CD ring system with desired stereochemistry at the C13 quaternary center. Other important steps enabling completion of this synthesis included an intermolecular aldol condensation to link the ABCD core with the EF fragment and a Cu-mediated 1,4-addition to stereoselectively install the C21 stereogenic center. The chemistry developed for this total synthesis of (-)-spirochensilide A (1) will aid the synthesis of polycyclic natural products bearing this unique spiral ring system.

Asymmetric Total Synthesis of (-)-Spirochensilide A, Part 1: Diastereoselective Synthesis of the ABCD Ring and Stereoselective Total Synthesis of 13(R)-Demethyl Spirochensilide A.

A concise and diastereoselective construction of the ABCD ring system of spirochensilide A is described. The key steps of this synthesis are a semipinacol rearrangement reaction to stereoselectively construct the AB ring system bearing two vicinal quaternary chiral centers and a Co-mediated Pauson-Khand reaction to form the spiro-based bicyclic CD ring system. This chemistry leads to the stereoselective synthesis of 13(R)-demethyl spirochensilide A, paving the way for the first asymmetric total synthesis of (-)-spirochensilide A.

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma.

Plexiform neurofibroma (pNF) in the head and neck is a characteristic feature in patients with neurofibromatosis type 1 (NF1) and is associated with significant disfigurement and psychological distress. Yes-associated protein (YAP), the key molecule involved in the Hippo pathway, is a vital transductor that regulates the proliferation and remyelinating of Schwann cells. The functional status of YAP and its feasibility as a potential target are still unknown in pNF. A total of 17 pNF tumor tissue specimens from the head and neck were collected at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Histologically, diagnosis of the Schwann cell region in pNF was achieved with hematoxylin-eosin staining, positive reactions for S100, SOX10, ERK and p-ERK, and low identification of Ki67 and SMA. Compared with normal nerve tissue, obviously increased nuclear YAP was detected in the Schwann cell region of pNF, with a mean nuclear staining rate of 67.11%. Based on the shNF1 Schwann cell model (the RSC96 cell line), with upregulated expression of RAS, ERK and p-ERK, p-YAP (Ser127) and p-YAP (Ser397) were significantly decreased and total YAP and nuclear YAP were increased. According to a confocal assay, the interference of shNF1 substantially promoted YAP nuclear translocation. Compared with control Schwann cells, the YAP inhibitor CA3 might have a more sensitive effect (IC50: NC=0.96±0.04, shNF1=0.71±0.02, P<0.05) on the shNF1 Schwann cell model than the classic MEK1/2 inhibitor selumetinib (IC50: NC=14.36±0.95, shNF1=24.83±0.98, P>0.05). For in vivo inhibition, the CA3 group and the selumetinib group displayed a similar inhibition effect with no significant difference. Increased nuclear translation and the functional state of YAP implies that the YAP-Hippo pathway might play an important role in the formation and remyelination of pNF. Compared with selumetinib, the YAP inhibitor can exhibit a similar but more sensitive effect on NF1-/- Schwann cells. These observations imply that YAP as a novel or adjuvant therapy target in the treatment of pNF.

Dynamic multi-objective programming model for improving consumer satisfaction within water supply system under uncertain environment.

Water scarcity poses a real crisis for decision makers of water supply system because satisfying growing demand and, as a result, achieving full consumer satisfaction in different sectors of the system remains a major problem. Therefore, this study develops a dynamic multi-objective model of water supply optimization under different scenarios to improve multisectoral consumer satisfaction. To diminish the negative effects of the water crisis on long-term consumer satisfaction, the performance of the dynamic water supply system is evaluated and optimized, which can change the situation from a state of dissatisfaction to satisfaction. In this regard, to analyze the developed model, a real case study of the Hamoun wetland in southeastern Iran is considered. According to the proposed model, various strategies are performed along with the analysis of two scenarios related to runoff uncertainty in order to investigate the consumer satisfaction status in detail. However, given to the final results, which show the greater impact of the two sensitive factors of reliability and vulnerability on consumer satisfaction, the highest level of dissatisfaction is related to the agricultural sector because it has less reliability and higher vulnerability compared to other sectors. In this regard, by proposing policies such as weight scenarios and demand reduction scheme, the situation of consumer satisfaction has improved much more desirable.

Stereoselective Synthesis of Cyclohepta[b]indoles by Visible-Light-Induced [2+2]-Cycloaddition/retro-Mannich-type Reactions.

A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible-light-induced, photocatalyzed [2+2]-cycloaddition/ retro-Mannich-type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single-electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical-cation state to form cyclohepta[b]indoles.

Resolution enhancement for flexible microscopic imaging based on dictionary learning.

The idea of combining a flexible fiber bundle with the microscopic imaging system provides the possibility of the cross-scale detection of defects and textures on large-scale complex components. However, the pixelization artifacts caused by the inter-core spacing of the fibers degrade the image quality and make it difficult to identify the micro-features. A high-resolution reconstruction strategy is proposed based on dictionary learning. By training the high- and low-resolution image pairs after image registration, a coupled dictionary is obtained. Then high-quality images are obtained from the trained dictionary. Experimental results demonstrate that the pixelization artifacts can be effectively addressed, and the resolution of the reconstructed images can be promoted by 1.8 times.

Borate bioactive glass prevents zoledronate-induced osteonecrosis of the jaw by restoring osteogenesis and angiogenesis.

OBJECTIVES: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of systemic nitrogen-containing bisphosphonate (N-BP) administration, which leads to osteonecrosis, pain, and infection. Despite much effort, effective remedies are yet to be established. This study aimed to investigate potential recovery effect of borate bioactive glass (BBG) in vitro and in vivo. METHODS: The effect of BBG on zoledronate-treated bone marrow mesenchymal cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) was explored by cell counting kit-8, EdU assay, flow cytometry, alkaline phosphatase staining, alizarin red staining, angiogenesis experiment, and real-time quantitative polymerase chain reaction. The preventive effect of BBG on zoledronate-induced osteonecrosis of the jaw in rat model was examined by micro-CT, HE staining, and immunohistochemistry. RESULTS: Exposure of BBG to BMSCs and HUVECs increased cell proliferation and restored their osteogenesis and angiogenesis potential in vitro. The BRONJ lesions were satisfactorily repaired and bone mineral density, bone volume/tissue volume, trabecula number, OCN-positive cells, and CD31-positive cells were increased in the BBG-treated groups compared with saline-treated groups. CONCLUSIONS: Exposure of BMSCs and HUVECs to BBG restores osteogenesis and angiogenesis inhibited by zoledronate. BBG successfully restores extraction socket healing of BRONJ in rat model.

Infection of cotton bollworm by Helicoverpa armigera iflavirus decreases larval fitness.

Previously, we reported a novel iflavirus in Helicoverpa armigera (helicoverpa armigera iflavirus, HaIV) and here we report the effects of HaIV on its host. In a laboratory bioassay, HaIV-positive larvae and pupae developed more slowly and had higher mortality than HaIV-negative larvae, suggesting that the virus is pathogenic. The relative fitness of H. armigera decreased with HaIV infection by a ratio of 0.65. Transcriptional analysis indicated that infection significantly changed the expression levels of host genes, with more genes affected at 72 h after inoculation than at 48 h (138 up- and 229 downregulated at 48 h; 185 up- and 299 downregulated at 72 h). Interestingly, pathways related to digestion and absorption were significantly enriched, e.g., protein digestion and absorption, suggesting developmental regulation of the host by HaIV via these pathways. HaIV-infected H. armigera showed significantly downregulated expression of genes encoding cuticular proteins (CPs), essential for structural and protective functions, at 48 h and 72 h, suggesting that HaIV increased larval mortality by downregulating CP gene expression.

Development and validation of a nomogram to predict perioperative blood transfusion in patients undergoing total knee arthroplasty.

BACKGROUND: The need for a transfusion is one of the adverse events following total knee arthroplasty (TKA), and accurately predicting this need remains challenging for arthroplasty surgeons. The purpose of the present research is to study the preoperative predictors of transfusion risk in patients following TKA and develop a nomogram. METHODS: The nomogram was developed based on a training set of 5402 patients who underwent TKA at the Affiliated Hospital of Qingdao University between September 2013 and November 2018. The independent predictors of transfusion were identified by univariate, LASSO, and binary logistic regression analyses. Then, a nomogram was established based on these independent predictors. The area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were selected to evaluate the nomogram. The results were validated using an independent set of 1116 patients who underwent TKA between December 2018 and September 2019. In addition, we also carried out subgroup analyses in the training and testing sets based on the independent predictors. RESULTS: Five independent predictors were identified by multivariate analysis and were used to establish the nomogram. The AUCs of the nomogram were 0.884 (95% CI: 0.865-0.903) and 0.839 (95% CI, 0.773-0.905) in the training and testing sets, respectively. In both the training and testing sets, the calibration curve indicated that the prediction by the nomogram was highly consistent with the actual observation, and the DCA indicated that the nomogram had a favorable level of clinical usefulness. In addition, the AUC of the nomogram was significantly higher than the AUC of any independent predictor for predicting transfusion risk following TKA, and the subgroup analysis showed good performance in 20 subgroups. CONCLUSION: Lower preoperative Hb levels, simultaneous bilateral TKA, lower BMI, older age, and coronary heart disease were identified as independent predictors of postoperative transfusion in patients following TKA. A nomogram incorporating the above five predictors could accurately predict the transfusion risk.

Biomineralization of dentin.

A single biomineralization of demineralized dentin is significant to restore the demineralized dentin due to dental caries or erosion. In recent years, meaningful progress has been made regarding the mechanisms involved in the biomineralization of dentin collagen. Concepts changing from the classical ion-based crystallization to non-classical particle-based crystallization, inspired a different strategy to infiltrate the demineralized dentin collagen. The remarkable discovery was the report of liquid-like amorphous calcium phosphate as nanoprecursor particles to carbonated hydroxyapatite. The non-collagenous proteins and their analogues are widely investigated, for their key role in controlling mineralization during the process of crystal nucleation and growth. The in-depth studies of the gap zone provided significant improvements in our understanding of the structure of collagen and of the intrafibrillar remineralization of collagen fibrils. The collagen is not a passive substrate as previously supposed, and the active role of guiding nanoprecursor infiltration and mediating its nucleation has been demonstrated. Furthermore, recovery of mechanical properties has been evaluated to determine the effectiveness of dentin remineralization. Finally, the problems regarding the origin formation of the calcium phosphate that is deposited in the collagen, and the exact interactions between the non-collagenous proteins, amorphous calcium phosphate and collagen are still unclear. We reviewed the importance of these findings in enriching our understanding of dentin biomineralization, while addressing certain limitations that are inherent to in vitro studies.

Precision enhancement of three-dimensional displacement tracing for nano-fabrication based on low coherence interferometry.

In the nano-fabrication field, high precision displacement tracing of the fabricating beam is extensively required. Due to the coherence noise and the sensitivity to environmental disturbances, the commonly used measuring methods base on the laser interferometry are unstable. In this paper, a high-precision measuring method for the three-dimensional displacements is developed based on the low coherence interferometry. The interferogram at a particular location is unique and distinctive, which can be applied as a benchmark for the absolute measurement of positions. Consequently, interferograms are continuously acquired during the movement of the nano-stage, then the quantitative relationship between the stage position/tilt and the interferograms is established by analytic calculation. Besides, the influence of random errors can be suppressed by the averaging effect of the least squares fitting, thereby enhancing the precision by more than an order of magnitude compared with traditional methods. The measuring uncertainty is derived and the impacts of the main influencing factors are investigated. Experiments demonstrate that the measuring repeatability can achieve 1.16 nm. As a result, the proposed method can reliably obtain the absolute position and three dimensional trajectory of the nano-stage, and it is of significance to improve the reliability of nano-measurement and fabrication.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.