Aminoselenation and Dehydroaromatization of Cyclohexanones with Anilines and Diselenides.

A three-component cascade reaction involving cyclohexanones, anilines, and diaryl diselenides under metal-free conditions is reported. The ortho-selenation of cyclohexanones with diaryl diselenides, followed by sequential dehydroaromatization with anilines, enables the preparation of a variety of o-selanyl anilines in moderate to excellent yields. This innovative transformation is notable for its excellent tolerance of functional groups and is suitable for the late-stage modification of complex pharmaceuticals.

Two-Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I poison.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

Pure-high-even-order dispersion bound solitons complexes in ultra-fast fiber lasers.

Temporal solitons have been the focus of much research due to their fascinating physical properties. These solitons can form bound states, which are fundamentally crucial modes in fiber laser and present striking analogies with their matter molecules counterparts, which means they have potential applications in large-capacity transmission and all-optical information storage. Although traditionally, second-order dispersion has been the dominant dispersion for conventional solitons, recent experimental and theoretical research has shown that pure-high-even-order dispersion (PHEOD) solitons with energy-width scaling can arise from the interaction of arbitrary negative-even-order dispersion and Kerr nonlinearity. Despite these advancements, research on the bound states of PHEOD solitons is currently non-existent. In this study, we obtained PHEOD bound solitons in a fiber laser using an intra-cavity spectral pulse shaper for high-order dispersion management. Specifically, we experimentally demonstrate the existence of PHEOD solitons and PHEOD bound solitons with pure-quartic, -sextic, -octic, and -decic dispersion. Numerical simulations corroborate these experimental observations. Furthermore, vibrating phase PHEOD bound soliton pairs, sliding phase PHEOD bound soliton pairs, and hybrid phase PHEOD bound tri-soliton are discovered and characterized. These results broaden the fundamental understanding of solitons and show the universality of multi-soliton patterns.

Elemental partitioning-mediated crystalline-to-amorphous phase transformation under quasi-static deformation.

The transformation induced plasticity phenomenon occurs when one phase transforms to another one during plastic deformation, which is usually diffusionless. Here we present elemental partitioning-mediated crystalline-to-amorphous phase transformation during quasi-static plastic deformation, in an alloy in form of a Cr-Ni-Co (crystalline)/Zr-Ti-Nb-Hf-Ni-Co (amorphous) nanolaminated composite, where the constitute elements of the two phases have large negative mixing enthalpy. Upon plastic deformation, atomic intermixing occurs between adjacent amorphous and crystalline phases due to extensive rearrangement of atoms at the interfaces. The large negative mixing enthalpy among the constituent elements promotes amorphous phase transformation of the original crystalline phase, which shows different composition and short-range-order structure compared with the other amorphous phase. The reduced size of the crystalline phase shortens mean-free-path of dislocations, facilitating strain hardening. The enthalpy-guided alloy design based on crystalline-to-amorphous phase transformation opens up an avenue for the development of crystal-glass composite alloys with ultrahigh strength and large plasticity.

Substantial removal of four pesticide residues in three fruits with ozone microbubbles.

Developing a straightforward method to remove pesticide residues from fruits is essential for food safety. In this study, ozone microbubble treatment was performed on three fruits (strawberry, cherry, and apricot) to remove four pesticide residues (emamectin benzoate, azoxystrobin, boscalid, and difenoconazole) while comparing removal efficiency. The concentration of hydroxyl radicals in different washing orientations was homogeneous at a concentration ranging between 8.9 and 10.2 µmol·L-1. Under long washing time (18 min), strawberry, cherry, and apricot obtained higher removal rates of 51 %∼65 %, 51 %∼59 % and 24 %∼70 %, respectively. Moreover, scanning electron microscopy (SEM) and contact angle (CA) revealed that apricot has better hydrophobicity, leading to a higher pesticide removal of 45 âˆ¼ 84 % with less water and more vigorous washing. Notably, vitamin C content in fruits remain largely unchanged following ozone microbubble treatment. This study demonstrated the effectiveness of ozone microbubble treatment as pollution-free method for enhancing food safety by removing pesticide residues on fruits.

Orthokeratology combined with spectacles in moderate to high myopia adolescents.

PURPOSE: Wearing ortho-k lenses overnight may not fully correct their daytime refractory errors of adolescents with moderate to high myopia. There are three common ways to deal with the daytime residual refractive error (RRE): 1) wearing spectacles to correct the RRE; 2) wear ortho-k lenses during the daytime instead of overnight.; 3) not correcting the residual refractive error. According to previous laboratory studies, myopic peripheral refraction is associated with better myopic control. This study had two aims:1) to compare relative peripheral refractive error (RPRE) among these ways after one-month stabilization; 2) to assess the axial length changes over 2 years of ortho-k lens overnight wear combined with spectacle glasses. METHODS: This was a prospective, non-controlled, non-randomized, observational study in which a total of 27 subjects (20 females, 7 males, mean age 12.48 ± 2.23Y) with spherical equivalent refractive error from -5.00 to -8.25D were enrolled. All participants in the study wore orthokeratology (ortho-k) lenses overnight for a minimum of one month. Subsequently, their peripheral refractive error (PRE) was assessed using an open-field autorefractor. During the assessment, the participants underwent three conditions in a random order in a same morning: 1) unaided eye after orthokeratology (referred to as the Unaided-eye condition), 2) wearing glasses to correct any remaining refractive errors after orthokeratology (referred to as the Spec-RE condition), and 3) wearing ortho-k lenses during the daytime (referred to as the Continuous OK wear condition). After testing, all subjects were instructed to wear ortho-k lenses overnight and glasses during the daytime to correct their RRE for the next 2 years, during which time the progression of their axial length was followed up. RESULTS: 1) RPRE in either Unaided-eye or Spec-RE condition subjects were significantly more myopic than those in the Continuous OK wear condition. 2) No difference in RPRE was seen between Unaided-eye and Spec-RE conditions. 3) Axial length growth was 0.05 ± 0.20 mm and 0.17 ± 0.32 mm (mean ± standard deviation) at 1-year and 2-year follow-ups after the initial visit, respectively, which were comparable to mild myopia patients after orthokeratology. 4) After orthokeratology, axial length change had negative correlation with the initial age (p = 0.001, r = -0.616) and residual diopter (p = 0.022). CONCLUSIONS: For myopes above refraction < -5.00D, wearing Ortho-k lenses overnight and glasses to correct the RRE in the daytime is recommended to ensure good visual quality and have more myopic RPRE for potential myopia control.

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization.

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models. Methods: We developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356 - 385) against NMDARs in 3-week-old female C57BL/6J mice. Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed. Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

Divergent Trideuteromethylthiolation and Aminotrideuteromethylthiolation of Alkenes with N-Fluorobenzenesulfonimide and CD3SSO3Na.

A metal-free oxidative trideuteromethylthiolation of alkenes with CD3SSO3Na using NFSI as an oxidant has been developed. The aminotrideuteromethylthiolation of a three-component reaction could be easily achieved in the presence of a cobalt catalyst. The divergent trideuteromethylthiolation of alkenes, readily available trideuteromethylthiolation reagent, and versatile synthetic strategy allow for late-stage modification of drug molecules.

Novel in-house knowledge-based automated planning system for lung cancer treated with intensity-modulated radiotherapy.

PURPOSE: The goal of this study was to propose a knowledge-based planning system which could automatically design plans for lung cancer patients treated with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: From May 2018 to June 2020, 612 IMRT treatment plans of lung cancer patients were retrospectively selected to construct a planning database. Knowledge-based planning (KBP) architecture named αDiar was proposed in this study. It consisted of two parts separated by a firewall. One was the in-hospital workstation, and the other was the search engine in the cloud. Based on our previous study, A­Net in the in-hospital workstation was used to generate predicted virtual dose images. A search engine including a three-dimensional convolutional neural network (3D CNN) was constructed to derive the feature vectors of dose images. By comparing the similarity of the features between virtual dose images and the clinical dose images in the database, the most similar feature was found. The optimization parameters (OPs) of the treatment plan corresponding to the most similar feature were assigned to the new plan, and the design of a new treatment plan was automatically completed. After αDiar was developed, we performed two studies. The first retrospective study was conducted to validate whether this architecture was qualified for clinical practice and involved 96 patients. The second comparative study was performed to investigate whether αDiar could assist dosimetrists in improving the quality of planning for the patients. Two dosimetrists were involved and designed plans for only one trial with and without αDiar; 26 patients were involved in this study. RESULTS: The first study showed that about 54% (52/96) of the automatically generated plans would achieve the dosimetric constraints of the Radiation Therapy Oncology Group (RTOG) and about 93% (89/96) of the automatically generated plans would achieve the dosimetric constraints of the National Comprehensive Cancer Network (NCCN). The second study showed that the quality of treatment planning designed by junior dosimetrists was improved with the help of αDiar. CONCLUSIONS: Our results showed that αDiar was an effective tool to improve planning quality. Over half of the patients' plans could be designed automatically. For the remaining patients, although the automatically designed plans did not fully meet the clinical requirements, their quality was also better than that of manual plans.

A Novel Al-Cu Composite with Ultra-High Strength at 350 °C via Dual-Phase Particle Reinforced Submicron-Structure.

Thermal stability determines a material's ability to maintain its performance at desired service temperatures. This is especially important for aluminum (Al) alloys, which are widely used in the commercial sector. Herein, an ultra-strong and heat-resistant Al-Cu composite is fabricated with a structure of nano-AlN and submicron-Al2 O3 particles uniformly distributed in the matrix. At 350 °C, the (8.2AlN+1Al2 O3 )p /Al-0.9Cu composite achieves a high strength of 187 MPa along with a 4.6% ductility under tension. The high strength and good ductility benefit from strong pinning effect on dislocation motion and grain boundary sliding by uniform dispersion of nano-AlN particles, in conjunction with the precipitation of Guinier-Preston (GP) zones, enhancing strain hardening capacity during plastic deformation. This work can expand the selection of Al-Cu composites for potential applications at service temperatures as high as ≈350 °C.

Both epilepsy and anti-seizure medications affect bone metabolism in children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.

Alkyltin fluorides as alkylating reagent in aminoalkylation of maleimides.

Alkyltin fluoride is a frequently used electrophilic stannylation reagent via the cleavage of the Sn-F bond in traditional organic synthetic chemistry. Herein, we report the unprecedented copper-catalyzed aminoalkylation of maleimides using alkyltin fluoride as alkylating reagent through cleavage of the C-Sn bond via a radical pathway. Excellent functional group tolerance, use of O2 as green oxidant and late-stage modification of some drug intermediates are the standout features of the current toolbox. Mechanistic studies reveal that alkyltin fluorides are capable of producing alkyl radicals in a Cu/O2 catalytic system.

Artificial intelligence - based ultrasound elastography for disease evaluation - a narrative review.

Ultrasound elastography (USE) provides complementary information of tissue stiffness and elasticity to conventional ultrasound imaging. It is noninvasive and free of radiation, and has become a valuable tool to improve diagnostic performance with conventional ultrasound imaging. However, the diagnostic accuracy will be reduced due to high operator-dependence and intra- and inter-observer variability in visual observations of radiologists. Artificial intelligence (AI) has great potential to perform automatic medical image analysis tasks to provide a more objective, accurate and intelligent diagnosis. More recently, the enhanced diagnostic performance of AI applied to USE have been demonstrated for various disease evaluations. This review provides an overview of the basic concepts of USE and AI techniques for clinical radiologists and then introduces the applications of AI in USE imaging that focus on the following anatomical sites: liver, breast, thyroid and other organs for lesion detection and segmentation, machine learning (ML) - assisted classification and prognosis prediction. In addition, the existing challenges and future trends of AI in USE are also discussed.

Substantially enhanced homogeneous plastic flow in hierarchically nanodomained amorphous alloys.

To alleviate the mechanical instability of major shear bands in metallic glasses at room temperature, topologically heterogeneous structures were introduced to encourage the multiplication of mild shear bands. Different from the former attention on topological structures, here we present a compositional design approach to build nanoscale chemical heterogeneity to enhance homogeneous plastic flow upon both compression and tension. The idea is realized in a Ti-Zr-Nb-Si-XX/Mg-Zn-Ca-YY hierarchically nanodomained amorphous alloy, where XX and YY denote other elements. The alloy shows ~2% elastic strain and undergoes highly homogeneous plastic flow of ~40% strain (with strain hardening) in compression, surpassing those of mono- and hetero-structured metallic glasses. Furthermore, dynamic atomic intermixing occurs between the nanodomains during plastic flow, preventing possible interface failure. Our design of chemically distinct nanodomains and the dynamic atomic intermixing at the interface opens up an avenue for the development of amorphous materials with ultrahigh strength and large plasticity.

Palladium-Catalyzed N-Alkenylation of N-Aryl Phosphoramidates with Alkenes.

Versatile and concise Pd-catalyzed oxidative N-alkenylation of N-aryl phosphoramidates with alkenes is described in this study, a reaction that is of great significance but surprisingly unexploited. The transformation proceeds under mild reaction conditions, using O2 as a green oxidant and TBAB as an effective additive. An efficient catalytic system allows a variety of drug-related substrates to participate in these transformations, which is of great interest in the drug discovery and development of phosphoramidates.

Ondansetron: recommended antiemetics for patients with acute pancreatitis? a population-based study.

Objective: Ondansetron administration is a common antemetic of acute pancreatitis therapy in the intensive care unit (ICU), but its actual association with patients' outcomes has not been confirmed. The study is aimed to determine whether the multiple outcomes of ICU patients with acute pancreatitis could benefit from ondansetron. Methods: 1,030 acute pancreatitis patients diagnosed in 2008-2019 were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database as our study cohort. The primary outcome we considered is the 90-day prognosis, and secondary outcomes included in-hospital survival and overall prognosis. Results: In MIMIC-IV, 663 acute pancreatitis patients received ondansetron administration (OND group) during their hospitalization, while 367 patients did not (non-OND group). Patients in the OND group presented better in-hospital, 90-day, and overall survival curves than the non-OND group (log-rank test: in-hospital: p < 0.001, 90-day: p = 0.002, overall: p = 0.009). After including covariates, ondansetron was associated with better survival in patients with multiple outcomes (in-hospital: HR = 0.50, 90-day: HR = 0.63, overall: HR = 0.66), and the optimal dose inflection points were 7.8 mg, 4.9 mg, and 4.6 mg, respectively. The survival benefit of ondansetron was unique and stable in the multivariate analyses after consideration of metoclopramide, diphenhydramine, and prochlorperazine, which may also be used as antiemetics. Conclusion: In ICU acute pancreatitis patients, ondansetron administration was associated with better 90-day outcomes, while results were similar in terms of in-hospital and overall outcomes, and the recommended minimum total dose might be suggested to be 4-8 mg.

Integrative analyses of ferroptosis and immune related biomarkers and the osteosarcoma associated mechanisms.

Osteosarcoma (OS) is the most common primary malignant bone tumor with high metastatic potential and relapse risk. To study the regulatory mechanism of the OS microenvironment, a complex regulatory network involving the ferroptosis- and immune response-related genes remains to be established. In the present study, we determined the effect of a comprehensive evaluation system established on the basis of ferroptosis- and immune-related genes on the immune status, related biomarkers, prognosis, and the potential regulatory networks underlying OS based on the TARGET and Gene Expression Omnibus databases that contain information on OS patients by bioinformatics analyses. We first characterized individual ferroptosis scores and immune scores through gene set variation analysis (GSVA) against TARGET-OS datasets. We then identified differentially expressed genes by score groups. Weighted gene co-expression network analysis was performed to identify the most relevant ferroptosis-related and immune-related gene modules, which facilitated the identification of 327 ferroptosis gene and 306 immune gene candidates. A 4-gene (WAS, CORT, WNT16, and GLB1L2) signature was constructed and valuation using the least absolute shrinkage and selection operator-Cox regression models to effectively predict OS prognosis. The prediction efficiency was further validated by GSE39055. We stratified patients based on the prognostic scoring systems. Eight hub genes (namely CD3D, CD8A, CD3E, IL2, CD2, MYH6, MYH7, and MYL2) were identified, and TF-miRNA target regulatory networks were constructed. Furthermore, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis, and GSVA were used to determine the signature's potential pathways and biological functions, which showed that the hub genes were enriched in ferroptosis-associated biological functions and immune-associated molecular mechanisms. Thereafter, we investigated the proportion and infiltration extent of 22 infiltrating immune cells by using CIBERSORT, which revealed significant subgroup differences in CD8 + T cells, M0 macrophages, and M2 macrophages. In conclusion, we determined a new ferroptosis-related and immune-related gene signature for predicting OS patients' prognosis and further explored the ferroptosis and immunity interactions during OS development, which provides insights into the exploration of molecular mechanisms and targeted therapies in patients with OS.

Creeping and erupting dynamics in a pure-quartic soliton fiber laser.

Pure-quartic solitons (PQSs) are gradually becoming a hotspot in recent years due to their potential advantage to achieve high energy. Meanwhile, the fundamental research of PQSs is still in the fancy stage, and exploring soliton dynamics can promote the development of PQSs. Herein, we comprehensively and numerically investigate the impact of saturation power, small-signal gain, and output coupler on PQS dynamics in passively mode-locked fiber lasers. The result indicates that altering the above parameters makes PQSs exhibit pulsating or creeping dynamics similar to traditional solitons. Moreover, introducing an intra-cavity filter combined with intra-cavity large fourth-order dispersion makes PQSs go through stationary, pulsating to erupting. That is, the intra-cavity filter changes PQS dynamics. These findings provide new insights into PQS dynamics in fiber lasers.

Live-cell imaging analysis on the anti-apoptotic function of the Bcl-xL transmembrane carboxyl terminal domain.

The Transmembrane Carboxyl Terminal Domain (TMD) of some Bcl-2 family proteins has been demonstrated to play a key role in modulating apoptosis. We here ustilzed live-cell fluorescence imaging to evaluate how the Bcl-xL TMD (XT) regulate apoptosis. Cell viability assay revealed that XT had strong anti-apoptotic ability similarly to the full-length Bcl-xL. Fluorescence images of living cells co-expressing CFP-XT and Bad-YFP or YFP-Bax revealed that XT recruited Bad to mitochondria but prevented Bax translocation to mitochondria, and also significantly suppressed Bad/Bax-mediated apoptosis, indicating that XT prevents the pro-apoptotic function of Bad and Bax. Fluorescence Resonance Energy Transfer (FRET) analyses determined that XT directly interacted with Bad and Bax, and deletion of XT completely eliminated the mitochondrial localization and homo-oligomerization of Bcl-xL. Fluorescence images of living cells co-expressing CFP-XT and YFP-Bax revealed that XT significantly prevented mitochondrial Bax oligomerization, resulting in cytosolic Bax distribution. Collectively, XT is necessary for the mitochondrial localization and anti-apoptotic capacity of Bcl-xL, and XT, similarly to the full-length Bcl-xL, forms homo-oligomers on mitochondria to directly interact with Bad and Bax to inhibit their apoptotic functions.