Carboxyl-Modified Quantum Dots for NIR-IIb Bone Marrow Imaging.

Real-time, noninvasive, and nonradiative bone imaging can directly visualize bone health but requires bone-targeted probes with high specificity. Herein, we propose that carboxyl-rich fluorescent nanoprobes are easily absorbed by macrophages in bone marrow during circulation, enabling optical bone marrow imaging in vivo. We used PbS/CdS core-shell quantum dots with NIR-IIb (1500-1700 nm) emission as substrates to prepare the carboxyl-rich nanoprobe. In vivo NIR-IIb fluorescence imaging with the nanoprobes showed high resolution and penetration depth in bone tissues and allowed for imaging-guided fracture diagnosis. Bone tissue slices showed substantial accumulation of carboxyl nanoprobes in the bone marrow and strong colocalization with macrophages. Similar results with CdSe quantum dots and an organic nanofluorophore suggest that carboxyl surface modification is effective to achieve bone marrow targeting, providing a novel strategy for developing bone/bone marrow imaging probes.

NIR-II Emissive Superoxide Radical Photogenerator for Photothermal/Photodynamic Therapy against Hypoxic Tumor.

Due to the "Achilles' heels" of hypoxia, complicated location in solid tumor, small molecular photosensitizers with second near-infrared window (NIR-II) fluorescence, type-I photodynamic therapy (PDT), and photothermal therapy (PTT) have attracted great attention. However, these photosensitizers are still few but yet challenging. Herein, an "all in one" NIR-II acceptor-donor-acceptor fused-ring photosensitizer, Y6-Th, is presented for the in-depth diagnosis and efficient treatment of cancer. Benefiting from the strong intramolecular charge transfer, promoted highly efficient intersystem crossing, largely p-conjugated fused-ring structure, and reduced planarity, the fabricated nanoparticles (Y6-Th nanoparticles) can emit NIR-II fluorescence with the peak located at 1020 nm, exclusively generate O2•- for type-I PDT, and display excellent PTT performance under an 808 nm laser stimulation. These characteristics make Y6-Th a distinguished NIR-wavelength-triggered phototheranostic agent, which can effectively therapy the hypoxic tumor using NIR-II-fluorescence-guided type-I PDT/PTT. This work provides a valuable guideline for fabricating high-performing NIR-II emissive superoxide radical photogenerators.

Preoperative and Prognostic Prediction of Microvascular Invasion in Hepatocellular Carcinoma: A Review Based on Artificial Intelligence.

Microvascular invasion of hepatocellular carcinoma is an important factor affecting tumor recurrence after liver resection and liver transplantation. There are many ways to classify microvascular invasion, however, an international consensus is urgently needed. Recently, artificial intelligence has emerged as an important tool for improving the clinical management of hepatocellular carcinoma. Many studies about microvascular invasion currently focus on preoperative and prognosis prediction of microvascular invasion using artificial intelligence. In this paper, we review the definition and staging of microvascular invasion, especially the diagnosis of it by using artificial intelligence. In preoperative prediction, deep learning based on multimodal data modeling of radiomics-screened features, clinical features, and medical images is currently the most effective means. In prognostic prediction, pathology is the gold standard, and the techniques used should more effectively utilize the global features of the pathology images.

Total Syntheses of Rhodomollins A and B.

The first and asymmetric total syntheses of rhodomollins A and B, two rhodomollane type grayanoids featuring a d-homograyanane carbon skeleton and an oxa-bicyclo[3.2.1] core, were accomplished via a convergent strategy. A Stille coupling and a lithium-halogen exchange/intramolecular nucleophilic addition to the aldehyde sequence were employed to assemble two enantioenriched fragments. The oxa-bicyclo[3.2.1] core was achieved through an intramolecular SN2 substitution of cyclic sulfate of 1,2-diols (Williamson ether synthesis). The A ring oxidation states were adjusted by a Payne/Meinwald rearrangement sequence and subsequent redox transformations.

Pharmacokinetic and safety profile of PT109B, a novel multi-targeted compound against Alzheimer's disease.

PT109B, 5-(1,2-dithiolan-3-yl)-N-((1r,4r)-4-(isoquinolin-5-ylamino) cyclohexyl) pentanamide, a novel compound structurally related to Fasudil, has been reported as a promising candidate for treating Alzheimer's disease. To investigate the pharmacokinetics and acute toxicity of PT109B in rodents, we first developed and validated a UPLC-MS/MS analytical method to detect PT109B concentration in the biological matrix. The proposed method could separate and quantify the PT109B with good precision and accuracy. The pharmacokinetic results showed that the concentrations of PT109B in rat plasma increased with the dose, but not proportionally. Meanwhile, the double-peak phenomenon disappeared when decreasing the oral administration dosage. In addition, we found that PT109B could be detected in the central nervous system, and highly distributed in the liver and kidney. At the same time, the gender difference of PT109B in rats was observed, and the exposure of PT109B in female rats was significantly higher than that in male rats after oral administration. Finally, we found that oral administration of 750 mg/kg PT109B to C57 BL/6 mice caused significant liver injury in females, which was specifically manifested as hepatomegaly, increased liver coefficient, and hepatocyte ballooning. However, no significant damage was observed in other organs, which may be related to the distribution of PT109B in the liver. In summary, we first established a UPLC-MS/MS method for the analysis of PT109B in a biological matrix and described the characteristics of pharmacokinetics, and acute toxicity of PT109B in rodents, providing a sufficient pharmacokinetic basis for further study of PT109B.

Relationship between social support and 7-year trajectories of cognitive decline: results from the China Health and Retirement Longitudinal Study.

BACKGROUND: Social support is associated with cognitive function at an older age, but how distinct dimensions of social support affect trajectories of cognitive decline in older Chinese adults remains unclear. METHODS: Using longitudinal data (waves 1-4) from the China Health and Retirement Longitudinal Study, 7-year trajectories of cognitive decline by various social support markers, including family support, financial support, public support and perceived support, were estimated using latent growth curve modelling for adults aged 60 and over (N=6795). RESULTS: After adjusting for baseline sociodemographics, behaviours, body mass index and health conditions, all social support markers were associated with baseline cognitive function, except for living with spouse. Participants living with spouse experienced a slower cognitive decline (0.069 per year, 95% CI 0.006, 0.133) than those who were not. A faster cognitive decline was associated with co-residing with children (-0.053 per year, 95% CI -0.104, -0.003), receiving ≥¥5000 from children (-0.095 per year, 95% CI -0.179, -0.011), receiving financial support from others (-0.108 per year, 95% CI -0.208, -0.008) and perceived support (-0.068 per year, 95% CI -0.123, -0.013). When all markers were mutually adjusted for, the associations of living with spouse and receiving financial support from others with cognitive decline disappeared. Stratifying by rural-urban residence, medical insurance and meeting children 1-3 times per month were associated with a slower rate of cognitive decline in urban residents but not in rural residents. CONCLUSION: Overall, our findings confirm that the effects of distinct domains of social support on cognitive decline vary. More equally good social security systems should be established in urban and rural China.

Synthesis, structure-activity relationship, and biological evaluation of quinolines for development of anticancer agents.

Tetrahydro-ß-carbolines (THßCs) are a kind of natural alkaloids with multiple pharmaceutical activities. Herein, a focused compound library derived from THßCs was synthesized and their anticancer activities were studied in several cancer cell lines. Among them, three compounds showed considerable anticancer activities with low micromolar to submicromolar IC50 values. The abilities to induce apoptosis and alter mitochondrial membrane potential levels, which are comparable to those of the commercial anticancer drug adriamycin, were confirmed by one representative compound (21) on the B16/F10 cell line. Our preliminary structure-activity relationship studies indicated that alkylamines with suitable lengths are very important for potency improvement.

BODIPY-Based NO Probe for Macrophage-Targeted Immunotherapy Response Monitoring.

Precise and rapid detection of immune responses is critical for timely therapeutic regimen adjustment. Immunomodulation of tumor-associated macrophages (TAMs) from a protumorigenic phenotype (M2) to an antitumorigenic phenotype (M1) is crucial in macrophage-targeted immunotherapy. Herein, we developed a boron dipyrromethene (BODIPY)-based fluorescence probe BDP3 to detect the immune responses after immunotherapy by monitoring the nitric oxide (NO) released by M1 TAMs. With an aromatic primary monoamine structure and a p-methoxyanilin electron donor in the meso-position, BDP3 not only specifically activates stable and sensitive fluorescence by NO via a photoinduced electron transfer (PET) process but also achieves a long emission wavelength for efficient in vitro and in vivo imaging. Such NO-induced fluorescence signals of BDP3 are validated to correlate well with the phenotypes of TAMs detected in macrophage cell lines and tumor tissues. The distinct sensing effects toward two types of clinically used immunotherapeutic drugs further confirm the ability of BDP3 for specific monitoring of the M1/M2 switch in response to the macrophage-targeted immunotherapy. By virtue of good biocompatibility and appropriate tumor retention time, BDP3 could be a potential fluorescent probe for noninvasive evaluation of the immunotherapeutic efficacy of macrophage-targeted immunotherapy in living animals.

Interface contact and modulated electronic properties by in-plain strains in a graphene-MoS2 heterostructure.

Designing a specific heterojunction by assembling suitable two-dimensional (2D) semiconductors has shown significant potential in next-generation micro-nano electronic devices. In this paper, we study the structural and electronic properties of graphene-MoS2 (Gr-MoS2) heterostructures with in-plain biaxial strain using density functional theory. It is found that the interaction between graphene and monolayer MoS2 is characterized by a weak van der Waals interlayer coupling with the stable layer spacing of 3.39 Å and binding energy of 0.35 J m-2. In the presence of MoS2, the linear bands on the Dirac cone of graphene are slightly split. A tiny band gap about 1.2 meV opens in the Gr-MoS2 heterojunction due to the breaking of sublattice symmetry, and it could be effectively modulated by strain. Furthermore, an n-type Schottky contact is formed at the Gr-MoS2 interface with a Schottky barrier height of 0.33 eV, which can be effectively modulated by in-plane strain. Especially, an n-type ohmic contact is obtained when 6% tensile strain is imposed. The appearance of the non-zero band gap in graphene has opened up new possibilities for its application and the ohmic contact predicts the Gr-MoS2 van der Waals heterojunction nanocomposite as a competitive candidate in next-generation optoelectronics and Schottky devices.

Facile preparation of Au- and BODIPY-grafted lipid nanoparticles for synergized photothermal therapy.

Gold nanoparticles with large size exhibit preferable properties for photothermal therapy (PTT). However, the prolonged tissue retention and slow elimination of gold nanoparticles limit their therapeutic applications. Previously, gold nanoclusters carrying lipid nanoparticles (Au-LNPs) have been reported after simply mixing Au3+ with preformed diethylenetriaminepentaacetic acid lipid nanoparticles to solve this contradiction. Au-LNPs demonstrated enhanced photothermal effects in comparison to neat gold nanoparticles. To further improve the photothermal activity, we introduced the organic photothermal agent boron dipyrromethene (BODIPY) to Au-LNPs for synergistic PTT. Au- and BODIPY-grafted LNPs (AB-LNPs) were formed by simply mixing Au-LNPs with BODIPY. The BODIPY could be associated stably to Au-LNPs, and the release of BODIPY from AB-LNPs could be accelerated by laser irradiation. AB-LNPs are scalable and showed excellent photothermal effects. AB-LNPs showed enhanced cellular uptake efficiency compared to free BODIPY in 4T1 breast cancer cells. Under laser irradiation, AB-LNPs exhibited synergistic photothermal effects with significantly reduced dosage compared to monotherapy (treatments with Au-LNPs or free BODIPY alone). This study thus provides a facile and adaptive strategy for the development of a scalable and safe high-performance nanoplatform for synergistic PTT in the treatment of cancer and other diseases.

Low-molecular-weight heparin in addition to low-dose aspirin for preventing preeclampsia and its complications: A systematic review and meta-analysis.

Background: In this systematic review, we aimed to investigate the efficacy and safety of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin (LDA) started ≤16 weeks'gestation in the prevention of preeclampsia (PE) in high-risk women. Methods: PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases were searched from their inception to April 2022 for randomized controlled trials (RCTs) that to determine whether the combined treatment of LMWH and LDA is better than single anticoagulant drugs in preventing PE and improving live birth rate of fetus in high-risk women with pregnancy ≤16 weeks. We also searched Embase, OVID MEDLINE and OVID MEDLINE in-process using the OVID platform. Results: 14 RCTs involving 1,966 women were found. The LMWH (or unfractionated heparin) and LDA groups included 1,165 wemen, and the LDA group included 960 women. The meta-analysis showed that the addition of LMWH to LDA reduced the risk of PE (RR: 0.59, 95% CI: 0.44-0.79, P < 0.05), small-for-gestational age (SGA, RR: 0.71, 95% CI: 0.52-0.97, P = 0.03), fetal and neonatal death (RR: 0.45, 95% CI: 0.23-0.88, P = 0.02) and gestational hypertension (RR: 0.47, 95% CI: 0.25-0.90, P = 0.02). It is worth emphasizing that LMWH (or unfractionated heparin) combined with LDA did not increase the risk of bleeding. Conclusions: LMWH combined with LDA can effectively improve the pregnancy outcome of women with high risk factors for PE and its complications. Although this study showed that combined medication also did not increase the risk of bleeding, but such results lack the support of large sample size studies. The clinical safety analysis of LMWH combined with LDA in patients with PE should be more carried out.

Advances in the study of HSP70 inhibitors to enhance the sensitivity of tumor cells to radiotherapy.

The 70 kDa heat shock protein (HSP70) is one of the most conserved proteins and a ubiquitous molecular chaperone that plays a role in the folding, remodeling, and degradation of various proteins to maintain proteostasis. It has been shown that HSP70 is abundantly expressed in cancer and enhances tumor resistance to radiotherapy by inhibiting multiple apoptotic pathways, such as interfering with the cellular senescence program, promoting angiogenesis, and supporting metastasis. Thus, HSP70 provides an effective target for enhancing the effects of radiation therapy in the clinical management of cancer patients. Inhibition of HSP70 enhances the radiation-induced tumor-killing effect and thus improves the efficacy of radiotherapy. This article reviews the sensitivity of Hsp70 and its related inhibitors to radiotherapy of tumor cells.

Total Synthesis of Mollanol A.

Mollanol A is the first isolated member of the mollane-type grayanoids which possesses an unprecedented C-nor-D-homograyanane carbon skeleton and an 5,8-epoxide. Due to its transcriptional activation effects on the Xbp1 upstream promoters in different cell types, it has a potential therapeutic effect on inflammatory bowel disease. Here we report the first total synthesis of mollanol A, which constitutes a 15-step synthesis from commercially available materials via a convergent strategy. The synthesis involves an InCl3-catalyzed Conia-ene cyclization reaction to construct the bicyclo[3.2.1]octane moiety and a vinylogous aldol reaction/intramolecular oxa-Michael addition sequence to rapidly assemble the oxa-bicyclo[3.2.1] core.

Chemical Modification of Chitosan for Developing Cancer Nanotheranostics.

Cancer is a worldwide public health issue that has not been conquered. Theranostics, the combination of a therapeutic drug and imaging agent in one formulation using nanomaterials, has been developed to better cure cancer in recent years. Although diverse biomaterials have been applied in cancer theranostics, chitosan (CS), a natural polysaccharide bearing easy modification sites with excellent biocompatibility and biodegradability, shows great potential for developing cancer nanotheranostics. In this review, we seek to describe the chemical functionalities of CS used in cancer theranostics and their synthesis methods. We also present recent discoveries and research progresses on how the CS functionalization could improve the delivery efficiency of CS-based nanotheranostics. Finally, we report several case studies about the application of CS-based nanotheranostics. This paper focuses on the strategies to construct CS-based theranostics systems via chemical routes and highlights their applications in cancer treatment, which can provide useful references for further studies.

Programmable System of Cas13-Mediated RNA Modification and Its Biological and Biomedical Applications.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas13 has drawn broad interest to control gene expression and cell fate at the RNA level in general. Apart from RNA interference mediated by its endonuclease activity, the nuclease-deactivated form of Cas13 further provides a versatile RNA-guided RNA-targeting platform for manipulating kinds of RNA modifications post-transcriptionally. Chemical modifications modulate various aspects of RNA fate, including translation efficiency, alternative splicing, RNA-protein affinity, RNA-RNA interaction, RNA stability and RNA translocation, which ultimately orchestrate cellular biologic activities. This review summarizes the history of the CRISPR-Cas13 system, fundamental components of RNA modifications and the related physiological and pathological functions. We focus on the development of epi-transcriptional editing toolkits based on catalytically inactive Cas13, including RNA Editing for Programmable A to I Replacement (REPAIR) and xABE (adenosine base editor) for adenosine deamination, RNA Editing for Specific C-to-U Exchange (RESCUE) and xCBE (cytidine base editor) for cytidine deamination and dm6ACRISPR, as well as the targeted RNA methylation (TRM) and photoactivatable RNA m6A editing system using CRISPR-dCas13 (PAMEC) for m6A editing. We further highlight the emerging applications of these useful toolkits in cell biology, disease and imaging. Finally, we discuss the potential limitations, such as off-target editing, low editing efficiency and limitation for AAV delivery, and provide possible optimization strategies.

Proline-glucose Amadori compounds: Aqueous preparation, characterization and saltiness enhancement.

Amadori rearrangement product (ARP) derived from proline and glucose was prepared in aqueous medium, and purified by ion exchange chromatography and identified by mass spectrometry and nuclear magnetic resonance spectrometry. The ARP was confirmed as 1-deoxy-1-L-proline-D-fructose (C11H19O7N, 277 Da) with four main isomers. A preliminary vacuum dehydration coupled with subsequent spray drying was used to improve the yield of ARP conversion from 3.63% to 69.15%. Furthermore, the taste characteristics of spray dried ARP products were analyzed by electronic tongue and sensory evaluation. The results indicated that when the dosage of ARP products was above 0.4%, a 20% salt reduction could be achieved without reduction in the salty taste as well as having a significant enhancement in the umami attribute. The products at low- and medium- extents of reaction could stimulate more secretion of aldosterone in oral cavity and then improve its sensitivity to the salt, while the product at high- extent of reaction inhibits aldosterone secretion.

Analysis of the dissipation kinetics of thiophanate-methyl and its metabolite carbendazim in apple leaves using a modified QuEChERS-UPLC-MS/MS method.

As one of the main fungicides for the apple leaf disease control, thiophanate-methyl (TM) mainly exerts its fungicidal activity in the form of its metabolite carbendazim (MBC), whose dissipation kinetics is very distinct from that of its parent but has been paid little attention. The aim of this work was to investigate the dissipation kinetics of TM and its active metabolite MBC in apple leaves using a modified QuEChERS-UPLC-MS/MS method. The results showed that TM and MBC could be quickly extracted by this modified QuEChERS procedure with recoveries of 81.7-96.5%. The method linearity was in the range of 0.01-50.0 mg kg-1 with the quantification limit of 0.01 mg kg-1 . Then this method was applied to the analysis of fungicide dissipation kinetics in apple leaves. The results showed that the dissipation kinetics of TM for the test in 3 months can be described by a first-order kinetics model with a DT50 (dissipation half-life) range of 5.23-6.03 days and the kinetics for MBC can be described by a first-order absorption-dissipation model with the Tmax (time needed to reach peak concentration) range of 4.78-7.09 days. These models can scientifically describe the behavior of TM and MBC in apple leaves, which provides necessary data for scientific application.

Using Machine Learning To Predict Suitable Conditions for Organic Reactions.

Reaction condition recommendation is an essential element for the realization of computer-assisted synthetic planning. Accurate suggestions of reaction conditions are required for experimental validation and can have a significant effect on the success or failure of an attempted transformation. However, de novo condition recommendation remains a challenging and under-explored problem and relies heavily on chemists' knowledge and experience. In this work, we develop a neural-network model to predict the chemical context (catalyst(s), solvent(s), reagent(s)), as well as the temperature most suitable for any particular organic reaction. Trained on ∼10 million examples from Reaxys, the model is able to propose conditions where a close match to the recorded catalyst, solvent, and reagent is found within the top-10 predictions 69.6% of the time, with top-10 accuracies for individual species reaching 80-90%. Temperature is accurately predicted within ±20 °C from the recorded temperature in 60-70% of test cases, with higher accuracy for cases with correct chemical context predictions. The utility of the model is illustrated through several examples spanning a range of common reaction classes. We also demonstrate that the model implicitly learns a continuous numerical embedding of solvent and reagent species that captures their functional similarity.

ERP evidence for consumer evaluation of copycat brands.

Copycat brands mimic brand leaders to free ride on the latter's equity. However, little is known regarding if and how consumers confuse copycat as leading brand in purchasing. In this study, we applied a word-pair evaluation paradigm in which the first word was a brand name (copycat vs. normal brand both similar with a leading brand in category), followed by a product name (near vs. far from the leading brand's category). Behavioral results showed that, when the product is near the leader's category, the copycat strategy (CN) was more preferred compared to the normal brand (NN) but not different in the far product condition (CF and NF). Event-related potential (ERP) data provided further insight into the mechanism. The N400 amplitude elicited by the CN condition was significantly smaller than NN. However, when products are far from the leader's category, there was no significant difference in N400 amplitudes. For the late positive component (LPC), the CN gave rise to a larger amplitude than the CF. The N400 amplitude was suggested to reflect the categorization process, and the LPC demonstrated the recollection process in long-term memory. These findings imply that the copycat brand strategy is generally only effective when products are within the category of the leading brand, which offers important implications for marketing practices.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.