Theranostic Nanoplatform Based on Polydopamine-Coated Magnetic Mesoporous Silicon for Precise Cancer Triplex Nanotherapy and Multimodal Imaging.

Although targeted therapy has revolutionized oncotherapy, engineering a versatile oncotherapy nanoplatform integrating both diagnostics and therapeutics has always been an intractable challenge to overcome the limitations of monotherapy. Herein, a theranostics platform based on DI/MP-MB has successfully realized the fluorescence detection of disease marker miR-21 and the gene/photothermal/chemo triple synergetic cancer therapy, which can trace the tumor through photothermal and fluorescence dual-mode imaging and overcome the limitations of monotherapy to improve the treatment efficiency of tumors. DI/MP-MB was prepared by magnetic mesoporous silicon nanoparticles (M-MSNs) loaded with doxorubicin (Dox) and new indocyanine green (IR820), and subsequently coating polydopamine as a "gatekeeper", followed by the surface adsorbed with molecular beacons capable of targeting miR-21 for responsive imaging. Under the action of enhanced permeability retention and external magnetic field, DI/MP-MB were targeted and selectively accumulated in the tumor. MiR-21 MB hybridized with miR-21 to form a double strand, which led to the desorption of miR-21 MB from the polydopamine surface and the fluorescence recovery to realize gene silencing and fluorescence imaging for tracking the treatment process. Meanwhile, with the response to the near-infrared irradiation and the tumor's microacid environment, the outer layer polydopamine will decompose, releasing Dox and IR820 to realize chemotherapy and photothermal therapy. Finally, the ability of DI/MP-MB to efficiently suppress tumor growth was comprehensively assessed and validated both in vitro and in vivo. Noteworthily, the excellent anticancer efficiency by the synergistic effect of gene/photothermal/chemo triple therapy of DI/MP-MB makes it an ideal nanoplatform for tumor therapy and imaging.

Management of gestational diabetes mellitus via nutritional interventions: The relevance of gastric emptying.

Gestational diabetes mellitus (GDM) represents one of the most common medical complications of pregnancy and is important to the well-being of both mothers and offspring in the short and long term. Lifestyle intervention remains the mainstay for the management of GDM. The efficacy of nutritional approaches (e.g. calorie restriction and small frequent meals) to improving the maternal-neonatal outcomes of GDM was attested to by Chinese population data, discussed in two articles in recent issues of this journal. However, a specific focus on the relevance of postprandial glycaemic control was lacking. Postprandial rather than fasting hyperglycaemia often represents the predominant manifestation of disordered glucose homeostasis in Chinese women with GDM. There is now increasing appreciation that the rate of gastric emptying, which controls the delivery of nutrients for digestion and absorption in the small intestine, is a key determinant of postprandial glycaemia in both health, type 1 and 2 diabetes. It remains to be established whether gastric emptying is abnormally rapid in GDM, particularly among Chinese women, thus contributing to a predisposition to postprandial hyperglycaemia, and if so, how this influences the therapeutic response to nutritional interventions. It is essential that we understand the role of gastric emptying in the regulation of postprandial glycaemia during pregnancy and the potential for its modulation by nutritional strategies in order to improve post-prandial glycaemic control in GDM.

High-entropy superparaelectrics with locally diverse ferroic distortion for high-capacitive energy storage.

Superparaelectrics are considered promising candidate materials for achieving superior energy storage capabilities. However, due to the complicated local structural design, simultaneously achieving high recoverable energy density (Wrec) and energy storage efficiency (η) under high electric fields remains a challenge in bulk superparaelectrics. Here, we propose utilizing entropy engineering to disrupt long-range ferroic orders into local polymorphic distortion disorder with multiple BO6 tilt types and diverse heterogeneous polarization configurations. This strategy reduces the switching barriers, thereby facilitating the emergence of superparaelectric behaviors with ideal polarization forms. Furthermore, it enables high polarization response, negligible remnant polarization, delayed polarization saturation, and enhanced breakdown electric fields (Eb) in high-entropy superparaelectrics. Consequently, an extraordinary Wrec of 15.48 J cm-3 and an ultrahigh η of 90.02% are achieved at a high Eb of 710 kV cm-1, surpassing the comprehensive energy storage performance of previously reported bulk superparaelectrics. This work demonstrates that entropy engineering is a viable strategy for designing high-performance superparaelectrics.

Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics.

BACKGROUND: Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer. However, the underlying mechanisms remain elusive. AIM: To detect the differential expression profiles of plasma exosomal microRNAs (miRNAs) in poor and good responders and explore the potential mechanisms of chemoresistance. METHODS: In this study, the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses (poor/good responders) and treatment courses (pre/post-nCRT) using RNA sequencing. RESULTS: Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT. Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways, such as the MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, Toll-like receptor signaling pathway, VEGF signaling pathway, and mTOR signaling pathway. Further analysis indicated that MAPK3, RAX2, and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer, and the profiles of MAPK3, TSPYL5, and ZNF417 were correlated with tumor stage. In addition, the expression profiles of MAPK3, RNF165, and ZNF417 were negatively correlated with inhibitory concentration 50 values. Accordingly, an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed. CONCLUSION: This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs. However, further research is required within the framework of our established miRNA-mRNA network.

Toward a neurocircuit-based sequential transcranial magnetic stimulation treatment of pediatric bipolar II disorder.

BACKGROUND: Abnormalities in large-scale neuronal networks-the frontoparietal central executive network (CEN)-are consistent findings in bipolar disorder and potential therapeutic targets for transcranial magnetic stimulation (TMS). OBJECTIVE: The present study aimed to assess the effects of CEN neurocircuit-based sequential TMS on the clinical symptoms and cognitive functions of adolescents with bipolar II disorder. METHODS: The study was a single-blinded, randomized, placebo-control trial. Participants with DSM-5-defined bipolar disorder II were recruited and randomized to receive either a sham treatment (n = 20) or an active TMS treatment (n = 22). The active group patients were taking medication, with intermittent theta burst stimulation (iTBS) treatment provided as adjunctive treatment targeting the left DLPFC, the left ITG, and the left PPC nodes consecutively. Patients completed the measurements of HAMD and the Das-Naglieri Cognition Assessment System at baseline and 3 weeks after the intervention. RESULTS: A significant group-by-time interaction was observed in the HAMD, total cognition, and planning. Post-hoc analysis revealed that patients in the active group significantly improved HAMD scores following neurostimulation. Moreover, within-subject analysis indicated that the active group significantly improved in scores of total cognition and planning, while the sham group did not. No significant differences were seen in the other cognitive measures. CONCLUSION: The neurocircuit-based sequential TMS protocol targeting three CEN nodes, in conjunction with medication, safely and effectively improved depressive symptoms and cognitive function in adolescents with bipolar II disorder.

3D-printed microrobots for biomedical applications.

Microrobots, which can perform tasks in difficult-to-reach parts of the human body under their own or external power supply, are potential tools for biomedical applications, such as drug delivery, microsurgery, imaging and monitoring, tissue engineering, and sensors and actuators. Compared with traditional fabrication methods for microrobots, recent improvements in 3D printers enable them to print high-precision microrobots, breaking through the limitations of traditional micromanufacturing technologies that require high skills for operators and greatly shortening the design-to-production cycle. Here, this review first introduces typical 3D printing technologies used in microrobot manufacturing. Then, the structures of microrobots with different functions and application scenarios are discussed. Next, we summarize the materials (body materials, propulsion materials and intelligent materials) used in 3D microrobot manufacturing to complete body construction and realize biomedical applications (e.g., drug delivery, imaging and monitoring). Finally, the challenges and future prospects of 3D printed microrobots in biomedical applications are discussed in terms of materials, manufacturing and advancement.

Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction.

Acute cerebral infarction (ACI) is a lethal disease whose early diagnosis is critical for treatment. microRNA (miR)-19a targets CC chemokine ligand 20 (CCL20) in myocardial infarction. We investigated the expression patterns of serum miR-19a and CCL20 of ACI patients and assessed their clinical values. Serum samples of 50 healthy subjects and110 ACI patients were collected. Serum levels of miR-19a, CCL20 mRNA, and biochemical indexes were assessed. miR-19a downstream target gene and the binding relationship between miR-19a and CCL20 were predicted and verified. miR-19a and CCL20 mRNA were subjected to correlation and diagnostic efficiency analysis. miR-19a was poorly expressed in the serum of ACI patients, especially in patients with unstable plaque and large infarction. tumor necrosis factor-α, low-density lipoprotein, and platelet/lymphocyte ratio negatively correlated with serum miR-19a level and positively correlated with CCL20. Dual-luciferase assay revealed that miR-19a could negatively regulate CCL20 expression. CCL20 was highly expressed in the serum of ACI patients. The area under receiver-operating characteristic curve of miR-19a combined with CCL20 was 0.9741 (98.00% specificity, 90.91% sensitivity), higher than their single diagnosis. Collectively, miR-19a had high diagnostic value for ACI and could target to restrain CCL20. The combination of miR-19a and CCL20 improved diagnostic value for ACI.

Fluorinated Naphthalene Diimides as Buried Electron Transport Materials Achieve Over 23% Efficient Perovskite Solar Cells.

Naphthalene diimides (NDI) are widely serving as the skeleton to construct electron transport materials (ETMs) for optoelectronic devices. However, most of the reported NDI-based ETMs suffer from poor interfaces with the perovskite which deteriorates the carrier extraction and device stability. Here, a representative design concept for editing the peripheral groups of NDI molecules to achieve multifunctional properties is introduced. The resulting molecule 2,7-bis(2,2,3,3,4,4,4-heptafluorobutyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (NDI-C4F) incorporated with hydrophobic fluorine units contributes to the prevention of excessive molecular aggregation, the improvement of surface wettability and the formation of strong chemical coordination with perovskite precursors. All these features favor retarding the perovskite crystallization and achieving superior buried interfaces, which subsequently promote charge collection and improve the structural compatibility between perovskite and ETMs. The corresponding PSCs based on low-temperature processed NDI-C4F yield a record efficiency of 23.21%, which is the highest reported value for organic ETMs in n-i-p PSCs. More encouragingly, the unencapsulated devices with NDI-C4F demonstrate extraordinary stability by retaining over 90% of their initial PCEs after 2600 h in air. This work provides an alternative molecular strategy to engineer the buried interfaces and can trigger further development of organic ETMs toward reliable PSCs.

A Survey on Nutrition Labeling for Sodium, Potassium, and Phosphorus of Packaged Food and Beverages.

OBJECTIVES: Nutrition labeling is important to guide patients with chronic kidney disease to make informed choices. This study aimed to evaluate the extent and accessibility of nutrition labeling for sodium, potassium, and phosphorus on food and beverage products in a supermarket. METHODS: A cross-sectional survey was conducted in a Malaysian supermarket. Information on sodium, potassium, and phosphorus contents was collected from the nutrition fact panel, while information on food additives containing sodium, potassium, and phosphorus was collected from the ingredient list. RESULTS: The survey included 2,577 foods and beverages, and 79.4% of the products included sodium information in nutrition fact panels, but only 11.7% and 2.0% disclosed potassium and phosphorus content, respectively. Sodium-containing additives were found in 78.6% of products; potassium- and phosphorus-containing additives were reported in 28.5% and 46.9% of products, respectively. Sodium-containing additives were typically listed as "salt," potassium-containing additives as "alternative names," and phosphorus-containing additives as "starch" and "E numbers." Imported products were more likely to include sodium (P < .001) and phosphorus (p = .036) contents, while more locally manufactured products reported sodium- (p = .003) and phosphorus- (P = .004) containing additives. CONCLUSION: There is limited availability of potassium and phosphorus information on nutrition labels in Malaysia food and beverage products, which presents significant challenges for individuals with chronic kidney disease in choosing appropriate products for their dietary needs.

NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment.

CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.

A target-triggered strand displacement-assisted target recycling based on carbon dots-based fluorescent probe and MSNs@PDA nanoparticles for miRNA amplified detection and fluorescence imaging.

A target-triggered strand displacement-assisted target recycling based on carbon dots-based fluorescent probe and mesoporous silica nanoparticles@polydopamine (MSNs@PDA) was established to detect miRNA. The surface of MSNs rich in mesopores was coated with a layer of PDA, which can adsorb and quench the fluorescence of single-stranded Fuel DNA with fluorescent carbon dots (CDs) modified at the end through fluorescence resonance energy transfer (FRET). After adding double-stranded DNA-gold nanoparticles (dsDNA-AuNPs) and target let-7a, it will trigger two toehold-mediated strand displacement reactions (TSDR), leading to the recovery of fluorescence and the recycling of target let-7a (excitation wavelength: 380 nm; emission wavelength: 458 nm). The recovery value of fluorescence is proportional to the logarithm of the target microRNA let-7a concentration, thus realizing the sensitivity amplification detection of disease markers. The MSNs@PDA@Fuel DNA-CDs/dsDNA-AuNPs nanoplatform based on the strategy of "on-off-on" and TSDR cyclic amplification may hold great potential as an effective and safe nanoprobe for accurate fluorescence imaging of diseases related to miRNA with low abundances.

The combined toxicity of polystyrene nano/micro-plastics and triphenyl phosphate (TPHP) on HepG2 cells.

Combined toxicity is a critical concern during the risk assessment of environmental pollutants. Due to the characteristics of strong hydrophobicity and large specific surface area, microplastics (MPs) and nanoplastics (NPs) have become potential carriers of organic pollutants that may pose a health risk to humans. The co-occurrence of organic pollutants and MPs would cause adverse effects on aquatic organism, while the information about combined toxicity induced by organophosphorus flame retardants and MPs on human cells was limited. This study aimed to reveal the toxicity effects of co-exposure to triphenyl phosphate (TPHP) and polystyrene (PS) particles with micron-size/nano-size on HepG2 cell line. The adsorption behaviors of TPHP on PS particles was observed, with the PS-NP exhibiting a higher adsorption capacity. The reactive oxygen species generation, mitochondrial membrane potential depolarization, lactate dehydrogenase release and cell apoptosis proved that PS-NPs/MPs exacerbated TPHP-induced cytotoxicity. The particle size of PS would affect the toxicity to HepG2 cells that PS-NP (0.07 µm) exhibited more pronounced combined toxicity than PS-MP (1 µm) with equivalent concentrations of TPHP. This study provides fundamental insights into the co-toxicity of TPHP and PS micro/nanoplastics in HepG2 cells, which is crucial for validating the potential risk of combined toxicity in humans.

Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1ß. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1ß, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

Custom-tailored hole transport layer using oxalic acid for high-quality tin-lead perovskites and efficient all-perovskite tandems.

All-perovskite tandem solar cells (TSCs) have exhibited higher efficiencies than single-junction perovskite solar cells (PSCs) but still suffer from the unsatisfactory performance of low-bandgap (LBG) tin-lead (Sn-Pb) subcells. The inherent properties of PEDOT:PSS are crucial to high-performance Sn-Pb perovskite films and devices; however, the underlying mechanism has not been fully explored and revealed. Here, we report a facile oxalic acid treatment of PEDOT:PSS (OA-PEDOT:PSS) to precisely regulate its work function and surface morphology. OA-PEDOT:PSS shows a larger work function and an ordered reorientation and fiber-shaped film morphology with efficient hole transport pathways, leading to the formation of more ideal hole-selective contact with Sn-Pb perovskite for suppressing interfacial nonradiative recombination losses. Moreover, OA-PEDOT:PSS induces (100) preferred orientation growth of perovskite for higher-quality Sn-Pb films. Last, the OA-PEDOT:PSS-tailored LBG PSC yields an impressive efficiency of up to 22.56% (certified 21.88%), enabling 27.81% efficient all-perovskite TSC with enhanced operational stability.

Ligand-free Pd-catalyzed highly selective arylation of activated and unactivated alkenes via oxidative and reductive heck coupling.

In this work, an eco-friendly, green, efficient approach for oxidative and reductive Heck-Mizoroki (HM) reactions was developed, which offered acceptable yields from first-pass experiments. Mono-arylation was achieved without the use of ligands, directing groups, or prefunctionalized alkenes. Considering mild reaction conditions, good functional group compatibility, and great regioselectivity, the method can find broad applications in novel medicine and material development and discovery processes.

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.

Enantioselective Total Synthesis of (-)-Daphenylline.

A concise enantioselective total synthesis of (-)-daphenylline, a hexacyclic Daphniphyllum alkaloid with a unique benzene ring, was achieved in 14 steps. The synthesis commences with two chiral stereocenters, C2 and C18, readily installed via Carreira's Ir/amine dual-catalyzed allylation. The allylic bridgehead amine 6 was rapidly prepared through Wickens' photoredox-catalyzed hydrocarboxylation of olefin and CuBr2-catalyzed α-amination of ketone. The tetracycle 4 was formed via Pd-catalyzed reductive Heck reaction or, more concisely, by Krische's Rh-catalyzed reductive 1,6-enyne cyclization. In this synthesis, newly reported Wickens' photoredox-catalyzed hydrocarboxylation was used twice, and Friedel-Crafts acylation thrice.

Class-Incremental Unsupervised Domain Adaptation via Pseudo-Label Distillation.

Class-Incremental Unsupervised Domain Adaptation (CI-UDA) requires the model can continually learn several steps containing unlabeled target domain samples, while the source-labeled dataset is available all the time. The key to tackling CI-UDA problem is to transfer domain-invariant knowledge from the source domain to the target domain, and preserve the knowledge of the previous steps in the continual adaptation process. However, existing methods introduce much biased source knowledge for the current step, causing negative transfer and unsatisfying performance. To tackle these problems, we propose a novel CI-UDA method named Pseudo-Label Distillation Continual Adaptation (PLDCA). We design Pseudo-Label Distillation module to leverage the discriminative information of the target domain to filter the biased knowledge at the class- and instance-level. In addition, Contrastive Alignment is proposed to reduce domain discrepancy by aligning the class-level feature representation of the confident target samples and the source domain, and exploit the robust feature representation of the unconfident target samples at the instance-level. Extensive experiments demonstrate the effectiveness and superiority of PLDCA. Code is available at code.

Physiological and Pathological Roles of NTSR2 in Several Organs and Diseases (Review).

Neurotensin (NTS) and its receptors (NTSRs) have long been the subject of study and have shown to have a vital function in a variety of systems. They are specifically implicated in the development of tumors and have both oncogenic and anti-apoptotic effects. Neurotensin receptor 2 (NTSR2), like NTSR1, belongs to the G protein-coupled receptor family and has been linked to analgesia, mental disorders, and hematological cancers. However, several research reports have revealed that it exists in numerous different systems. As a result, it seems to be an extremely promising therapeutic target for a variety of diseases. As NTSR2 is particularly prevalent in the brain and has different distribution and developmental characteristics from NTSR1, it may play a specific role in the nervous system. The present review summarizes the expression and function of NTSR2 in different systems, to highlight its potential as a diagnostic tool or therapeutic target.