High-speed and large-scale intrinsically stretchable integrated circuits.

Intrinsically stretchable electronics with skin-like mechanical properties have been identified as a promising platform for emerging applications ranging from continuous physiological monitoring to real-time analysis of health conditions, to closed-loop delivery of autonomous medical treatment1-7. However, current technologies could only reach electrical performance at amorphous-silicon level (that is, charge-carrier mobility of about 1 cm2 V-1 s-1), low integration scale (for example, 54 transistors per circuit) and limited functionalities8-11. Here we report high-density, intrinsically stretchable transistors and integrated circuits with high driving ability, high operation speed and large-scale integration. They were enabled by a combination of innovations in materials, fabrication process design, device engineering and circuit design. Our intrinsically stretchable transistors exhibit an average field-effect mobility of more than 20 cm2 V-1 s-1 under 100% strain, a device density of 100,000 transistors per cm2, including interconnects and a high drive current of around 2 µA µm-1 at a supply voltage of 5 V. Notably, these achieved parameters are on par with state-of-the-art flexible transistors based on metal-oxide, carbon nanotube and polycrystalline silicon materials on plastic substrates12-14. Furthermore, we realize a large-scale integrated circuit with more than 1,000 transistors and a stage-switching frequency greater than 1 MHz, for the first time, to our knowledge, in intrinsically stretchable electronics. Moreover, we demonstrate a high-throughput braille recognition system that surpasses human skin sensing ability, enabled by an active-matrix tactile sensor array with a record-high density of 2,500 units per cm2, and a light-emitting diode display with a high refreshing speed of 60 Hz and excellent mechanical robustness. The above advancements in device performance have substantially enhanced the abilities of skin-like electronics.

High-brightness all-polymer stretchable LED with charge-trapping dilution.

Next-generation light-emitting displays on skin should be soft, stretchable and bright1-7. Previously reported stretchable light-emitting devices were mostly based on inorganic nanomaterials, such as light-emitting capacitors, quantum dots or perovskites6-11. They either require high operating voltage or have limited stretchability and brightness, resolution or robustness under strain. On the other hand, intrinsically stretchable polymer materials hold the promise of good strain tolerance12,13. However, realizing high brightness remains a grand challenge for intrinsically stretchable light-emitting diodes. Here we report a material design strategy and fabrication processes to achieve stretchable all-polymer-based light-emitting diodes with high brightness (about 7,450 candela per square metre), current efficiency (about 5.3 candela per ampere) and stretchability (about 100 per cent strain). We fabricate stretchable all-polymer light-emitting diodes coloured red, green and blue, achieving both on-skin wireless powering and real-time displaying of pulse signals. This work signifies a considerable advancement towards high-performance stretchable displays.

scDOT: enhancing single-cell RNA-Seq data annotation and uncovering novel cell types through multi-reference integration.

The proliferation of single-cell RNA-seq data has greatly enhanced our ability to comprehend the intricate nature of diverse tissues. However, accurately annotating cell types in such data, especially when handling multiple reference datasets and identifying novel cell types, remains a significant challenge. To address these issues, we introduce Single Cell annotation based on Distance metric learning and Optimal Transport (scDOT), an innovative cell-type annotation method adept at integrating multiple reference datasets and uncovering previously unseen cell types. scDOT introduces two key innovations. First, by incorporating distance metric learning and optimal transport, it presents a novel optimization framework. This framework effectively learns the predictive power of each reference dataset for new query data and simultaneously establishes a probabilistic mapping between cells in the query data and reference-defined cell types. Secondly, scDOT develops an interpretable scoring system based on the acquired probabilistic mapping, enabling the precise identification of previously unseen cell types within the data. To rigorously assess scDOT's capabilities, we systematically evaluate its performance using two diverse collections of benchmark datasets encompassing various tissues, sequencing technologies and diverse cell types. Our experimental results consistently affirm the superior performance of scDOT in cell-type annotation and the identification of previously unseen cell types. These advancements provide researchers with a potent tool for precise cell-type annotation, ultimately enriching our understanding of complex biological tissues.

The structure of the archaeal nuclease RecJ2 implicates its catalytic mechanism and inability to interact with GINS.

Bacterial RecJ exhibits 5'→3' exonuclease activity that is specific to ssDNA; however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins.

Integrating massive RNA-seq data to elucidate transcriptome dynamics in Drosophila melanogaster.

The volume of ribonucleic acid (RNA)-seq data has increased exponentially, providing numerous new insights into various biological processes. However, due to significant practical challenges, such as data heterogeneity, it is still difficult to ensure the quality of these data when integrated. Although some quality control methods have been developed, sample consistency is rarely considered and these methods are susceptible to artificial factors. Here, we developed MassiveQC, an unsupervised machine learning-based approach, to automatically download and filter large-scale high-throughput data. In addition to the read quality used in other tools, MassiveQC also uses the alignment and expression quality as model features. Meanwhile, it is user-friendly since the cutoff is generated from self-reporting and is applicable to multimodal data. To explore its value, we applied MassiveQC to Drosophila RNA-seq data and generated a comprehensive transcriptome atlas across 28 tissues from embryogenesis to adulthood. We systematically characterized fly gene expression dynamics and found that genes with high expression dynamics were likely to be evolutionarily young and expressed at late developmental stages, exhibiting high nonsynonymous substitution rates and low phenotypic severity, and they were involved in simple regulatory programs. We also discovered that human and Drosophila had strong positive correlations in gene expression in orthologous organs, revealing the great potential of the Drosophila system for studying human development and disease.

Continuously Tunable MOFs Enable Precise Mass Transfer for High-Performance Isomer Separation.

Modulating mass transfer is crucial for optimizing the catalytic and separation performances of porous materials. Here, we systematically developed a series of continuously tunable MOFs (CTMOFs) that exhibit incessantly increased mass transfer. This was achieved through the strategic blending of ligands with different lengths and ratios in MOFs featuring the fcu topology. By employing a proportional mixture of two ligands in the synthesis of UiO-66, the micropores expanded, facilitating faster mass transfer. The mass transfer rate was evaluated by dye adsorption, dark-field microscopy, and gas chromatography (GC). The GC performance proved that both too-fast and too-slow mass transfer led to low separation performance. The optimized mass transfer in CTMOFs resulted in an exceptionally high separation resolution (5.96) in separating p-xylene and o-xylene. Moreover, this study represents the first successful use of MOFs for high-performance separation of propylene and propane by GC. This strategy provides new inspiration in regulating mass transfer in porous materials.

New G-Triplex DNA Dramatically Activates the Fluorescence of Thioflavin T and Acts as a Turn-On Fluorescent Sensor for Uracil-DNA Glycosylase Activity Detection.

G-triplexes are G-rich oligonucleotides composed of three G-tracts and have absorbed much attention due to their potential biological functions and attractive performance in biosensing. Through the optimization of loop compositions, DNA lengths, and 5'-flanking bases of G-rich sequences, a new stable G-triplex sequence with 14 bases (G3-F15) was discovered to dramatically activate the fluorescence of Thioflavin T (ThT), a water-soluble fluorogenic dye. The fluorescence enhancement of ThT after binding with G3-F15 reached 3200 times, which was the strongest one by far among all of the G-rich sequences. The conformations of G3-F15 and G3-F15/ThT were studied by circular dichroism. The thermal stability measurements indicated that G3-F15 was a highly stable G-triplex structure. The conformations of G3-F15 and G3-F15/ThT in the presence of different metal cations were studied thoroughly by fluorescent spectroscopy, circular dichroism, and nuclear magnetic resonance. Furthermore, using the G3-F15/ThT complex as a fluorescent probe, a robust and simple turn-on fluorescent sensor for uracil-DNA glycosylase activity was developed. This study proposes a new systematic strategy to explore new functional G-rich sequences and their ligands, which will promote their applications in diagnosis, therapy, and biosensing.

High-Throughput Screening of pH-Dependent ß-sheet Self-Assembling Peptide.

pH-dependent peptide biomaterials hold tremendous potential for cell delivery and tissue engineering. However, identification of responsive self-assembling sequences with specified secondary structure remains a challenge. In this work, An experimental procedure based on the one-bead one-compound (OBOC) combinatorial library is developed to rapidly screen self-assembling ß-sheet peptides at neutral aqueous solution (pH 7.5) and disassemble at weak acidic condition (pH 6.5). Using the hydrophobic fluorescent molecule thioflavin T (ThT) as a probe, resin beads displaying self-assembling peptides show fluorescence under pH 7.5 due to the insertion of ThT into the hydrophobic domain, and are further cultured in pH 6.5 solution. The beads with extinguished fluorescence are selected. Three heptapeptides are identified that can self-assemble into nanofibers or nanoparticles at pH 7.5 and disassemble at pH 6.5. P1 (LVEFRHY) shows a rapid acid response and morphology transformation with pH modulation. Changes in the charges of histidine and hydrophobic phenyl motif of phenylalanine may play important roles in the formation of pH-responsive ß-sheet nanofiber. This high-throughput screening method provides an efficient way to identify pH-dependent ß-sheet self-assembling peptide and gain insights into structural design of such nanomaterials.

Demographic dynamics and molecular evolution of the rare and endangered subsect. Gerardianae of Pinus: insights from chloroplast genomes and mitochondrial DNA markers.

MAIN CONCLUSION: The divergence of subsect. Gerardianae was likely triggered by the uplift of the Qinghai-Tibetan Plateau and adjacent mountains. Pinus bungeana might have probably experienced expansion since Last Interglacial period. Historical geological and climatic oscillations have profoundly affected patterns of nucleotide variability, evolutionary history, and species divergence in numerous plants of the Northern Hemisphere. However, how long-lived conifers responded to geological and climatic fluctuations in East Asia remain poorly understood. Here, based on paternally inherited chloroplast genomes and maternally inherited mitochondrial DNA markers, we investigated the population demographic history and molecular evolution of subsect. Gerardianae (only including three species, Pinus bungeana, P. gerardiana, and P. squamata) of Pinus. A low level of nucleotide diversity was found in P. bungeana (π was 0.00016 in chloroplast DNA sequences, and 0.00304 in mitochondrial DNAs). The haplotype-based phylogenetic topology and unimodal distributions of demographic analysis suggested that P. bungeana probably originated in the southern Qinling Mountains and experienced rapid population expansion since Last Interglacial period. Phylogenetic analysis revealed that P. gerardiana and P. squamata had closer genetic relationship. The species divergence of subsect. Gerardianae occurred about 27.18 million years ago (Mya) during the middle to late Oligocene, which was significantly associated with the uplift of the Qinghai-Tibetan Plateau and adjacent mountains from the Eocene to the mid-Pliocene. The molecular evolutionary analysis showed that two chloroplast genes (psaI and ycf1) were under positive selection, the genetic lineages of P. bungeana exhibited higher transition and nonsynonymous mutations, which were involved with the strongly environmental adaptation. These findings shed light on the population evolutionary history of white pine species and provide striking insights for comprehension of their species divergence and molecular evolution.

A novel antimicrobial peptide S24 combats serious wound infections caused by Pseudomonas aeruginosa and Acinetobacter baumannii.

OBJECTIVES: Pseudomonas aeruginosa and Acinetobacter baumannii are ranked as top-priority organisms by WHO. Antimicrobial peptides (AMPs) are promising antimicrobial agents that are highly effective against serious bacterial infections. METHODS: In our previous study, a series of α-helical AMPs were screened using a novel multiple-descriptor strategy. The current research suggested that S24 exhibited strong antimicrobial activity against major pathogenic bacteria, and displayed minimal haemolysis, good serum stability and maintained salt resistance. RESULTS: We found that S24 exerted an antimicrobial effect by destroying outer membrane permeability and producing a strong binding effect on bacterial genomic DNA that inhibits genomic DNA migration. Furthermore, S24 exerted a strong ability to promote healing in wound infected by P. aeruginosa, A. baumannii and mixed strains in a mouse model. CONCLUSIONS: Overall, S24 showed good stability under physiological conditions and excellent antimicrobial activity, suggesting it may be a potential candidate for the development of serious bacterial infection treatment.

Differential response of HBV envelope-specific CD4 + T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy.

BACKGROUND AND AIM: Long-term maintenance of viral control, even HBsAg loss, remains a challenge for chronic hepatitis B (CHB) patients undergoing nucleos(t)ide analogue (NA) discontinuation. This study aimed to investigate the relationship between HBV-specific T-cell responses targeting peptides spanning the whole proteome and clinical outcomes in CHB patients after NA discontinuation. APPROACH AND RESULTS: Eighty-eight CHB patients undergoing NA discontinuation were classified as responders (remained relapse-free up to 96 weeks) or relapsers (relapsed patients who underwent NA retreatment for up to 48 weeks and reachieved stable viral control). HBV-specific T-cell responses were detected at baseline and longitudinally throughout the follow-up. We found responders had a greater magnitude of HBV polymerase (Pol)-specific T-cell responses than relapsers at baseline. After long-term NA discontinuation, simultaneously enhanced HBV Core-induced and Pol-induced responses were observed in responders. Particularly, responders with HBsAg loss possessed enhanced HBV Envelope (Env)-induced responses after short-term and long-term follow-up. Notably, CD4 + T cells accounted for the predominance of HBV-specific T-cell responses. Correspondingly, CD4-deficient mice showed attenuated HBV-specific CD8 + T-cell responses, reduced HBsAb-producing B cells, and delayed HBsAg loss; in contrast, in vitro addition of CD4 + T cells promoted HBsAb production by B cells. Besides, IL-9, rather than PD-1 blockade, enhanced HBV Pol-specific CD4 + T-cell responses. CONCLUSION: HBV-specific CD4 + T-cell responses induced by the targeted peptide possess specificities for long-term viral control and HBsAg loss in CHB patients undergoing NA discontinuation, indicating that CD4 + T cells specific to distinct HBV antigens may endow with divergent antiviral potential.

Cataract Surgery and Cognitive Benefits in the Older Person: A Systematic Review and Meta-analysis.

TOPIC: This systematic review and meta-analysis aims to clarify the association of cataract surgery with cognitive impairment and dementia. CLINICAL RELEVANCE: The association between vision impairment and cognitive decline is well-established. However, the cognitive benefits of cataract surgery are less clear. Given the lack of cure for dementia, identifying modifiable risk factors is key in caring for patients with cognitive deficits. METHODS: The study was conducted following Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. PubMed, Embase, and Cochrane Library were searched from inception through October 11, 2022, for studies reporting the effect of cataract surgery on cognitive impairment and dementia. We pooled maximally adjusted hazard ratios (HRs) for dichotomous outcomes and ratio of means (RoM) for continuous outcomes using a random-effects model. Heterogeneity was examined using sensitivity and subgroup analyses. The quality of evidence was evaluated using the Newcastle-Ottawa scale, Cochrane risk-of-bias tool for randomized trials, and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. RESULTS: This review included 24 articles comprising 558 276 participants, of which 19 articles were analyzed qualitatively. The bias of studies ranged from low to moderate, and GRADE extended from very low to low. Cataract surgery was associated with a 25% reduced risk of long-term cognitive decline compared with those with uncorrected cataracts (HR, 0.75; 95% confidence interval [CI], 0.72-0.78). This cognitive benefit was seen across various cognitive outcomes and remained robust to sensitivity analyses. Participants who underwent cataract surgery showed a similar risk of long-term cognitive decline as healthy controls without cataracts (HR, 0.84; 95% CI, 0.66-1.06). Additionally, cataract surgery was associated with a 4% improvement in short-term cognitive test scores among participants with normal cognition (RoM, 0.96; 95% CI, 0.94-0.99), but no significant association was observed among participants with preexisting cognitive impairment. DISCUSSION: Cataract surgery may be associated with a lower risk of cognitive impairment and dementia, and cataract-associated vision impairment may be a modifiable risk factor for cognitive decline. Physicians should be aware of the cognitive sequelae of cataracts and the possible benefits of surgery. The cognitive benefits of cataract surgery should be investigated further in randomized trials. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A generalized QUCESOP method with evaluating CEST peak overlap.

The overlapping peaks of the target chemical exchange saturation transfer (CEST) solutes and other unknown CEST solutes affect the quantification results and accuracy of the chemical exchange parameters-the fractional concentration, f b , exchange rate, k b , and transverse relaxation rate, R 2 b -for the target solutes. However, to date, no method has been established for assessing the overlapping peaks. This study aimed to develop a method for quantifying the f b , k b , and R 2 b values of a specific CEST solute, as well as assessing the overlap between the CEST peaks of the specific solute(s) and other unknown solutes. A simplified R 1 ρ model was proposed, assuming linear approximation of the other solutes' contributions to R 1 ρ . A CEST data acquisition scheme was applied with various saturation offsets and saturation powers. In addition to fitting the f b , k b , and R 2 b values of the specific solute, the overlapping condition was evaluated based on the root mean square error (RMSE) between the trajectories of the acquired and synthesized data. Single-solute and multi-solute phantoms with various phosphocreatine (PCr) concentrations and pH values were used to calculate the f b and k b of PCr and the corresponding RMSE. The feasibility of RMSE for evaluating the overlapping condition, and the accurate fitting of f b and k b in weak overlapping conditions, were verified. Furthermore, the method was employed to quantify the nuclear Overhauser effect signal in rat brains and the PCr signal in rat skeletal muscles, providing results that were consistent with those reported in previous studies. In summary, the proposed approach can be applied to evaluate the overlapping condition of CEST peaks and quantify the f b , k b , and R 2 b values of specific solutes, if the weak overlapping condition is satisfied.

Characterization the prognosis role and effects of snoRNAs in melanoma patients.

Melanoma is a melanocyte-derived malignant cancer and is known for its early metastasis and high mortality rates. It is a highly cutaneous tumour disease that could be related to the abnormal immune microenvironment, and the identification of reliable diagnostic and prognostic markers is crucial for improving patient outcomes. In the search for biomarkers, various types of RNAs have been discovered and recognized as reliable prognostic markers. Among these, small nucleolar RNAs (snoRNAs) have emerged as a promising avenue for studying early diagnosis and prognostic markers in tumours due to their widespread presence in tissues, tumour specificity and stability. In our study, we analysed snoRNAs data from melanoma samples in the TCGA-SKCM cohort and developed a prognostic model comprising 12 snoRNAs (SNORD9, SNORA31, SNORD14E, SNORA14A, SNORA5A, SNORD83A, SNORA75, AL096855, AC007684, SNORD14A, SNORA65 and AC004839). This model exhibited unique prognostic accuracy and demonstrated a significant correlation with the immune infiltration tumour microenvironment. Additionally, analysis of the GSE213145 dataset, which explored the sensitivity and resistance of immune checkpoint inhibitors, further supported the potential of snoRNAs as prognostic markers for immunotherapy. Overall, our study contributes reliable prognostic and immune-related biomarkers for melanoma patients. These findings can offer valuable insights for the future discovery of novel melanoma treatment strategies and hold promise for improving clinical outcomes in melanoma patients.

Microporous Polyelectrolyte Complexes by Hydroplastic Foaming.

Polyelectrolyte complexes (PECs) have emerged as an attractive category of materials for their water processability and some similarities to natural biopolymers. Herein, we employ the intrinsic hydroplasticity of PEC materials to enable the generation of porous structures with the aid of gas foaming. Such foamable materials are fabricated by simply mixing polycation, polyanion, and a UV-initiated chemical foaming agent in an aqueous solution, followed by molding into thin films. The gas foaming of the PEC films can be achieved upon exposure to UV illumination under water, where the films are plasticized and the gaseous products from the photolysis of foaming agents afford the formation, expanding, and merging of numerous bubbles. The porosity and morphology of the resulting porous films can be customized by tuning film composition, foaming conditions, and especially the degree of plasticizing effect, illustrating the high flexibility of this hydroplastic foaming method. Due to the rapid initiation of gas foaming, the present method enables the formation of porous structures via an instant one-step process, much more efficient than those existing strategies for porous PEC materials. More importantly, such a pore-forming mechanism might be extended to other hydroplastic materials (e.g., biopolymers) and help to yield hydroplasticity-based processing strategies.

Glycosylation editing: an innovative therapeutic opportunity in precision oncology.

Cancer is still one of the most arduous challenges in the human society, even though humans have found many ways to try to conquer it. With our incremental understandings on the impact of sugar on human health, the clinical relevance of glycosylation has attracted our attention. The fact that altered glycosylation profiles reflect and define different health statuses provide novel opportunities for cancer diagnosis and therapeutics. By reviewing the mechanisms and critical enzymes involved in protein, lipid and glycosylation, as well as current use of glycosylation for cancer diagnosis and therapeutics, we identify the pivotal connection between glycosylation and cellular redox status and, correspondingly, propose the use of redox modulatory tools such as cold atmospheric plasma (CAP) in cancer control via glycosylation editing. This paper interrogates the clinical relevance of glycosylation on cancer and has the promise to provide new ideas for laboratory practice of cold atmospheric plasma (CAP) and precision oncology therapy.

Cell-type annotation with accurate unseen cell-type identification using multiple references.

The recent advances in single-cell RNA sequencing (scRNA-seq) techniques have stimulated efforts to identify and characterize the cellular composition of complex tissues. With the advent of various sequencing techniques, automated cell-type annotation using a well-annotated scRNA-seq reference becomes popular. But it relies on the diversity of cell types in the reference, which may not capture all the cell types present in the query data of interest. There are generally unseen cell types in the query data of interest because most data atlases are obtained for different purposes and techniques. Identifying previously unseen cell types is essential for improving annotation accuracy and uncovering novel biological discoveries. To address this challenge, we propose mtANN (multiple-reference-based scRNA-seq data annotation), a new method to automatically annotate query data while accurately identifying unseen cell types with the aid of multiple references. Key innovations of mtANN include the integration of deep learning and ensemble learning to improve prediction accuracy, and the introduction of a new metric that considers three complementary aspects to distinguish between unseen cell types and shared cell types. Additionally, we provide a data-driven method to adaptively select a threshold for identifying previously unseen cell types. We demonstrate the advantages of mtANN over state-of-the-art methods for unseen cell-type identification and cell-type annotation on two benchmark dataset collections, as well as its predictive power on a collection of COVID-19 datasets. The source code and tutorial are available at https://github.com/Zhangxf-ccnu/mtANN.

The cross-sectional and prospective associations of parental practices and environmental factors with 24-hour movement behaviours among school-aged Asian children.

BACKGROUND: Parental practices and neighbourhood environmental factors may influence children's movement behaviours. We aimed to investigate the cross-sectional and prospective associations of parental practices and neighbourhood environmental factors with accelerometer-measured 24-hour movement behaviours (24 h-MBs) among school-aged children in Singapore. METHODS: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study collected information on dimensions of parental practices and neighbourhood environment at age 5.5 years. Confirmatory factor analyses were performed to generate latent variables and used to compute overall parental practices [involvement in PA + support for PA + control of screen viewing context] and environmental scores [facilities for active play + active mobility facilitators + barriers*-1]. Children wore an accelerometer on their non-dominant wrist for seven consecutive days at ages 5.5 and 8 years. The R-package GGIR 2.6 was used to derive moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), inactivity, and total-sleep (napping+night sleep) minutes per day. Associations were determined using compositional data analysis with multivariate linear regression models, taking into account potential confounders. RESULTS: Among 425 children (48% girls, 59% Chinese), higher parental involvement in PA, parental support for PA and overall parental practices were associated with 24 h-MBs at ages 5.5 and 8 years, specifically with greater time spent in MVPA and less time being inactive relative to the remaining movement behaviours. The corresponding mean changes in the overall 24 h-MB for increasing parental practices from lowest to highest scores (- 2 to + 2 z-scores) indicated potential increases of up to 15-minutes in MVPA, 20-minutes in LPA, 5-minutes in sleep duration, and a reduction of 40-minutes in inactivity at age 5.5 years. At age 8 years, this could translate to approximately 15-minutes more of MVPA, 20-minutes more of LPA, a 20-minute reduction in sleep duration, and a 20-minute reduction in inactivity. Parental control of screen viewing contexts and neighbourhood environmental factors were not associated with 24 h-MBs. CONCLUSIONS: Parental practices but not environmental factors were associated with higher MVPA and lower inactivity among Singaporean children, even at a later age. Further research may provide insights that support development of targeted public health strategies to promote healthier movement behaviours among children. STUDY REGISTRATION: This study was registered on 4th August 2010 and is available online at ClinicalTrials.gov: NCT01174875.

Calycosin inhibited MIF-mediated inflammatory chemotaxis of macrophages to ameliorate ischemia reperfusion-induced acute kidney injury.

BACKGROUND: Inflammatory macrophage infiltration plays a critical role in acute kidney disease induced by ischemia-reperfusion (IRI-AKI). Calycosin is a natural flavone with multiple bioactivities. This study aimed to investigate the therapeutic role of calycosin in IRI-AKI and its underlying mechanism. METHODS: The renoprotective and anti-inflammatory effects of calycosin were analyzed in C57BL/6 mice with IRI-AKI and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. RNA-seq was used for mechanism investigation. The molecular target of calycosin was screened by in silico methods and validated by surface plasmon resonance (SPR). Macrophage chemotaxis was analyzed using Transwell and agarose gel spot assays. RESULTS: Calycosin treatment significantly reduced serum creatinine and urea nitrogen and attenuated tubular destruction in IRI-AKI mice. Additionally, calycosin markedly suppressed NF-κB signaling activation and the expression of inflammatory mediators IL-1ß and TNF-α in IRI-AKI kidneys and LPS-stimulated RAW 264.7 cells. Interestingly, RNA-seq revealed calycosin remarkably downregulated chemotaxis-related pathways in RAW 264.7 cells. Among the differentially expressed genes, Ccl2/MCP-1, a critical chemokine mediating macrophage inflammatory chemotaxis, was downregulated in both LPS-stimulated RAW 264.7 cells and IRI-AKI kidneys. Consistently, calycosin treatment attenuated macrophage infiltration in the IRI-AKI kidneys. Importantly, in silico target prediction, molecular docking, and SPR assay demonstrated that calycosin directly binds to macrophage migration inhibitory factor (MIF). Functionally, calycosin abrogated MIF-stimulated NF-κB signaling activation and Ccl2 expression and MIF-mediated chemotaxis in RAW 264.7 cells. CONCLUSIONS: In summary, calycosin attenuates IRI-AKI by inhibiting MIF-mediated macrophage inflammatory chemotaxis, suggesting it could be a promising therapeutic agent for the treatment of IRI-AKI.