Atractylodes macrocephala III suppresses EMT in cervical cancer by regulating IGF2BP3 through ETV5.

Atractylodes macrocephala III (ATL III), with anti-inflammatory and antitumor effects, is the main compound of Atractylodes macrocephala. Whether ATL III has an effect on cervical cancer and the specific mechanism are still unclear. Here, we investigated the effects of ATL III on cervical cancer cells at different concentrations and found that ATL III downregulates insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which was found to be highly expressed in cervical cancer tissue by RNA-Seq. In this study, we found that ATL III promotes apoptosis and regulates epithelial-mesenchymal transition (EMT) in cervical cancer cells (HeLa and SiHa cells) and that IGF2BP3 is a common target gene of ATL III in HeLa and SiHa cells. The expression level of IGF2BP3 in cervical cancer cells was proportional to their migration and invasion abilities. This was verified by transfection of cells with a small interfering RNA and an IGF2BP3 overexpression plasmid. After ATL III treatment, the migration and invasion abilities of cervical cancer cells were obviously reduced, but these effects were attenuated after overexpression of IGF2BP3. In addition, the transcription factor IGF2BP3 was predicted by the JASPAR system. After intersection with our sequencing results, we verified the promotional effect of ETV5 (ETS translocation variant 5) on IGF2BP3 and found that ALT III inhibited ETV5. In general, our research showed that ATL III inhibits the migration and invasion of cervical cancer cells by regulating IGF2BP3 through ETV5.

FoxO1 silencing in Atp7b-/- neural stem cells attenuates high copper-induced apoptosis via regulation of autophagy.

Wilson disease (WD) is a severely autosomal genetic disorder triggered by dysregulated copper metabolism. Autophagy and apoptosis share common modulators that process cellular death. Emerging evidences suggest that Forkhead Box O1 over-expression (FoxO1-OE) aggravates abnormal autophagy and apoptosis to induce neuronal injury. However, the underlying mechanisms remain undetermined. Herein, the aim of this study was to investigate how regulating FoxO1 affects cellular autophagy and apoptosis to attenuate neuronal injury in a well-established WD cell model, the high concentration copper sulfate (CuSO4, HC)-triggered Atp7b-/- (Knockout, KO) neural stem cell (NSC) lines. The FoxO1-OE plasmid, or siRNA-FoxO1 (siFoxO1) plasmid, or empty vector plasmid was stably transfected with recombinant lentiviral vectors into HC-induced Atp7b-/- NSCs. Toxic effects of excess deposited copper on wild-type (WT), Atp7b-/- WD mouse hippocampal NSCs were tested by Cell Counting Kit-8 (CCK-8). Subsequently, the FoxO1 expression was evaluated by immunofluorescence (IF) assay, western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Meanwhile, the cell autophagy and apoptosis were evaluated by flow cytometry (FC), TUNEL staining, 2,7-dichlorofluorescein diacetate (DCFH-DA), JC-1, WB, and qRT-PCR. The current study demonstrated a strong rise in FoxO1 levels in HC-treated Atp7b-/- NSCs, accompanied with dysregulated autophagy and hyperactive apoptosis. Also, it was observed that cell viability was significantly decreased with the over-expressed FoxO1 in HC-treated Atp7b-/- WD model. As intended, silencing FoxO1 effectively inhibited abnormal autophagy in HC-treated Atp7b-/- NSCs, as depicted by a decline in LC3II/I, Beclin-1, ATG3, ATG7, ATG13, and ATG16, whereas simultaneously increasing P62. In addition, silencing FoxO1 suppressed apoptosis via diminishing oxidative stress (OS), and mitochondrial dysfunction in HC-induced Atp7b-/- NSCs. Collectively, these results clearly demonstrate the silencing FoxO1 has the neuroprotective role of suppressing aberrant cellular autophagy and apoptosis, which efficiently attenuates neuronal injury in WD.

Apoptosis-related prognostic biomarkers and potential targets for acute kidney injury based on machine learning algorithm and in vivo experiments.

Acute kidney injury (AKI) is a common critical illness in hospitalized patients, characterized by a rapid decline in kidney function over a short period, which can seriously endanger the patient's life. Currently, there is a lack of precise and universal AKI diagnostic biomarkers in clinical practice. In this study, weighted gene coexpression network analysis (WGCNA), differential expression analysis, univariate and multivariate logistic regression analyses, receiver operating characteristic (ROC) curves, and immune cell infiltration were performed to identify apoptosis-related biomarkers that can be used for AKI diagnosis. Three core apoptosis-related genes (ARGs), CBFB, EGF and COL1A1, were identified as AKI biomarkers. More importantly, an apoptosis-related signature containing three hub ARGs was validated as a diagnostic model. The hub genes exhibited good correlations with glomerular filtration rate (GFR) and serum creatinine (SCr) in the Nephroseq kidney disease database. Additionally, CIBERSORT immune infiltration analysis indicated that these core ARGs may affect immune cell recruitment and infiltration in AKI patients. Subsequently, we investigated the alteration of the expression levels of three core ARGs in AKI samples using single-cell RNA sequencing analysis and analyzed the cell types that mainly expressed these ARGs. More importantly, the expression of core ARGs was validated in folic acid- and cisplatin-induced AKI mouse models. In summary, our study identified three diagnostic biomarkers for AKI, explored the roles of ARGs in AKI progression and provided new ideas for the clinical diagnosis and treatment of AKI.

A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

Vaginal microbial profile of cervical cancer patients receiving chemoradiotherapy: the potential involvement of Lactobacillus iners in recurrence.

The vaginal microbiome is an immune defense against reproductive diseases and can serve as an important biomarker for cervical cancer. However, the intrinsic relationship between the recurrence and the vaginal microbiome in patients with cervical cancer before and after concurrent chemoradiotherapy is poorly understood. Here, we analyzed 125 vaginal microbial profiles from a patient cohort of stage IB-IVB cervical cancer using 16S metagenomic sequencing and deciphered the microbial composition and functional characteristics of the recurrent and non-recurrent both before and after chemoradiotherapy. We demonstrated that the abundance of beneficial bacteria and stability of the microbial community in the vagina decreased in the recurrence group, implying the unique characteristics of the vaginal microbiome for recurrent cervical cancer. Moreover, using machine learning, we identified Lactobacillus iners as the most important biomarker, combined with age and other biomarkers (such as Ndongobacter massiliensis, Corynebacterium pyruviciproducens ATCC BAA-1742, and Prevotella buccalis), and could predict cancer recurrence phenotype before chemoradiotherapy. This study prospectively employed rigorous bioinformatics analysis and highlights the critical role of vaginal microbiota in post-treatment cervical cancer recurrence, identifying promising biomarkers with prognostic significance in the context of concurrent chemoradiotherapy for cervical cancer. The role of L. iners in determining chemoradiation resistance in cervical cancer warrants further detailed investigation. Our results expand our understanding of cervical cancer recurrence and help develop better strategies for prognosis prediction and personalized therapy.

Genetic architecture of ecological divergence between Oryza rufipogon and Oryza nivara.

Ecological divergence due to habitat difference plays a prominent role in the formation of new species, but the genetic architecture during ecological speciation and the mechanism underlying phenotypic divergence remain less understood. Two wild ancestors of rice (Oryza rufipogon and Oryza nivara) are a progenitor-derivative species pair with ecological divergence and provide a unique system for studying ecological adaptation/speciation. Here, we constructed a high-resolution linkage map and conducted a quantitative trait locus (QTL) analysis of 19 phenotypic traits using an F2 population generated from a cross between the two Oryza species. We identified 113 QTLs associated with interspecific divergence of 16 quantitative traits, with effect sizes ranging from 1.61% to 34.1% in terms of the percentage of variation explained (PVE). The distribution of effect sizes of QTLs followed a negative exponential, suggesting that a few genes of large effect and many genes of small effect were responsible for the phenotypic divergence. We observed 18 clusters of QTLs (QTL hotspots) on 11 chromosomes, significantly more than that expected by chance, demonstrating the importance of coinheritance of loci/genes in ecological adaptation/speciation. Analysis of effect direction and v-test statistics revealed that interspecific differentiation of most traits was driven by divergent natural selection, supporting the argument that ecological adaptation/speciation would proceed rapidly under coordinated selection on multiple traits. Our findings provide new insights into the understanding of genetic architecture of ecological adaptation and speciation in plants and help effective manipulation of specific genes or gene cluster in rice breeding.

Transcription factors-related molecular subtypes and risk prognostic model: exploring the immunogenicity landscape and potential drug targets in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, with a high mortality rate and poor prognosis. Mutated or dysregulated transcription factors (TFs) are significantly associated with carcinogenesis. The aim of this study was to develop a TF-related prognostic risk model to predict the prognosis and guide the treatment of HCC patients. METHODS: RNA sequencing data were obtained from the TCGA database. The ICGC and GEO databases were used as validation datasets. The consensus clustering algorithm was used to classify the molecular subtypes of TFs. Kaplan‒Meier survival analysis and receiver operating characteristic (ROC) analysis were applied to evaluate the prognostic value of the model. The immunogenic landscape differences of molecular subtypes were evaluated by the TIMER and xCell algorithms. Autodock analysis was used to predict possible binding sites of trametinib to TFs. RT‒PCR was used to verify the effect of trametinib on the expression of core TFs. RESULTS: According to the differential expression of TFs, HCC samples were divided into two clusters (C1 and C2). The survival time, signaling pathways, abundance of immune cell infiltration and responses to chemotherapy and immunotherapy were significantly different between C1 and C2. Nine TFs with potential prognostic value, including HMGB2, ESR1, HMGA1, MYBL2, TCF19, E2F1, FOXM1, CENPA and ZIC2, were identified by Cox regression analysis. HCC patients in the high-risk group had a poor prognosis compared with those in the low-risk group (p < 0.001). Moreover, the area under the ROC curve (AUC) values of the 1-year, 2-year and 3-year survival rates were 0.792, 0.71 and 0.695, respectively. The risk model was validated in the ICGC database. Notably, trametinib sensitivity was highly correlated with the expression of core TFs, and molecular docking predicted the possible binding sites of trametinib with these TFs. More importantly, the expression of core TFs was downregulated under trametinib treatment. CONCLUSIONS: A prognostic signature with 9 TFs performed well in predicting the survival rate and chemotherapy/immunotherapy effect of HCC patients. Trimetinib has potential application value in HCC by targeting TFs.

Advances in Bioinspired Artificial System Enabling Biomarker-Driven Therapy.

Bioinspired molecular engineering strategies have emerged as powerful tools that significantly enhance the development of novel therapeutics, improving efficacy, specificity, and safety in disease treatment. Recent advancements have focused on identifying and utilizing disease-associated biomarkers to optimize drug activity and address challenges inherent in traditional therapeutics, such as frequent drug administrations, poor patient adherence, and increased risk of adverse effects. In this review, we provide a comprehensive overview of the latest developments in bioinspired artificial systems (BAS) that use molecular engineering to tailor therapeutic responses to drugs in the presence of disease-specific biomarkers. We examine the transition from open-loop systems, which rely on external cues, to closed-loop feedback systems capable of autonomous self-regulation in response to disease-associated biomarkers. We detail various BAS modalities designed to achieve biomarker-driven therapy, including activatable prodrug molecules, smart drug delivery platforms, autonomous artificial cells, and synthetic receptor-based cell therapies, elucidating their operational principles and practical in vivo applications. Finally, we discuss the current challenges and future perspectives in the advancement of BAS-enabled technology and envision that ongoing advancements toward more programmable and customizable BAS-based therapeutics will significantly enhance precision medicine.

Deciphering microbiome and fungi-bacteria interactions in chronic wound infections using metagenomic sequencing.

PURPOSE: Chronic wounds caused by infections impose a considerable global healthcare burden. The microbial features of these infections and possible correlations between bacteria and fungi may influence wound healing. However, metagenomic next-generation sequencing (mNGS) analyses of these features remain sparse. Therefore, we performed mNGS on chronic wound infection samples to investigate features and correlations between the bacteriome and mycobiome in 66 patients (28: chronic wounds; 38: non-chronic wounds). METHODS: Microbial community characteristics in patients with wound infections, microbiome-systemic inflammation associations, and bacteria-fungi correlations were analyzed. RESULTS: Infections constituted the primary cause of wounds in this study. Nontuberculous mycobacteria (23%) and Mycobacterium tuberculosis (13%) were the most common pathogens associated with chronic wounds, whereas Staphylococcus aureus (15%) was the most prevalent in non-chronic wound infections. Patients with chronic wound infections had a higher abundance of Pseudomonas aeruginosa than those without chronic wounds. Microbes with a high relative abundance in chronic wound infections were less significantly associated with plasma inflammatory factors than those in non-chronic wound infections. Additionally, a positive correlation between Candida glabrata and P. aeruginosa and an association between Malassezia restricta and anaerobic species were detected in patients with chronic wound infections. CONCLUSION: Our results further support the hypothesis that P. aeruginosa is a microbial biomarker of chronic wound infection regardless of the causative pathogens. Moreover, we propose a positive correlation between C. glabrata and P. aeruginosa in chronic wound infections, which advances the current understanding of fungi-bacteria correlations in patients with chronic wound infections.

Spatial distribution of maternal factors in pig mature oocytes.

It is known that asymmetrical maternal transcripts play an important role in the cell fate of the early embryo, but few studies are available in mammal oocytes especially in pig. To investigate the spatial factors in pig oocytes, the oriented bisection was established for collecting karyoplasts (NSOs) and cytoplasts (SSOs) with more than 95% efficiency. Subsequently, RNA-Seq and LC-MS/MS analysis were performed on NSOs and SSOs. Although no differentially expressed genes (DEGs) could be detected between NSOs and SSOs, 89 of the differentially expressed proteins (DEPs) were detected, that 58 proteins higher expressed but 31 proteins lower expressed in NSOs compared with SSOs. These DEPs mainly participated in the 'cell cycle' and 'ribosome' pathway, while the up-regulated DEPs were mainly GO in 'spindle' and 'positive regulation of translation', and the down-regulated DEPs were in 'cytosolic small ribosomal subunit' and 'mRNA binding'. The up-regulated DEP SIRT5 which are related to the regulation of gene expression, epigenetic were further detected and revealed. A spatial asymmetry of maternal factors at the protein level was firstly detected in pig mature oocytes.

Logic Nanodevice-Mediated Receptor Assembly for Nongenetic Regulation of Cell Behavior in Tumor-like Microenvironment.

The reprogramming of cell signaling and behavior through the artificial control of cell surface receptor oligomerization shows great promise in biomedical research and cell-based therapy. However, it remains challenging to achieve combinatorial recognition in a complicated environment and logical regulation of receptors for desirable cellular behavior. Herein, we develop a logic-gated DNA nanodevice with responsiveness to multiple environmental inputs for logically controlled assembly of heterogeneous receptors to modulate signaling. The "AND" gate nanodevice uses an i-motif and an ATP-binding aptamer as environmental cue-responsive units, which can successfully implement a logic operation to manipulate receptors on the cell surface. In the presence of both protons and ATP, the DNA nanodevice is activated to selectively assemble MET and CD71, which modulate the HGF/MET signaling, resulting in cytoskeletal reorganization to inhibit cancer cell motility in a tumor-like microenvironment. Our strategy would be highly promising for precision therapeutics, including controlled drug release and cancer treatment.

Characterization and utilization potential of typical molybdenum tailings in Shaanxi Province, China.

Shaanxi Province is located in the most important molybdenum ore district in the world, but a lot of molybdenum tailings have been released, polluting the environment and wasting resources seriously. Taking eleven tailing samples collected at the main molybdenum tailings ponds in Shaanxi Province as the research object, the physical, chemical, and mineralogical characteristics were studied through scanning electron microscope, X-ray fluorescence, X-ray diffraction, inductively coupled plasma mass spectrometer, and others. The ecological risk and utilization potential of molybdenum tailings were investigated through leaching test, geo-accumulation index, potential ecological risk assessment, and other methods. The results demonstrated that the main chemical and mineralogical composition of various molybdenum tailings in Shaanxi Province is similar, and the predominant mineral composition is muscovite, quartz, microcline, and calcite. The potential ecological risk of heavy metals in six molybdenum tailings is high, while Pb and Cd are the main pollution risk elements. Molybdenum tailings contain considerable amounts of critical minerals with huge potential economic value, and molybdenum tailings with high environmental hazards could be converted into a possible source for critical minerals by recovering the critical minerals and repurposing the secondary tailings as an additive or cement substitute. This study provides an innovative idea for the pollution treatment of molybdenum tailings and indicates the prospect of molybdenum tailings as a secondary source for critical minerals.

Collagen Anchoring Protein-Nucleic Acid Chimeric Probe for In Situ In Vivo Mapping of a Tumor-Specific Protease.

In situ analysis of biomarkers in the tumor microenvironment (TME) is important to reveal their potential roles in tumor progression and early diagnosis of tumors but remains a challenge. In this work, a bottom-up modular assembly strategy was proposed for a multifunctional protein-nucleic chimeric probe (PNCP) for in situ mapping of cancer-specific proteases. PNCP, containing a collagen anchoring module and a target proteolysis-responsive isothermal amplification sensor module, can be anchored in the collagen-rich TME and respond to the target protease in situ and generate amplified signals through rolling cycle amplification of tandem fluorescent RNAs. Taking matrix metalloproteinase 2 (MMP-2), a tumor-associated protease, as the model, the feasibility of PNCP was demonstrated for the in situ detection of MMP-2 activity in 3D tumor spheroids. Moreover, in situ in vivo mapping of MMP-2 activity was also achieved in a metastatic solid tumor model with high sensitivity, providing a useful tool for evaluating tumor metastasis and distinguishing highly aggressive forms of tumors.

Development of synthetic modulator enabling long-term propagation and neurogenesis of human embryonic stem cell-derived neural progenitor cells.

Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies employing protein growth factors pose challenges in terms of both reproducibility and cost. In this study, we developed a novel DNA-based modulator to regulate FGFR signaling in NPCs, thereby facilitating the long-term maintenance of stemness and promoting neurogenesis. This DNA-based FGFR-agonist effectively stimulated FGFR1 phosphorylation and activated the downstream ERK signaling pathway in human embryonic stem cell (HESC)-derived NPCs. We replaced the basic fibroblast growth factor (bFGF) in the culture medium with our DNA-based FGFR-agonist to artificially modulate FGFR signaling in NPCs. Utilizing a combination of cell experiments and bioinformatics analyses, we showed that our FGFR-agonist could enhance NPC proliferation, direct migration, and promote neurosphere formation, thus mimicking the functions of bFGF. Notably, transcriptomic analysis indicated that the FGFR-agonist could specifically influence the transcriptional program associated with stemness while maintaining the neuronal differentiation program, closely resembling the effects of bFGF. Furthermore, our culture conditions allowed for the successful propagation of NPCs through over 50 passages while retaining their ability to efficiently differentiate into neurons. Collectively, our approach offers a highly effective method for expanding NPCs, thereby providing new avenues for disease-in-dish research and drug screening aimed at combating neural degeneration.

circ_0000337 Promotes the Progression of Cervical Cancer by miR-155-5p/RAB3B Axis.

Current study aims to investigate the biological function of circular RNA (circRNA, circ_0000337) in cervical cancer (CC). Bioinformatic analyses were used to predict targets for circ_0000337 and miR-155-5p, and analyze the gene expression differences between cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues and normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to assess mRNA and protein expressions of circ_0000337, microRNA-155-5p (miR-155-5p) and member RAS oncogene family (RAB3B), respectively. Following the establishment of gain/loss-of-function models, CCK-8 was performed to evaluate cell proliferation. Bioinformatics analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were used to identify the interaction in circ_0000337, miR-155-5p, and RAB3B. Circ_0000337 and RAB3B were upregulated, while miR-155-5p was downregulated in CC tissues and cell lines. circ_0000337 overexpression promoted cell proliferation, circ_0000337 knock down inhibited cell proliferation by sponging miR-155-5p. RAB3B was a target of miR-155-5p which was positively regulated by circ_0000337. In the collected CC tissues, there was a negative correlation between miR-155-5p and circ_0000337 or RAB3B, and a positive correlation between circ_0000337 and RAB3B. miR-155-5p was positively, while RAB3B was negatively correlated with OS in patients with CC, and they were negatively correlated. In conclusion, circ_0000337 upregulates RAB3B by sponging miR-155-5p to promote CC cell proliferation.

An Extracellular miRNA-Responsive Artificial Receptor via Dynamic DNA Nano-assembly for Biomarker-Driven Therapy.

MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease-associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA-responsive chimeric DNA receptor (miRNA-CDR) capable of biomarker-driven therapy. By grafting a miRNA-responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA-CDR can sense extracellular miRNA levels and autonomously induce dimerization-mediated receptor activation via the complementary-mediated strand displacement reaction-induced dynamic DNA assembly. The sequence programmability of miRNA-CDR allows it to sense and respond to a user-defined miRNA with tunable sensitivity. Moreover, the miRNA-CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug-induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA-CDR in rewiring the recognition of the DILI-elevated miR-122 to promote MET signaling of hepatocytes for biomarker-driven in situ repair and liver function restoration. Our synthetic miRNA-CDR platform provides a novel molecular device enabling biomarker-driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine.

Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 µg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 µg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

Advances in Designer DNA Nanorobots Enabling Programmable Functions.

The advent of DNA nanotechnology has paved the way for the development of nanoscale robotics capable of executing smart and sophisticated tasks in a programmed and automatic manner. The programmability and customizable functionality of designer DNA nanorobots interfacing with biology would offer great potential for basic and applied research in the interdisciplinary fields of chemistry, biology, and medicine. This review aims to summarize the latest progress in designer DNA nanorobotics enabling programmable functions. We first describe the state-of-art engineering principles and the functional modules used in the rational design of a dynamic DNA nanorobot. Subsequently, we summarize the distinct types of DNA nanorobots performing sensing tasks, sensing-and-actuation, or continuous actuation, highlighting the versatility of designer DNA nanorobots in accurate biosensing, targeted drug delivery, and autonomous molecular operations to promote desired cellular behavior. Finally, we discuss the challenges and opportunities in the development of functional DNA nanorobotics for biomedical applications. We envision that significant progress in DNA-enabled nanorobotics with programmable functions will improve precision medicine in the future.

Evaluation of antityrosinase activity and mechanism, antioxidation, and UV filter properties of theaflavin.

Tyrosinase is a key metalloenzyme for the biosynthesis of melanin that plays a critical role in the prevention of skin damage caused by ultraviolet (UV) radiation. However, the overproduction of melanin may cause a variety of skin diseases. Due to the toxicity and inefficiency of existing tyrosinase inhibitors, it is urgent to identify safe and potent alternatives from natural sources. Theaflavin, a single-component extracted from black tea, has been found to possess a variety of pharmacological activities. Herein, the inhibition kinetics of theaflavin on tyrosinase and inhibitory mechanism were determined using spectroscopy, molecular docking, and zebrafish model. The results showed that theaflavin inhibited the diphenolase activity of tyrosinase in a reversible mixed type manner with IC50 of 229.75 µmol/L and hindered the synthesis of melanin in zebrafish. This may be due to the formation of eight hydrogen bonds and hydrophobic effects between theaflavin and tyrosinase according to the results of molecular docking. To study the possible effects on the prevention of free radical-mediated skin cancer and photoaging caused by UV radiation, the antioxidation and UV filter properties of theaflavin were further verified. This study demonstrates that theaflavin is a potential multifunctional compound that can be used in cosmetic and medicinal products.

Preparation and chiral resolution properties of bridged bis(cyclodextrin)s hybrid spheres for high performance liquid chromatography.

Selenium-bridged bis(ß-cyclodextrin)s organic-inorganic hybrid silica material with regular spherical shape as new type of chiral stationary phase was directly synthesized under the one-pot hydrothermal synthesis method, and the chiral stationary phase was further characterized by infrared spectroscopy, scanning electron microscopy, thermogravimetry, and elemental analysis. The results of chiral separation showed that eight chiral compounds including various types of chiral alcohols and flavanone were successfully separated in the reversed-phase separation mode by high performance liquid chromatography, which showed the better chiral resolution effect than that on the C2 position of single ß-cyclodextrin. The mechanism of chiral separation was likely due to multiple interactions such as inclusion, hydrogen bonding, electrostatic interaction, dipole-dipole interaction, and the synergistic effect of two cyclodextrins during the chiral resolution process. The synergy of the two cyclodextrins has great potential for development in chiral resolution.