Enhancing antibody detection sensitivity in lateral flow immunoassays using endospores of Bacillus subtilis as signal amplifiers.

Antibody detection is the critical first step for tracking the spread of many diseases including COVID-19. Lateral flow immunoassay (LFIA) is the most commonly used method for rapid antibody detection because it is easy-to-use and inexpensive. However, LFIA has limited sensitivity when gold nanoparticles (AuNPs) are used as the signals. In this study, the endospores of Bacillus subtilis were used in combination with AuNP in a LFIA to detect antibodies. The endospores serve as a signal amplifier. The detection limit was about 10-8 M for anti-beta galactosidase antibody detection whereas the detection limit of conventional LFIA is about 10-6 M. Furthermore, the proposed methods have no additional user steps compared with the traditional LFIA. This method, therefore, improved the sensitivity 100-fold without compromising any advantages of LFIA. We believe that the proposed method will be useful for detection of antibodies against HIV, Zika virus, SARS-CoV-2, and so on.

AI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes.

Type 2 diabetes (T2D) presents a formidable global health challenge, highlighted by its escalating prevalence, underscoring the critical need for precision health strategies and early detection initiatives. Leveraging artificial intelligence, particularly eXtreme Gradient Boosting (XGBoost), we devise robust risk assessment models for T2D. Drawing upon comprehensive genetic and medical imaging datasets from 68,911 individuals in the Taiwan Biobank, our models integrate Polygenic Risk Scores (PRS), Multi-image Risk Scores (MRS), and demographic variables, such as age, sex, and T2D family history. Here, we show that our model achieves an Area Under the Receiver Operating Curve (AUC) of 0.94, effectively identifying high-risk T2D subgroups. A streamlined model featuring eight key variables also maintains a high AUC of 0.939. This high accuracy for T2D risk assessment promises to catalyze early detection and preventive strategies. Moreover, we introduce an accessible online risk assessment tool for T2D, facilitating broader applicability and dissemination of our findings.

Rapid altitude displacement induce zebrafish appearing acute high altitude illness symptoms.

Rapid ascent to high-altitude areas above 2500 m often leads to acute high altitude illness (AHAI), posing significant health risks. Current models for AHAI research are limited in their ability to accurately simulate the high-altitude environment for drug screening. Addressing this gap, a novel static self-assembled water vacuum transparent chamber was developed to induce AHAI in zebrafish. This study identified 6000 m for 2 h as the optimal condition for AHAI induction in zebrafish. Under these conditions, notable behavioral changes including slow movement, abnormal exploration behavior and static behavior in the Novel tank test. Furthermore, this model demonstrated changes in oxidative stress-related markers included increased levels of malondialdehyde, decreased levels of glutathione, decreased activities of superoxide dismutase and catalase, and increased levels of inflammatory markers IL-6, IL-1ß and TNF-α, and inflammatory cell infiltration and mild edema in the gill tissue, mirroring the clinical pathophysiology observed in AHAI patients. This innovative zebrafish model not only offers a more accurate representation of the high-altitude environment but also provides a high-throughput platform for AHAI drug discovery and pathogenesis research.

Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer.

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment. METHODS: By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG's catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition. RESULTS: Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors. CONCLUSIONS: We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

Global analysis of the adverse effects of micro- and nanoplastics on intestinal health and microbiota of fish.

The wide occurrence of micro- and nanoplastics (MPs/NPs) within aquatic ecosystems has raised increasing concerns regarding their potential effects on aquatic organisms. However, the effects of MPs/NPs on intestinal health and microbiota of fish remain controversial, and there is a lack of comprehensive understanding regarding how the impact of MPs/NPs is influenced by MPs/NPs characteristics and experimental designs. Here, we conducted a global analysis to synthesize the effects of MPs/NPs on 47 variables associated with fish intestinal health and microbiota from 118 studies. We found that MPs/NPs generally exerted obvious adverse effects on intestinal histological structure, permeability, digestive function, immune and oxidative-antioxidative systems. By contrast, MPs/NPs showed slight effects on intestinal microbial variables. Further, we observed that the responses of intestinal variables to MPs/NPs were significantly regulated by MPs/NPs characteristics and experimental designs. For instance, polyvinyl chloride plastics showed higher toxicity to fish gut than polyethylene and polystyrene did. Additionally, larval fish appeared to be more sensitive to MPs/NPs than juvenile fish. Collectively, this study highlights the potential impacts of MPs/NPs on intestinal health and microbiota of fish, and underscores the determinant role of MPs/NPs characteristics and experimental designs in MPs/NPs toxicity.

CARM1 hypermethylates the NuRD chromatin remodeling complex to promote cell cycle gene expression and breast cancer development.

Protein arginine methyltransferase CARM1 has been shown to methylate a large number of non-histone proteins, and play important roles in gene transcriptional activation, cell cycle progress, and tumorigenesis. However, the critical substrates through which CARM1 exerts its functions remain to be fully characterized. Here, we reported that CARM1 directly interacts with the GATAD2A/2B subunit in the nucleosome remodeling and deacetylase (NuRD) complex, expanding the activities of NuRD to include protein arginine methylation. CARM1 and NuRD bind and activate a large cohort of genes with implications in cell cycle control to facilitate the G1 to S phase transition. This gene activation process requires CARM1 to hypermethylate GATAD2A/2B at a cluster of arginines, which is critical for the recruitment of the NuRD complex. The clinical significance of this gene activation mechanism is underscored by the high expression of CARM1 and NuRD in breast cancers, and the fact that knockdown CARM1 and NuRD inhibits cancer cell growth in vitro and tumorigenesis in vivo. Targeting CARM1-mediated GATAD2A/2B methylation with CARM1 specific inhibitors potently inhibit breast cancer cell growth in vitro and tumorigenesis in vivo. These findings reveal a gene activation program that requires arginine methylation established by CARM1 on a key chromatin remodeler, and targeting such methylation might represent a promising therapeutic avenue in the clinic.

Engineered Cell Membrane-Coated Nanoparticles: New Strategies in Glioma Targeted Therapy and Immune Modulation.

Gliomas, the most prevalent primary brain tumors, pose considerable challenges due to their heterogeneity, intricate tumor microenvironment (TME), and blood-brain barrier (BBB), which restrict the effectiveness of traditional treatments like surgery and chemotherapy. This review provides an overview of engineered cell membrane technologies in glioma therapy, with a specific emphasis on targeted drug delivery and modulation of the immune microenvironment. This study investigates the progress in engineered cell membranes, encompassing physical, chemical, and genetic alterations, to improve drug delivery across the BBB and effectively target gliomas. The examination focuses on the interaction of engineered cell membrane-coated nanoparticles (ECM-NPs) with the TME in gliomas, emphasizing their potential to modulate glioma cell behavior and TME to enhance therapeutic efficacy. The review further explores the involvement of ECM-NPs in immunomodulation techniques, highlighting their impact on immune reactions. While facing obstacles related to membrane stability and manufacturing scalability, the review outlines forthcoming research directions focused on enhancing membrane performance. This review underscores the promise of ECM-NPs in surpassing conventional therapeutic constraints, proposing novel approaches for efficacious glioma treatment.

MazF-rolling circle amplification combined MALDI-TOF MS for site-specific detection of N6-methyladenosine RNA.

N6-methyladenosine (m6A) is one of the most abundant chemical modifications in RNA and has vital significance in cellular processes and tumor development. However, the accurate analysis of site-specific m6A modification remains a challenge. In this work, a MazF endoribonuclease activated rolling circle amplification (MazF-RCA) combined MALDI-TOF MS assay is developed for the detection of site-specific m6A-RNA. MazF endoribonuclease can specifically cleave the ACA motif, leaving methylated (m6A)CA motif intact. The intact methylated RNA can then be amplified through rolling circle amplification, and the generated reporter oligonucleotides are detected by MALDI-TOF MS. The assay exhibits good quantification ability, presenting a wide linear range (100 fM to 10 nM) with the limit-of-detection lower than 100 fM. Additionally, the assay can accurately detect methylated RNA in the presence of large amount of non-methylated RNA with a relative abundance of methylated RNA down to 0.5%. The developed assay was further applied to detect m6A-RNA spiked in MCF-7 cell RNA extracts, with the recovery rates in the range of 90.64-106.93%. The present assay provides a novel platform for the analysis of site-specific m6A-RNA at high specificity and sensitivity, which can promote the study of RNA methylation in clinical and biomedical research.

Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients.

Objective: Olanzapine has already been used to treat schizophrenia patients; however, the initial dosage recommendation when multiple drugs are used in combination, remains unclear. The purpose of this study was to explore the drug-drug interaction (DDI) of multiple drugs combined with olanzapine and to recommend the optimal administration of olanzapine in schizophrenia patients. Methods: In this study, we obtained olanzapine concentrations from therapeutic drug monitoring (TDM) database. In addition, related medical information, such as physiological, biochemical indexes, and concomitant drugs was acquired using medical log. Sixty-five schizophrenia patients were enrollmented for analysis using population pharmacokinetic model by means of nonlinear mixed effect (NONMEM). Results: Weight and combined use of aripiprazole significantly affected olanzapine clearance. Without aripiprazole, for once-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-70, and 70-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.6, 0.5 mg/kg/day were recommended for 40-60, and 60-100 kg schizophrenia patients, respectively. With aripiprazole, for once-daily olanzapine administration dosages, 0.4, 0.3 mg/kg/day were recommended for 40-53, and 53-100 kg schizophrenia patients, respectively; for twice-daily olanzapine administration dosages, 0.4 mg/kg/day was recommended for 40-100 kg schizophrenia patients, respectively. Conclusion: Aripiprazole significantly affected olanzapine clearance, and when schizophrenia patients use aripiprazole, the olanzapine dosages need adjust. Meanwhile, we firstly recommended the optimal initial dosages of olanzapine in schizophrenia patients.

Biochemical and structural characterization of chlorhexidine as an ATP-assisted inhibitor against type 1 methionyl-tRNA synthetase from Gram-positive bacteria.

Methionyl-tRNA synthetase (MetRS) catalyzes the attachment of l-methionine (l-Met) to tRNAMet to generate methionyl-tRNAMet, an essential substrate for protein translation within ribosome. Owing to its indispensable biological function and the structural discrepancies with human counterpart, bacterial MetRS is considered an ideal target for developing antibacterials. Herein, chlorhexidine (CHX) was identified as a potent binder of Staphylococcus aureus MetRS (SaMetRS) through an ATP-aided affinity screening. The co-crystal structure showed that CHX simultaneously occupies the enlarged l-Met pocket (EMP) and the auxiliary pocket (AP) of SaMetRS with its two chlorophenyl groups, while its central hexyl linker swings upwards to interact with some conserved hydrophobic residues. ATP adopts alternative conformations in the active site cavity, and forms ionic bonds and water-mediated hydrogen bonds with CHX. Consistent with this synergistic binding mode, ATP concentration-dependently enhanced the binding affinity of CHX to SaMetRS from 10.2 µM (no ATP) to 0.45 µM (1 mM ATP). While it selectively inhibited two representative type 1 MetRSs from S. aureus and Enterococcus faecalis, CHX did not show significant interactions with three tested type 2 MetRSs, including human cytoplasmic MetRS, in the enzyme inhibition and biophysical binding assays, probably due to the conformational differences between two types of MetRSs at their EMP and AP. Our findings on CHX may inspire the design of MetRS-directed antimicrobials in future.

Behavioral Studies of Zebrafish Reveal a New Perspective on the Reproductive Toxicity of Micro- and Nanoplastics.

The escalating prevalence of microplastics and nanoplastics in aquatic environments is a major challenge affecting the behavior and reproductive health of aquatic organisms while posing potential risks to human health and ecosystems. This review focuses on the neurobehavioral changes and reproductive toxicity of MNPs in zebrafish and their relationships. At the same time, the neurobehavioral changes caused by MNPs were studied, and the synergistic effects of the interaction of these pollutants with other environmental contaminants were explored. In addition, zebrafish, as a model organism, provide valuable insights into the subtle but important effects of MNPs on reproductive behavior, which is critical for understanding reproductive success, suggesting that behavioral changes can serve as an early biomarker of reproductive toxicity. In addition, based on classical endocrine disruptor models and behavioral research methods, the current status of the research on the reproductive toxicity of MNPs in zebrafish was reviewed, which further indicated that the behavioral parameters of zebrafish can be used as an effective and rapid tool to evaluate the reproductive toxicity of MNPs. However, behavioral methods for rapidly assessing the toxicity of MNPs are still an area of exploration. To address limitations and challenges in the current scope of research, this review outlines future research directions with the aim of improving our understanding of the environmental and health impacts of MNPs. This work aims to inform targeted environmental policies and advance public health strategies to address the growing challenge of MNPs pollution.

Interactive boxing-cycling on frailty and activity limitations in frail and prefrail older adults: A randomized controlled trial.

BACKGROUND: Frailty is common among older adults, often associated with activity limitations during physical and walking tasks. The interactive boxing-cycling combination has the potential to be an innovative and efficient training method, and our hypothesis was that interactive boxing-cycling would be superior to stationary cycling in improving frailty and activity limitations in frail and prefrail older adults. OBJECTIVE: To examine the impact of interactive boxing-cycling on frailty and activity limitations in frail and prefrail older adults compared to stationary cycling. MATERIALS AND METHODS: A single-blinded randomized controlled trial. Forty-five participants who met at least one frailty phenotype criteria were randomly assigned to receive either interactive boxing-cycling (n = 23) or stationary-cycling (n = 22) for 36 sessions over 12 weeks. The interactive boxing-cycling was performed on a cycle boxer bike with an interactive boxing panel fixed in front of the bike. The primary outcomes were frailty status, including score and phenotypes. Secondary outcomes included activity limitations during physical and walking tasks. The pre- and post-intervention data of both groups were analyzed using a repeated measures two-way ANOVA. RESULTS: Both types of cycling significantly improved frailty scores (p<0.001). Interactive boxing-cycling was more effective than stationary cycling in reversing the frailty phenotype of muscle weakness (p = 0.03, odds ratio 9.19) and demonstrated greater improvements than stationary cycling in arm curl (p = 0.002, η2=0.20), functional reach (p = 0.001, η2=0.22), and grip strength (p = 0.02, η2=0.12) tests. Additionally, interactive boxing-cycling exhibited a greater effect on gait speed (p = 0.02, η2=0.13) and gait variability (p = 0.01, η2=0.14) during dual-task walking. CONCLUSION: In frail and prefrail older adults, interactive boxing-cycling effectively improves frailty but is not superior to stationary cycling. However, it is more effective at improving certain activity limitations. REGISTRATION NUMBER: TCTR20220328001.

Magnetically controlled quantum thermal devices via three nearest-neighbor coupled spin-1/2 systems.

A quantum thermal device based on three nearest-neighbor coupled spin-1/2 systems controlled by the magnetic field is proposed. We systematically study the steady-state thermal behaviors of the system. When the two terminals of our system are in contact with two thermal reservoirs, respectively, the system behaves as a perfect thermal modulator that can manipulate heat current from zero to specific values by adjusting magnetic-field direction over different parameter ranges, since the longitudinal magnetic field can completely block the heat transport. Significantly, the modulator can also be achieved when a third thermal reservoir perturbs the middle spin. We also find that the transverse field can induce the system to separate into two subspaces in which neither steady-state heat current vanishes, thus providing an extra level of control over the heat current through the manipulation of the initial state. In addition, the performance of this device as a transistor can be enhanced by controlling the magnetic field, achieving versatile amplification behaviors, in particular substantial amplification factors.

Quantum heat valve and diode of strongly coupled defects in amorphous material.

The mechanical strain can control the frequency of two-level atoms in amorphous material. In this work, we would like to employ two coupled two-level atoms to manipulate the magnitude and direction of heat transport by controlling mechanical strain to realize the function of a thermal switch and valve. It is found that a high-performance heat diode can be realized in the wide piezo voltage range at different temperatures. We also discuss the dependence of the rectification factor on temperatures and couplings of heat reservoirs. We find that the higher temperature differences correspond to the larger rectification effect. The asymmetry system-reservoir coupling strength can enhance the magnitude of heat transfer, and the impact of asymmetric and symmetric coupling strength on the performance of the heat diode is complementary. It may provide an efficient way to modulate and control heat transport's magnitude and flow preference. This work may give insight into designing and tuning quantum heat machines.

Quaternary ammonium cations conjugated 5,15-diaryltetranaphtho[2,3]porphyrins as photosensitizers for photodynamic therapy.

In quest for new photosensitizers (PSs) with remarkable antitumor photodynamic efficacy, a series of fifteen quaternary ammonium (QA) cations conjugated 5,15-diaryltetranaphtho[2,3]porphyrins (Ar2TNPs) was synthesized and evaluated in vitro and in vivo to understand how variations in the length of the alkoxy group and the kind of QA cations on meso-phenyl influence the photodynamic antitumor activity. All final compounds (I1-5, II1-5, and III1-5) exhibited robust absorption at 729 nm with significant bathochromic shift and high molar extinction coefficients (1.16 × 105-1.41 × 105 M-1 cm-1), as well as other absorptions at 445, 475, 651, and 714 nm for tumors and other diseases of diverse sizes and depths. Upon exposure to 474 nm light, they displayed intense fluorescence emission with fluorescence quantum yields ranging from 0.32 to 0.43. The ability to generate reactive oxygen species (ROS) was also quantified, attaining a maximum rate of up to 0.0961 s-1. The IC50 values of all the compounds regarding phototoxicity and dark toxicity were determined using KYSE-150 cells, and the phototoxicity indices were calculated. Among these compounds, III1 demonstrated the highest phototoxic index with minimal dark toxicity, and suppressed successfully the growth of esophageal carcinoma xenograft with favorable tolerance in vivo. Furthermore, the histological results showed III1-mediated PDT had a significant cytotoxic effect on the tumor. These outcomes underscore the potential of III1 as a highly effective antitumor photosensitizer drug in photodynamic therapy (PDT).

Association between the levels of urinary cell cycle biomarkers and non-recovery of renal function among critically ill geriatric patients with acute kidney injury.

The lack of early renal function recovery among geriatric patients with acute kidney injury (AKI) in the intensive care unit (ICU) is a commonly observed and acknowledged poor prognostic factor, especially for older adults. However, no reliable prognostic biomarker is available for identifying individuals at risk of renal non-recovery or mortality in older adults. In this prospective observational cohort study, we enrolled critically ill older adults (aged ≥ 60 years) with AKI from the ICU and followed their disease progression. The primary endpoint was renal non-recovery within seven days of follow-up, while the secondary endpoint was the determinants of 30-day mortality after AKI. We assessed the predictive accuracy using receiver operating characteristic curves and performed between-group comparisons using the log-rank test. Among 209 older adults, 117 (56.0%) experienced renal recovery. Multiple regression analysis revealed that urine levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) multiplied by insulin-like growth factor-binding protein 7 (IGFBP7) ([TIMP-2]*[IGFBP7]), AKI stages 2-3, and the Acute Physiology and Chronic Health Evaluation (APACHE II) score were independently associated with renal non-recovery. The regression model incorporating [TIMP-2]*[IGFBP7] demonstrated a fair predictive value (AUC 0.774, p < 0.001), with the optimal threshold set at 0.81 (ng/mL)2/1000. When [TIMP-2]*[IGFBP7] was combined with AKI severity and the APACHE score, the AUC increased to 0.851. In conclusion, urine [TIMP-2]*[IGFBP7] is a reliable biomarker associated with renal non-recovery in critically ill older adults, and its predictive efficacy can be further enhanced when combined with AKI severity and the APACHE score.

ChemMORT: an automatic ADMET optimization platform using deep learning and multi-objective particle swarm optimization.

Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.

Optimizing the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels.

Background: The appropriate initial dosage of tacrolimus is undefined in Chinese pediatric lung transplant patients with normal hematocrit values. The purpose of this study is to optimize the initial dose of tacrolimus in Chinese children who are undergoing lung transplantation and have normal hematocrit levels. Methods: The present study is based on a published population pharmacokinetic model of tacrolimus in lung transplant patients and uses the Monte Carlo simulation to optimize the initial tacrolimus dosage in Chinese children with lung transplantation within normal hematocrit levels. Results: Within normal hematocrit levels, for children with lung transplantation who do not carry the CYP3A5*1 gene and have no coadministration with voriconazole, it is recommended to administer tacrolimus at a dosage of 0.02 mg/kg/day, divided into two doses, for children weighing 10-32 kg, and a dosage of 0.03 mg/kg/day, also divided into two doses, for children weighing 32-40 kg. For children with lung transplantation who carry the CYP3A5*1 gene and have no coadministration with voriconazole, tacrolimus dosages of 0.02, 0.03, and 0.04 mg/kg/day split into two doses are recommended for children weighing 10-15, 15-32, and 32-40 kg, respectively. For children with lung transplantation who do not carry the CYP3A5*1 gene and have coadministration with voriconazole, tacrolimus dosages of 0.01 and 0.02 mg/kg/day split into two doses are recommended for children weighing 10-17 and 17-40 kg, respectively. For children with lung transplantation who carry the CYP3A5*1 gene and have coadministration with voriconazole, a tacrolimus dosage of 0.02 mg/kg/day split into two doses is recommended for children weighing 10-40 kg. Conclusions: It is the first time to optimize the initial dosage of tacrolimus in Chinese children undergoing lung transplantation within normal hematocrit.

Andrographolide sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the EGFR/AKT and PDGFRß/AKT signaling pathways.

BACKGROUND: Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism. PURPOSE: This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT. METHODS: The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRß were used to evaluate the role of andrographolide on PDGFRß. The western blotting was used to investigate Wnt/ß-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo. RESULTS: Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRß and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/ß-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo. CONCLUSIONS: Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRß /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.