Unveiling the crucial role of ferroptosis in host resistance to streptococcus agalactiae infection.

IL-1ß represents an important inflammatory factor involved in the host response against GBS infection. Prior research has suggested a potential involvement of IL-1ß in the process of ferroptosis. However, the relationship between IL-1ß and ferroptosis in the context of anti-GBS infection remains uncertain. This research demonstrates that the occurrence of ferroptosis is essential for the host's defense against GBS infection in a mouse model of abdominal infection, with peritoneal macrophages identified as the primary cells undergoing ferroptosis. Further research indicates that IL-1ß induces lipid oxidation in macrophages through the upregulation of pathways related to lipid oxidation. Concurrently, IL-1ß is not only involved in the initiation of ferroptosis in macrophages, but its production is intricately linked to the onset of ferroptosis. Ultimately, we posit that ferroptosis acts as a crucial initiating factor in the host response to GBS infection, with IL-1ß playing a significant role in the resistance to infection by serving as a key inducer of ferroptosis.

Comprehensive transcriptome and scRNA-seq analyses uncover the expression and underlying mechanism of SYNJ2 in papillary thyroid carcinoma.

Synaptojanin 2 (SYNJ2) has crucial role in various tumors, but its role in papillary thyroid carcinoma (PTC) remains unexplored. This study first detected SYNJ2 protein expression in PTC using immunohistochemistry method and further assessed SYNJ2 mRNA expression through mRNA chip and RNA sequencing data and its association with clinical characteristics. Additionally, KEGG, GSVA, and GSEA analyses were conducted to investigate potential biological functions, while single-cell RNA sequencing data were used to explore SYNJ2's underlying mechanisms in PTC. Meanwhile, immune infiltration status in different SYNJ2 expression groups were analyzed. Besides, we investigated the immune checkpoint gene expression and implemented drug sensitivity analysis. Results indicated that SYNJ2 is highly expressed in PTC (SMD = 0.66 [95% CI: 0.17-1.15]) and could distinguish between PTC and non-PTC tissues (AUC = 0.74 [0.70-0.78]). Furthermore, the study identified 134 intersecting genes of DEGs and CEGs, mainly enriched in the angiogenesis and epithelial-mesenchymal transition (EMT) pathways. Subsequent analysis showed the above pathways were activated in PTC epithelial cells. PTC patients with high SYNJ2 expression showed higher sensitivity to the six common drugs. Summarily, SYNJ2 may promote PTC progression through angiogenesis and EMT pathways. High SYNJ2 expression is associated with better response to immunotherapy and chemotherapy.

Automated Quantification of HER2 Amplification Levels Using Deep Learning.

HER2 assessment is necessary for patient selection in anti-HER2 targeted treatment. However, manual assessment of HER2 amplification is time-costly, labor-intensive, highly subjective and error-prone. Challenges in HER2 analysis in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images include unclear and blurry cell boundaries, large variations in cell shapes and signals, overlapping and clustered cells and sparse label issues with manual annotations only on cells with high confidences, producing subjective assessment scores according to the individual choices on cell selection. To address the above-mentioned issues, we have developed a soft-sampling cascade deep learning model and a signal detection model in quantifying CEN17 and HER2 of cells to assist assessment of HER2 amplification status for patient selection of HER2 targeting therapy to breast cancer. In evaluation with two different kinds of clinical datasets, including a FISH data set and a DISH data set, the proposed method achieves high accuracy, recall and F1-score for both datasets in instance segmentation of HER2 related cells that must contain both CEN17 and HER2 signals. Moreover, the proposed method is demonstrated to significantly outperform seven state of the art recently published deep learning methods, including contour proposal network (CPN), soft label-based FCN (SL-FCN), modified fully convolutional network (M-FCN), bilayer convolutional network (BCNet), SOLOv2, Cascade R-CNN and DeepLabv3+ with three different backbones (p ≤ 0.01). Clinically, anti-HER2 therapy can also be applied to gastric cancer patients. We applied the developed model to assist in HER2 DISH amplification assessment for gastric cancer patients, and it also showed promising predictive results (accuracy 97.67 ±1.46%, precision 96.15 ±5.82%, respectively).

Experimental realization of multiple frequency photoassociation in an optical dipole trap.

The generation of cold molecules is an important topic in the field of cold atoms and molecules and has received relevant advanced research attention in ultracold chemistry, quantum computation, and quantum metrology. With a high atomic phase space density, optical dipole traps have been widely used to prepare, trap, and study cold molecules. In this work, Rb2 molecules were photoassociated in a magneto-optical trap to obtain a precise rovibrational spectrum, which provided accurate numerical references for the realization of multiple frequency photoassociation. By meeting the harsh requirements of photoassociation in optical dipole traps, the cold molecule photoassociation process was well explored, and different photoassociation resonances were simultaneously addressed in a single optical dipole trap. This method can be universally extended to simultaneously photoassociate cold molecules with different internal states or atomic species in a single optical dipole trap, thus advancing generous cold molecule studies such as cold molecule collision dynamics.

Ethnic Differences in the Safety and Efficacy of Tenecteplase Versus Alteplase for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Tenecteplase is a thrombolytic agent with pharmacological advantages over alteplase and has been shown to be noninferior to alteplase for acute ischemic stroke in randomized trials. However, evidence pertaining to the safety and efficacy of tenecteplase in patients from different ethnic groups is lacking. The aim of this systematic review and metaanalysis was to investigate ethnicity-specific differences in the safety and efficacy of tenecteplase versus alteplase in patients with acute ischemic stroke. METHODS: Following an International Prospective Register of Systematic Reviews (PROSPERO)- registered protocol (CRD42023475038), three authors conducted a systematic review of the PubMed/MEDLINE, Embase, Cochrane Library, and CINAHL databases for articles comparing the use of tenecteplase with any thrombolytic agent in patients with acute ischemic stroke up to November 20, 2023. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Two independent authors extracted data onto a standardized data collection sheet. A pairwise meta-analysis was conducted in risk ratios (RR). RESULTS: From 34 studies (59,601 participants), the rate of complete recanalization was significantly higher (P<0.01) in Asian (RR: 1.91, 95% confidence interval [CI]: 1.30 to 2.80) versus Caucasian patients (RR: 0.99, 95% CI: 0.87 to 1.14). However, Asian patients (RR: 1.18, 95% CI: 0.87 to 1.62) had significantly higher (P=0.01) rates of mortality compared with Caucasian patients (RR: 1.10, 95% CI: 1.00 to 1.22). Caucasian patients were also more likely to attain a modified Rankin Scale (mRS) score of 0 to 2 at follow-up (RR: 1.14, 95% CI, 1.10 to 1.19) compared with Asian (RR: 1.00, 95% CI, 0.95 to 1.05) patients. There was no significant difference in the rate of symptomatic intracranial hemorrhage (P=0.20) and any intracranial hemorrhage (P=0.83) between Asian and Caucasian patients. CONCLUSION: Tenecteplase was associated with significantly higher rates of complete recanalization in Asian patients compared with Caucasian patients. However, tenecteplase was associated with higher rates of mortality and lower rates of mRS 0 to 2 in Asian patients compared with Caucasian patients. It may be beneficial to study the variations in response to tenecteplase among patients of different ethnic groups in large prospective cohort studies.

Dual inhibition of topoisomerase II and microtubule of podophyllotoxin derivative 5p overcomes cancer multidrug resistance.

Compound 5p is a 4ß-N-substituted podophyllotoxin derivative, which exhibited potent activity toward drug-resistant K562/A02 cells and decreased MDR-1 mRNA expression. Here, we further investigated its detail mechanism and tested its antitumor activity. 5p exerted catalytic inhibition of topoisomerase IIα, and didn't show the inhibitor of topoisomerase I. 5p exhibited the inhibitory effect on microtubule polymerization. 5p showed potent anti-proliferation against breast cancer, oral squamous carcinoma, and their drug-resistant cell lines, with resistance index of 0.61 and 0.86, respectively. 5p downregulated the expression levels of P-gp in KBV200 cells and BCRP in MCF7/ADR cells in dose-dependent manner. Moreover, 5p induced KB and KBV200 cells arrest at G2/M phase by up-regulating the expression of γ-H2AX, p-Histone H3 and cyclin B1. 5p induced apoptosis and pyroptosis by increased the expression levels of cleaved-PARP, cleaved-caspase3, N-GSDME as well as LDH release in KB and KBV200 cells. In addition, 5p efficiently impaired tumor growth in KB and KBV200 xenograft mice. Conclusively, this work elucidated the dual inhibitor of topoisomerase II and microtubule of 5p and its mechanism of overcoming the multidrug resistance, indicating that 5p exerts the antitumor potentiality.

Mechanical properties of aeolian sand cemented via microbially induced calcite precipitation (MICP).

The cementation of desert aeolian sand is a key method to control land desertification and dust storms, so an economical, green and durable process to reach the binding between sand grains needs to be searched. The method based on the microbially induced calcite precipitation (MICP) appeared in recent years as a promising process that proved its efficiency. The feasibility of the MICP technique to treat aeolian sand composed by low clay content, fine particles, low water content and characterized by weak permeability was demonstrated in the present paper. The effects of initial dry density, cementation number and curing time on the permeability and strength of MICP-treated aeolian sand were investigated using permeability tests and unconfined compressive strength (UCS) tests. The microstructure of aeolian sand was observed by scanning electron microscopy (SEM) tests and X-ray diffraction (XRD), aiming to reveal the solidification principle of MICP. The tests result indicated that when the initial dry density and the cementation number rose, the hydraulic conductivity of aeolian sand decreased while the mechanical strength given by UCS values improved. When the initial dry density was 1.65 g/cm3, the curing time was 3 h and the cementation number reached 20, the hydraulic conductivity and UCS reached 0.00151 cm/s and 1050.30 kPa, respectively. With increasing curing time, the hydraulic conductivity first decreased, followed by an increase, while the UCS exhibited an up and then a downtrend. Furthermore, the correlation between UCS values and the CaCO3 content reached a high R2 value equal to 0.912, which confirmed that the cementation occurred in sandy material and governed the soil strengthening. Indeed, the calcium carbonate crystals observed by SEM and XRD enhanced the friction between particles when they wrapped around the sand grains surface, while carbonates reduced the soil permeability when filling the pores and sticking the sand particles together. Finally, the theoretical and scientific knowledge brought by the present study should help in managing sand in desert areas.

Initial dosage optimization of olanzapine in patients with bipolar disorder based on model-informed precision dosing: a study from the real world.

Objectives: Olanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study. Methods: Thirty-nine patients with BPD from the real-world study were collected to construct the MIPD model. Results: Weight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients. Conclusion: This study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients.

A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Synthesis and evaluation of 5,15-diaryltetrabenzoporphyrins as photosensitizers for photo-diagnosis and photodynamic activity of tumors.

Photodynamic therapy (PDT) is a well-established treatment modality, typically conducted with single-wavelength irradiation, which may not always be optimal for varying tumor locations and sizes. To address this, photosensitizers with absorption wavelengths ranging from 550 to 760 nm are being explored. Herein, a series of 5,15-diaryltetrabenzoporphyrins (Ar2TBPs) were synthesized. All compounds displayed obvious absorption at 550-700 nm (especially at ∼668 nm), intense fluorescence, efficient generation of singlet oxygen and good photodynamic antitumor effects. Notably, compound I3 (5,15-bis[(4-carboxymethoxy)phenyl]tetrabenzoporphyrin) showed excellent cytotoxicity against Eca-109 cell line upon red light irradiation, with an IC50 value of 0.45 µM, and phototherapeutic index of 25.8. Flow cytometry revealed that I3 could induce distinct cell apoptosis. In vivo studies revealed that compound I3 selectively accumulated at tumor site and exhibited outstanding PDT effect with antitumor activity under single-time administration and light irradiation, and revealed more efficiency than the clinical photosensitizer Verteporfin. These findings underscore the considerable promise of I3 as a robust theranostic agent, offering capabilities in real-time fluorescence imaging and serving as a potent photosensitizer for personalized and precise photodynamic therapy of tumors.

NeuroQuantify - An image analysis software for detection and quantification of neuron cells and neurite lengths using deep learning.

BACKGROUND: The segmentation of cells and neurites in microscopy images of neuronal networks provides valuable quantitative information about neuron growth and neuronal differentiation, including the number of cells, neurites, neurite length and neurite orientation. This information is essential for assessing the development of neuronal networks in response to extracellular stimuli, which is useful for studying neuronal structures, for example, the study of neurodegenerative diseases and pharmaceuticals. NEW METHOD: We have developed NeuroQuantify, an open-source software that uses deep learning to efficiently and quickly segment cells and neurites in phase contrast microscopy images. RESULTS: NeuroQuantify offers several key features: (i) automatic detection of cells and neurites; (ii) post-processing of the images for the quantitative neurite length measurement based on segmentation of phase contrast microscopy images, and (iii) identification of neurite orientations. COMPARISON WITH EXISTING METHODS: NeuroQuantify overcomes some of the limitations of existing methods in the automatic and accurate analysis of neuronal structures. It has been developed for phase contrast images rather than fluorescence images. In addition to typical functionality of cell counting, NeuroQuantify also detects and counts neurites, measures the neurite lengths, and produces the neurite orientation distribution. CONCLUSIONS: We offer a valuable tool to assess network development rapidly and effectively. The user-friendly NeuroQuantify software can be installed and freely downloaded from GitHub at https://github.com/StanleyZ0528/neural-image-segmentation.

Study on the Efficacy and Safety of the Huangqi Guizhi Wuwu Decoction in the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: Meta-Analysis of 32 Randomized Controlled Trials.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) still lacks efficient therapeutic drugs. This study aimed to systematically evaluate the effects of Huangqi Guizhi Wuwu Decoction (HGWD) alone or combined with positive drugs on CIPN prevention and treatment. Methods: The PubMed, Embase, Web of Science, Cochrane, China National Knowledge Infrastructure (CNKI), Wan Fang Data, China Science and Technology Journal (VIP) and Chinese Biomedical (CBM) databases were searched for randomized controlled trials (RCTs) of HGWD for CIPN prevention and treatment. The search time ranged from database establishment to October 17, 2023. The Cochrane risk-of-bias assessment tool was used for quality assessment, Review Manager 5.3 and STATA 12.0 were used for meta-analysis, and GRADEprofiler was used for evidence level assessment. Results: A total of 32 RCTs involving 1987 patients were included. The meta-analysis results revealed the following: 1. In terms of the total CIPN incidence, that in the HGWD group was lower than that in the blank control group. The incidence in both the HGWD and HGWD+positive drug groups was lower than that in the monotherapy-positive drug group. 2. In terms of the incidence of severe CIPN, that in the HGWD group was lower than that in the blank control and positive drug groups. There was no statistically significant difference between the HGWD+positive drug and positive drug groups. Sensitivity analysis revealed that the results of severe incidence in the HGWD group was lower than that in the positive drug group were unstable 3. HGWD did not increase the number of chemotherapy-related adverse events. Conclusion: HGWD can safely and effectively prevent CIPN, reduce symptoms, improve quality of life and reduce the impact of chemotherapy drugs on sensory nerve conduction. However, more high-quality RCTs are needed to compare the efficacy of HGWD with that of positive control drugs in preventing severe CIPN.

Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

OBJECTIVE: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. METHODS: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. RESULTS: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. CONCLUSION: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

Impacts of Environmental Concentrations of Nanoplastics on Zebrafish Neurobehavior and Reproductive Toxicity.

Nanoplastics, as emerging environmental pollutants, can transport contaminants across marine environments, polluting pristine ecosystems and being ingested by marine organisms. This transfer poses a severe threat to global aquatic ecosystems and potentially impacts human health through the food chain. Neurobehavioral and reproductive toxicity are critical areas of concern because they directly affect the survival, health, and population dynamics of aquatic species, which can have cascading effects on the entire ecosystem. Using zebrafish as a model organism, we investigated the toxic effects of environmental concentrations of polystyrene nanoplastics (PS-NPs). Behavioral assessments, including the novel tank test and open field test, demonstrated significant neurobehavioral changes, indicating increased anxiety and depressive behaviors. A pathological analysis of brain and gonadal tissues, along with evaluations of neurobehavioral and reproductive toxicity biomarkers, revealed that exposure to PS-NPs leads to brain tissue lesions, inflammatory responses, oxidative stress activation, hormone level disruptions, and gonadal damage. Real-time quantitative PCR studies of reproductive gene expression further showed that PS-NPs disrupt the endocrine regulation pathways of the brain-pituitary-gonadal (BPG) axis, causing reproductive toxicity with sex-specific differences. These findings provide crucial insights into the impacts of nanoplastics on aquatic organisms and their ecological risks, offering theoretical support for future environmental protection and pollutant management efforts.

Effects of Sex Differences and Combined Use of Clozapine on Initial Dosage Optimization of Valproic Acid in Patients with Bipolar Disorder.

BACKGROUND: Due to the narrow therapeutic window and large pharmacokinetic variation of valproic acid (VPA), it is difficult to make an optimal dosage regimen. The present study aims to optimize the initial dosage of VPA in patients with bipolar disorder. METHODS: A total of 126 patients with bipolar disorder treated by VPA were included to construct the VPA population pharmacokinetic model retrospectively. Sex differences and combined use of clozapine were found to significantly affect VPA clearance in patients with bipolar disorder. The initial dosage of VPA was further optimized in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. RESULTS: The CL/F and V/F of VPA in patients with bipolar disorder were 11.3 L/h and 36.4 L, respectively. It was found that sex differences and combined use of clozapine significantly affected VPA clearance in patients with bipolar disorder. At the same weight, the VPA clearance rates were 1.134, 1, 1.276884, and 1.126 in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study further optimized the initial dosage of VPA in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. CONCLUSION: This study is the first to investigate the initial dosage optimization of VPA in patients with bipolar disorder based on sex differences and the combined use of clozapine. Male patients had higher clearance, and the recommended initial dose decreased with increasing weight, providing a reference for the precision drug use of VPA in clinical patients with bipolar disorder.

Enhanced biosafety, anticancer and antibacterial photodynamic activities using silver-pyropheophorbide-a nanoconjugates.

Aim: A study of the enhancement of photodynamic activities of pyropheophorbide-a using PG-Ag-PPa nanoconjugates.Materials & methods: The nanoconjugates were formulated from silver nanoparticles and PPa via amide linkage, then characterized, and their photodynamic activities were examined.Results: The nanoconjugates displayed a higher rate of reactive oxygen species generation, commendable cellular uptake by Eca-109 cancer cells, higher photocytotoxicity toward the cancer cells and better bio-safety. They revealed strong antibacterial activity against Escherichia coli following internal reactive oxygen species generation and membrane disintegration. The in vivo anticancer studies confirmed higher cytotoxicity of the nanoconjugates toward cancer cells and better safety than PPa.Conclusion: Therefore, PG-Ag-PPa nanoconjugates could be considered potential nano photosensitizers for photodynamic therapy of tumors and bacterial infection with good bio-safety.

[Box: see text].

Comparative structure and evolution of the organellar genomes of Padina usoehtunii (Dictyotales) with the brown algal crown radiation clade.

BACKGROUND: Organellar genomes have become increasingly essential for studying genetic diversity, phylogenetics, and evolutionary histories of seaweeds. The order Dictyotales (Dictyotophycidae), a highly diverse lineage within the Phaeophyceae, is long-term characterized by a scarcity of organellar genome datasets compared to orders of the brown algal crown radiation (Fucophycidae). RESULTS: We sequenced the organellar genomes of Padina usoehtunii, a representative of the order Dictyotales, to investigate the structural and evolutionary differences by comparing to five other major brown algal orders. Our results confirmed previously reported findings that the rate of structural rearrangements in chloroplast genomes is higher than that in mitochondria, whereas mitochondrial sequences exhibited a higher substitution rate compared to chloroplasts. Such evolutionary patterns contrast with land plants and green algae. The expansion and contraction of the inverted repeat (IR) region in the chloroplast correlated with the changes in the number of boundary genes. Specifically, the size of the IR region influenced the position of the boundary gene rpl21, with complete rpl21 genes found within the IR region in Dictyotales, Sphacelariales and Ectocarpales, while the rpl21 genes in Desmarestiales, Fucales, and Laminariales span both the IR and short single copy (SSC) regions. The absence of the rbcR gene in the Dictyotales may indicate an endosymbiotic transfer from the chloroplast to the nuclear genome. Inversion of the SSC region occurred at least twice in brown algae. Once in a lineage only represented by the Ectocarpales in the present study and once in a lineage only represented by the Fucales. Photosystem genes in the chloroplasts experienced the strongest signature of purifying selection, while ribosomal protein genes in both chloroplasts and mitochondria underwent a potential weak purifying selection. CONCLUSIONS: Variations in chloroplast genome structure among different brown algal orders are evolutionarily linked to their phylogenetic positions in the Phaeophyceae tree. Chloroplast genomes harbor more structural rearrangements than the mitochondria, despite mitochondrial genes exhibiting faster mutation rates. The position and the change in the number of boundary genes likely shaped the IR regions in the chloroplast, and the produced structural variability is important mechanistically to create gene diversity in brown algal chloroplast.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Dietary fiber induces a fat preference associated with the gut microbiota.

Eating behavior is essential to human health. However, whether future eating behavior is subjected to the conditioning of preceding dietary composition is unknown. This study aimed to investigate the effect of dietary fiber consumption on subsequent nutrient-specific food preferences between palatable high-fat and high-sugar diets and explore its correlation with the gut microbiota. C57BL/6NJcl male mice were subjected to a 2-week dietary intervention and fed either a control (n = 6) or inulin (n = 6) diet. Afterward, all mice were subjected to a 3-day eating behavioral test to self-select from the simultaneously presented high-fat and high-sugar diets. The test diet feed intakes were recorded, and the mice's fecal samples were analyzed to evaluate the gut microbiota composition. The inulin-conditioned mice exhibited a preference for the high-fat diet over the high-sugar diet, associated with distinct gut microbiota composition profiles between the inulin-conditioned and control mice. The gut microbiota Oscillospiraceae sp., Bacteroides acidifaciens, and Clostridiales sp. positively correlated with a preference for fat. Further studies with fecal microbiota transplantation and eating behavior-related neurotransmitter analyses are warranted to establish the causal role of gut microbiota on host food preferences. Food preferences induced by dietary intervention are a novel observation, and the gut microbiome may be associated with this preference.