Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Pan-Cancer Single-Nucleus Total RNA Sequencing Using snHH-Seq.

Tumor heterogeneity and its drivers impair tumor progression and cancer therapy. Single-cell RNA sequencing is used to investigate the heterogeneity of tumor ecosystems. However, most methods of scRNA-seq amplify the termini of polyadenylated transcripts, making it challenging to perform total RNA analysis and somatic mutation analysis.Therefore, a high-throughput and high-sensitivity method called snHH-seq is developed, which combines random primers and a preindex strategy in the droplet microfluidic platform. This innovative method allows for the detection of total RNA in single nuclei from clinically frozen samples. A robust pipeline to facilitate the analysis of full-length RNA-seq data is also established. snHH-seq is applied to more than 730 000 single nuclei from 32 patients with various tumor types. The pan-cancer study enables it to comprehensively profile data on the tumor transcriptome, including expression levels, mutations, splicing patterns, clone dynamics, etc. New malignant cell subclusters and exploring their specific function across cancers are identified. Furthermore, the malignant status of epithelial cells is investigated among different cancer types with respect to mutation and splicing patterns. The ability to detect full-length RNA at the single-nucleus level provides a powerful tool for studying complex biological systems and has broad implications for understanding tumor pathology.

Mapping Cell Atlases at the Single-Cell Level.

Recent advancements in single-cell technologies have led to rapid developments in the construction of cell atlases. These atlases have the potential to provide detailed information about every cell type in different organisms, enabling the characterization of cellular diversity at the single-cell level. Global efforts in developing comprehensive cell atlases have profound implications for both basic research and clinical applications. This review provides a broad overview of the cellular diversity and dynamics across various biological systems. In addition, the incorporation of machine learning techniques into cell atlas analyses opens up exciting prospects for the field of integrative biology.

Construction of a cross-species cell landscape at single-cell level.

Individual cells are basic units of life. Despite extensive efforts to characterize the cellular heterogeneity of different organisms, cross-species comparisons of landscape dynamics have not been achieved. Here, we applied single-cell RNA sequencing (scRNA-seq) to map organism-level cell landscapes at multiple life stages for mice, zebrafish and Drosophila. By integrating the comprehensive dataset of > 2.6 million single cells, we constructed a cross-species cell landscape and identified signatures and common pathways that changed throughout the life span. We identified structural inflammation and mitochondrial dysfunction as the most common hallmarks of organism aging, and found that pharmacological activation of mitochondrial metabolism alleviated aging phenotypes in mice. The cross-species cell landscape with other published datasets were stored in an integrated online portal-Cell Landscape. Our work provides a valuable resource for studying lineage development, maturation and aging.

How many cell types are there in nature? How do they change during the life cycle? These are two fundamental questions that researchers have been trying to understand in the area of biology. In this study, single-cell mRNA sequencing data were used to profile over 2.6 million individual cells from mice, zebrafish and Drosophila at different life stages, 1.3 million of which were newly collected. The comprehensive datasets allow investigators to construct a cross-species cell landscape that helps to reveal the conservation and diversity of cell taxonomies at genetic and regulatory levels. The resources in this study are assembled into a publicly available website at http://bis.zju.edu.cn/cellatlas/.

Deep learning of cross-species single-cell landscapes identifies conserved regulatory programs underlying cell types.

Despite extensive efforts to generate and analyze reference genomes, genetic models to predict gene regulation and cell fate decisions are lacking for most species. Here, we generated whole-body single-cell transcriptomic landscapes of zebrafish, Drosophila and earthworm. We then integrated cell landscapes from eight representative metazoan species to study gene regulation across evolution. Using these uniformly constructed cross-species landscapes, we developed a deep-learning-based strategy, Nvwa, to predict gene expression and identify regulatory sequences at the single-cell level. We systematically compared cell-type-specific transcription factors to reveal conserved genetic regulation in vertebrates and invertebrates. Our work provides a valuable resource and offers a new strategy for studying regulatory grammar in diverse biological systems.

Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development.

Waddington's epigenetic landscape is a metaphor frequently used to illustrate cell differentiation. Recent advances in single-cell genomics are altering our understanding of the Waddington landscape, yet the molecular mechanisms of cell-fate decisions remain poorly understood. We constructed a cell landscape of mouse lineage differentiation during development at the single-cell level and described both lineage-common and lineage-specific regulatory programs during cell-type maturation. We also found lineage-common regulatory programs that are broadly active during the development of invertebrates and vertebrates. In particular, we identified Xbp1 as an evolutionarily conserved regulator of cell-fate determinations across different species. We demonstrated that Xbp1 transcriptional regulation is important for the stabilization of the gene-regulatory networks for a wide range of mouse cell types. Our results offer genetic and molecular insights into cellular gene-regulatory programs and will serve as a basis for further advancing the understanding of cell-fate decisions.

A simple and green method to prepare non-typical yolk/shell nanoreactor with dual-shells and multiple-cores: Enhanced catalytic activity and stability in Fenton-like reaction.

Nowadays, non-typical yolk/shell structure has drawn much attentions due to the better catalytic performance than traditional counterparts (one yolk/one shell). In this study, ZIF-67 @Co2SiO4/SiO2 yolk/shell structure was prepared in one-step at room temperature, in which ZIF-67 was served as the hard-template, H2O was served as etchant and tetraethyl orthosilicat was served as the raw material for Co2SiO4/SiO2. After calcination, the non-typical CoxOy @Co2SiO4/SiO2 yolk/shell nanoreactor with Co2SiO4/SiO2 dual-shells and CoxOy multiple-cores was obtained. On the one hand, more active sites were exposed on multiple-cores surface and better protection were provided by dual-shells. On the other hand, the sheet-like Co2SiO4 inner shell not only extended the travel path and retention time of pollutants trapped in cavity, but also separated the multiple-cores from aggregation. Therefore, the nanoreactor displayed the outstanding catalytic activity and recyclability in Fenton-like reaction. Metronidazole (20 mg/L) was completely degraded after 30 min, rhodamine B (50 mg/L) and methyl orange (20 mg/L) were removed even within 5.0 min. Catalytic mechanism indicated that 1O2 greatly contributed to the pollutant degradation. This paper presented a simple, versatile, green and energy-saving method for non-typical yolk/shell nanoreactor, and it could inspire to prepare other catalysts with high activity and stability for environmental remediation.

Optimization of initial dose regimen of tacrolimus in paediatric lung transplant recipients based on Monte Carlo simulation.

WHAT IS KNOWN AND OBJECTIVES: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients. METHODS: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients. RESULTS: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively. WHAT IS NEW AND CONCLUSIONS: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients.

Z-scheme Fe2(MoO4)3/Ag/Ag3PO4 heterojunction with enhanced degradation rate by in-situ generated H2O2: Turning waste (H2O2) into wealth (•OH).

Ag3PO4-based photocatalysts have been deeply studied in environmental remediation; however, two problems limited their further application: photocorrosion and quenching effect by in-situ generated H2O2. To addressed these two questions simultaneously, Fe2(MoO4)3 was coupled with Ag3PO4 to construct Z-scheme Fe2(MoO4)3/Ag/Ag3PO4 heterojunction driven by internal-electric-field. The rhodamine B degradation rate of heterojunction was 254 and 7.0 times higher than those of Fe2(MoO4)3 and Ag3PO4, respectively. The outstanding photoactivity was due to the high visible-light harvest, low interface resistance, high separation efficiency of charge carriers, long lifetime of hole (h+) and electron (e-), well-preserved oxidation potential of h+, and especially photocatalytic produced H2O2 inside the system. The in-situ generated H2O2 was fully activated to be •OH on the Fe2(MoO4)3 surface via a Fenton reaction, leading to the elimination of quenching effect on h+ and e-, and generation of more •OH. Additionally, in Z-scheme heterojunction, e- transferred from Ag3PO4 to Fe2(MoO4)3, avoiding the accumulation on Ag3PO4 surface, and hence suppressing the photocorrosion. As a result, 91.2% of degradation efficiency remained after 5 cycles. This paper provides a new method to simultaneously increase the degradation rate by utilizing the in-situ generated H2O2 and improve the stability of Ag3PO4 via constructing a Z-scheme heterojunction.

Internal-electric-field induced high efficient type-I heterojunction in photocatalysis-self-Fenton reaction: Enhanced H2O2 yield, utilization efficiency and degradation performance.

Herein, a type-I phosphorus-doped carbon nitride/oxygen-doped carbon nitride (P-C3N4/O-C3N4) heterojunction was designed for photocatalysis-self-Fenton reaction (photocatalytic H2O2 production and following Fenton reaction). In P-C3N4/O-C3N4, the photoinduced charge carriers were effectively separated with the help of internal-electric-field near the interface, ensuring the high catalytic performance. As a result, the production rate of H2O2 in an air-saturated solution was 179 µM·h-1, about 7.2, 2.5, 2.5 and 2.1 times quicker than that on C3N4, P-C3N4, O-C3N4, and phosphorus and oxygen co-doped C3N4, respectively. By taking advantage of the cascade mode in photocatalysis-self-Fenton reaction, H2O2 utilization efficiency was remarkably improved to 77.7%, about 9.0 times higher than that of traditional homogeneous Fenton reaction. Befitting from the superior yield and utilization efficiency, the degradation performance of P-C3N4/O-C3N4 was undoubtedly superior than other photocatalysts. This work well addressed two bottlenecks in traditional Fenton reaction: source of H2O2 and their low utilization efficiency, and the findings were beneficial to understand the mechanism and advantage of the photocatalysis-self-Fenton system in environmental remediation.

Tracing cell-type evolution by cross-species comparison of cell atlases.

Cell types are the basic building units of multicellular life, with extensive diversities. The evolution of cell types is a crucial layer of comparative cell biology but is thus far not comprehensively studied. We define a compendium of cell atlases using single-cell RNA-seq (scRNA-seq) data from seven animal species and construct a cross-species cell-type evolutionary hierarchy. We present a roadmap for the origin and diversity of major cell categories and find that muscle and neuron cells are conserved cell types. Furthermore, we identify a cross-species transcription factor (TF) repertoire that specifies major cell categories. Overall, our study reveals conservation and divergence of cell types during animal evolution, which will further expand the landscape of comparative genomics.

Construction of phosphorus-doped carbon nitride/phosphorus and sulfur co-doped carbon nitride isotype heterojunction and their enhanced photoactivity.

Photocatalysis was one of the most promising techniques for environmental remediation. Exploring photocatalysts with high efficiency, low cost and easy preparation was still an ongoing issue. In this work, phosphorus-doped carbon nitride/phosphorus and sulfur co-doped carbon nitride (P-C3N4/PS-C3N4) isotype heterojunction was prepared by a two-step calcination method. The composite displayed a sheet-like structure with a surface area of 23 m2/g. Compared with pure C3N4, band gaps of P-C3N4 and PS-C3N4 were only slightly modified during the heteroatom-doping process. Therefore, a well-matched band alignment was constructed, which not only improved the separation efficiency of photogenerated electron-hole pairs, but also well preserved the high oxidizability of holes on valance band and good reducibility of electrons on conduction band. Because of the similarity in physicochemical properties, the interface resistance between P-C3N4 and PS-C3N4 was low, which accelerated the electron transfer and prolonged the lifetime of charge carriers. Although the visible-light utilization was somewhat low in comparison with P-C3N4 and PS-C3N4, by taking advantage of above merits, P-C3N4/PS-C3N4 displayed the high photocatalytic activity in rhodamine B degradation, and the reaction rate constant was 0.183 min-1, about 8.7 and 4.0 times higher than those of P-C3N4 and PS-C3N4. Besides high catalytic activity, isotype heterojunction displayed good recyclability, since 95.3% of catalytic activity was maintained after the 5th cycle. The method presented here was facile, economic and environmentally benign, thus it was highly attractive for the application in environmental remediation.

One-step preparation of reduced graphene oxide aerogel loaded with mesoporous copper ferrite nanocubes: A highly efficient catalyst in microwave-assisted Fenton reaction.

Heterogeneous Fenton reaction is an attractive method for degradation of organic pollutants due to its high efficiency and non-selectivity and it also causes no secondary pollution. However, low degradation rate and poor recyclability of the catalysts limit its applications for water purification. To overcome this, herein, copper ferrite/reduced graphene oxide (CF/rGO) aerogel was prepared by a one-step hydrothermal method, as a highly efficient catalyst for the microwave-assisted Fenton reaction (MAFR). Under optimal conditions (500 W of microwave power, 600 µL of H2O2, 15 mg of catalyst, and 30 mg/L of RhB), the degradation efficiency of CF/rGO aerogel at 1.0 min (95.7%) was higher than that of reference samples at 3.0 min. Thermodynamical study showed the activation energy, enthalpy change, entropy change, and Gibbs free energy change were 0.73 kJ/mol, -49.5 kJ/mol, -0.135 kJ/mol·K, and -6.8 kJ/mol, respectively, indicating that MAFR was an endothermic and non-spontaneous process.Radical trapping experiments showed that OH, O2-, and h+ played a combined role in RhB degradation. Besides high catalytic activity, CF/rGO aerogel also displayed good reusability, showing removal efficiency of 87.4% after 5 cycles. The high efficiency, good reusability, and simple process make CF/rGO aerogel a promising catalyst for wastewater treatment.

The efficacy of intravenous thrombolysis in acute ischemic stroke patients with white matter hyperintensity.

OBJECTIVES: We aimed to investigate effects of deep white matter hyperintensity (DWMH) and periventricular hyperintensity (PVH) on the efficacy of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS). METHODS: A total of 113 AIS patients with WMH were categorized into the PVH group and the DWMH group according to the lesion location, with the division of two subgroups based on whether or not they received IVT treatment: the thrombolysis group and the control group. Kaplan-Meier analysis was used for proportional hazards of recurrent stroke. Further, multivariate Cox regression analysis was employed. RESULTS: Of total patients, there were 62 PVH patients and 51 DWMH patients: 27 of PVH patients and 22 of DWMH patients received IVT, and the remaining patients only received routine treatment. DWMH patients had a higher risk of END (36.4% vs. 11.1%; p = 0.034) and HT (22.7% vs. 3.7%; p = 0.038) than PVH patients in the thrombolysis group. Moreover, DWMH patients undergoing IVT also had a higher risk of END (36.4% vs. 10.3%; x2  = 5.050; p = 0.025) and HT (22.7% vs. 3.4%; x2  = 4.664; p = 0.031) than DWMH patients without IVT. Again, PVH patients had a higher rate of recurrent stroke (20.0% vs. 3.4%; p = 0.034) than DWMH patients in the control group after 90-day follow-up. Kaplan-Meier analysis showed a significant difference in cumulative probability of no major endpoint events (p = 0.039). Further, multivariate Cox regression revealed that PVH is an independent risk factor for stroke recurrence in AIS patients after adjusting confounding factors. CONCLUSIONS: The location of WMH is closely associated with the efficacy of IVT in AIS patients.