Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor.

Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

Metformin-mediated effects on mesenchymal stem cells and mechanisms: proliferation, differentiation and aging.

Mesenchymal stem cells (MSCs) are a type of pluripotent adult stem cell with strong self-renewal and multi-differentiation abilities. Their excellent biological traits, minimal immunogenicity, and abundant availability have made them the perfect seed cells for treating a wide range of diseases. After more than 60 years of clinical practice, metformin is currently one of the most commonly used hypoglycaemic drugs for type 2 diabetes in clinical practice. In addition, metformin has shown great potential in the treatment of various systemic diseases except for type 2 diabetes in recent years, and the mechanisms are involved with antioxidant stress, anti-inflammatory, and induced autophagy, etc. This article reviews the effects and the underlying mechanisms of metformin on the biological properties, including proliferation, multi-differentiation, and aging, of MSCs in vitro and in vivo with the aim of providing theoretical support for in-depth scientific research and clinical applications in MSCs-mediated disease treatment.

Design and Synthesis of 7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme.

The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC50 = 33.8/0.9 µM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.

Ultrafast Dual-Shock Chemistry Synthesis of Ordered/Disordered Hybrid Carbon Anodes: High-Rate Performance of Li-Ion Batteries.

Graphite exhibits crystal anisotropy, which impedes the mass transfer of ion intercalation and extraction processes in Li-ion batteries. Herein, a dual-shock chemical strategy has been developed to synthesize the carbon anode. This approach comprised two key phases: (1) a thermal shock utilizing ultrahigh temperature (3228 K) can thermodynamically facilitate graphitization; (2) a mechanical shock (21.64 MPa) disrupting the π-π interactions in the aromatic chains of carbon can result in hybrid-structured carbon composed of crystalline and amorphous carbon. The optimized carbon (DSC-200-0.3) demonstrates a capacity of 208.61 mAh/g at a 10C rate, with a significant enhancement comparing with 15 mAh/g of the original graphite. Impressively, it maintains 81.06% capacity even after 3000 charge-discharge cycles. Dynamic process analysis reveals that this superior rate performance is attributed to a larger interlayer spacing facilitating ion transport comparing with the original graphite, disordered amorphous carbon for additional lithium storage sites, and crystallized carbon for enhanced charge transfer. The dual-shock chemical approach offers a cost-effective and efficient method to rapidly produce hybrid-structured carbon anodes, enabling 10C fast charging capabilities in lithium-ion batteries.

A centrifugal-driven spiral microchannel microfiltration chip for emulsion and deformable particle sorting.

Droplet sorting and enrichment, as a prominent field within microfluidic technology, represent a pivotal stage in the manipulation of droplets and particles. In recent times, droplet sorting methods based on lab-on-disk (LOD) have garnered significant interest among researchers for their inherent merits, including high throughput, ease of operation, seamless device integration, and independence from supplementary driving forces. This study introduces a centrifugal force-driven microfluidic chip comprising spiral microchannels. The chip incorporates microhole arrays along the sidewall of the spiral channels, enabling size-based sorting and enrichment of microdroplets under the influence of multiple forces. Firstly, a comparative analysis was performed to assess the influence of the separation port structure and rotational speed on efficiency, and a mechanical modeling approach was employed to conduct kinetic analyses of droplet behavior during instantaneous separation. Those findings demonstrated a good agreement with the experimental results at ω < 100 rpm. Subsequently, sorting experiments on homogeneous droplets indicated that repetitive sorting could increase the recovery ratios, RT(α), of high-concentration droplets (20.7%) from 35.3% to over 80%. We also conducted a sorting experiment on three-component homogeneous-phase emulsions using a serially connected chip array, and the sorting throughput was 0.58 mL min-1. As a result, the RT(α) for 60 and 160 µm droplets were 99.4% and 88.9%, respectively. Lastly, we conducted elution experiments and dual-sample sorting on a single chip, and the fluorescence results demonstrated that this study provided an efficient and non-cross-contaminating sorting method for non-homogenous phase multi-sample microreactor units.

Exploring the Water-Soil-Crop Dynamic Process and Water Use Efficiency of Typical Irrigation Units in the Agro-Pastoral Ecotone of Northern China.

Groundwater resources serve as the primary source of water in the agro-pastoral ecotone of northern China, where scarcity of water resources constrains the development of agriculture and animal husbandry. As a typical rainfed agricultural area, the agro-pastoral ecotone in Inner Mongolia is entirely dependent on groundwater for agricultural irrigation. Due to the substantial groundwater consumption of irrigated farmland, groundwater levels have been progressively declining. To obtain a sustainable irrigation pattern that significantly conserves water, this study faces the challenge of unclear water transport relationships among water, soil, and crops, undefined water cycle mechanism in typical irrigation units, and water use efficiency, which was not assessed. Therefore, this paper, based on in situ experimental observations and daily meteorological data in 2022-2023, utilized the DSSAT model to explore the growth processes of potato, oat, alfalfa, and sunflower, the soil water dynamics, the water balance, and water use efficiency, analyzed over a typical irrigation area. The results indicated that the simulation accuracy of the DSSAT model was ARE < 10%, nRMSE/% < 10%, and R2 ≥ 0.85. The consumption of the soil moisture during the rapid growth stage for the potatoes, oats, alfalfa, and sunflower was 7-13% more than that during the other periods, and the yield was 67,170, 3345, 6529, and 4020 kg/ha, respectively. The soil evaporation of oat, potato, alfalfa, and sunflower accounted for 18-22%, 78-82%; 57-68%, and 32-43%, and transpiration accounted for 40-44%, 56-60%, 45-47%, and 53-55% of ETa (333.8 mm-369.2 mm, 375.2 mm-414.2 mm, 415.7 mm-453.7 mm, and 355.0 mm-385.6 mm), respectively. It was advised that irrigation water could be appropriately reduced to decrease ineffective water consumption. The water use efficiency and irrigation water use efficiency for potatoes was at the maximum amount, ranging from 16.22 to 16.62 kg/m3 and 8.61 to 10.81 kg/m3, respectively, followed by alfalfa, sunflowers, and oats. For the perspective of water productivity, it was recommended that potatoes could be extensively cultivated, alfalfa planted appropriately, and oats and sunflowers planted less. The findings of this study provided a theoretical basis for efficient water resource use in the agro-pastoral ecotone of Northern China.

Joint regional uptake quantification of thorium-227 and radium-223 using a multiple-energy-window projection-domain quantitative SPECT method.

Thorium-227 (227Th)-based α-particle radiopharmaceutical therapies (α-RPTs) are currently being investigated in several clinical and pre-clinical studies. After administration, 227Th decays to 223Ra, another α-particle-emitting isotope, which redistributes within the patient. Reliable dose quantification of both 227Th and 223Ra is clinically important, and SPECT may perform this quantification as these isotopes also emit X- and γ-ray photons. However, reliable quantification is challenging for several reasons: the orders-of-magnitude lower activity compared to conventional SPECT, resulting in a very low number of detected counts, the presence of multiple photopeaks, substantial overlap in the emission spectra of these isotopes, and the image-degrading effects in SPECT. To address these issues, we propose a multiple-energy-window projection-domain quantification (MEW-PDQ) method that jointly estimates the regional activity uptake of both 227Th and 223Ra directly using the SPECT projection data from multiple energy windows. We evaluated the method with realistic simulation studies conducted with anthropomorphic digital phantoms, including a virtual imaging trial, in the context of imaging patients with bone metastases of prostate cancer who were treated with 227Th-based α-RPTs. The proposed method yielded reliable (accurate and precise) regional uptake estimates of both isotopes and outperformed state-of-the-art methods across different lesion sizes and contrasts, as well as in the virtual imaging trial. This reliable performance was also observed with moderate levels of intra-regional heterogeneous uptake as well as when there were moderate inaccuracies in the definitions of the support of various regions. Additionally, we demonstrated the effectiveness of using multiple energy windows and the variance of the estimated uptake using the proposed method approached the Cramér-Rao-lower-bound-defined theoretical limit. These results provide strong evidence in support of this method for reliable uptake quantification in 227Th-based α-RPTs.

Low-dose immune tolerance induction for severe hemophilia A inhibitor patients: Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL.

Importance: It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS40 regimen). Objective: To compare the efficacy of the LD-ITI-IS200 regimen with that of the LD-ITI-IS40 regimen for SHA patients with high-titer inhibitors. Methods: A prospective cohort study on patients receiving LD-ITI-IS200 compared to those receiving LD-ITI-IS40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS200 regimen and ≥40 BU/mL in the LD-ITI-IS40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected. Results: We enrolled 30 patients on LD-ITI-IS200 and 64 patients on LD-ITI-IS40, with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS200 regimen compared to the LD-ITI-IS40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS200 vs. LD-ITI-IS40) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS200 than for LD-ITI-IS40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS200 regimen) and 28 IS-using (on LD-ITI-IS40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months). Interpretation: In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL.

Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA.

Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif-dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA-induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.

Approaching Ultimate Synthesis Reaction Rate of Ni-Rich Layered Cathodes for Lithium-Ion Batteries.

Nickel-rich layered oxide LiNixCoyMnzO2 (NCM, x + y + z = 1) is the most promising cathode material for high-energy lithium-ion batteries. However, conventional synthesis methods are limited by the slow heating rate, sluggish reaction dynamics, high energy consumption, and long reaction time. To overcome these challenges, we first employed a high-temperature shock (HTS) strategy for fast synthesis of the NCM, and the approaching ultimate reaction rate of solid phase transition is deeply investigated for the first time. In the HTS process, ultrafast average reaction rate of phase transition from Ni0.6Co0.2Mn0.2(OH)2 to Li- containing oxides is 66.7 (% s-1), that is, taking only 1.5 s. An ultrahigh heating rate leads to fast reaction kinetics, which induces the rapid phase transition of NCM cathodes. The HTS-synthesized nickel-rich layered oxides perform good cycling performances (94% for NCM523, 94% for NCM622, and 80% for NCM811 after 200 cycles at 4.3 V). These findings might also assist to pave the way for preparing effectively Ni-rich layered oxides for lithium-ion batteries.

DIPAN: Detecting personalized intronic polyadenylation derived neoantigens from RNA sequencing data.

Intronic polyadenylation (IPA) refers to a particular type of alternative polyadenylation where a gene makes use of a polyadenylation site located within its introns. Aberrant IPA events have been observed in various types of cancer. IPA can produce noncoding transcripts or truncated protein-coding transcripts with altered coding sequences in the resulting protein product. Therefore, IPA events hold the potential to act as a reservoir of tumor neoantigens. Here, we developed a computational method termed DIPAN, which incorporates IPA detection, protein fragmentation, and MHC binding prediction to predict IPA-derived neoantigens. Utilizing RNA-seq from breast cancer cell lines and ovarian cancer clinical samples, we demonstrated the significant contribution of IPA events to the neoantigen repertoire. Through mass spectrometry immunopeptidome analysis, we further illustrated the processing and presentation of IPA-derived neoantigens on the surface of cancer cells. While most IPA-derived neoantigens are sample-specific, shared neoantigens were identified in both cancer cell lines and clinical samples. Furthermore, we demonstrated an association between IPA-derived neoantigen burden and overall survival in cancer patients.

WIN-PDQ: A Wiener-estimator-based projection-domain quantitative SPECT method that accounts for intra-regional uptake heterogeneity.

SPECT can enable the quantification of activity uptake in lesions and at-risk organs in {\alpha}-particle-emitting radiopharmaceutical therapies ({\alpha}-RPTs). But this quantification is challenged by the low photon counts, complicated isotope physics, and the image-degrading effects in {\alpha}-RPT SPECT. Thus, strategies to optimize the SPECT system and protocol designs for the task of regional uptake quantification are needed. Objectively performing this task-based optimization requires a reliable (accurate and precise) regional uptake quantification method. Conventional reconstruction-based quantification (RBQ) methods have been observed to be erroneous for {\alpha}-RPT SPECT. Projection-domain quantification methods, which estimate regional uptake directly from SPECT projections, have demonstrated potential in providing reliable regional uptake estimates, but these methods assume constant uptake within the regions, an assumption that may not hold. To address these challenges, we propose WIN-PDQ, a Wiener-estimator-based projection-domain quantitative SPECT method. The method accounts for the heterogeneity within the regions of interest while estimating mean uptake. An early-stage evaluation of the method was conducted using 3D Monte Carlo-simulated SPECT of anthropomorphic phantoms with radium-223 uptake and lumpy-model-based intra-regional uptake heterogeneity. In this evaluation with phantoms of varying mean regional uptake and intra-regional uptake heterogeneity, the WIN-PDQ method yielded ensemble unbiased estimates and significantly outperformed both reconstruction-based and previously proposed projection-domain quantification methods. In conclusion, based on these preliminary findings, the proposed method is showing potential for estimating mean regional uptake in {\alpha}-RPTs and towards enabling the objective task-based optimization of SPECT system and protocol designs.

Dependence of evolution of Cyanobacteria superiority on temperature and nutrient use efficiency in a meso-eutrophic plateau lake.

Algal blooms in lakes have been a challenging environmental issue globally under the dual influence of human activity and climate change. Considerable progress has been made in the study of phytoplankton dynamics in lakes; The long-term in situ evolution of dominant bloom-forming cyanobacteria in meso-eutrophic plateau lakes, however, lacks systematic research. Here, the monthly parameters from 12 sampling sites during the period of 1997-2022 were utilized to investigate the underlying mechanisms driving the superiority of bloom-forming cyanobacteria in Erhai, a representative meso-eutrophic plateau lake. The findings indicate that global warming will intensify the risk of cynaobacteria blooms, prolong Microcystis blooms in autumn to winter or even into the following year, and increase the superiority of filamentous Planktothrix and Cylindrospermum in summer and autumn. High RUETN (1.52 Biomass/TN, 0.95-3.04 times higher than other species) under N limitation (TN < 0.5 mg/L, TN/TP < 22.6) in the meso-eutrophic Lake Erhai facilitates the superiority of Dolichospermum. High RUETP (43.8 Biomass/TP, 2.1-10.2 times higher than others) in TP of 0.03-0.05 mg/L promotes the superiority of Planktothrix and Cylindrospermum. We provided a novel insight into the formation of Planktothrix and Cylindrospermum superiority in meso-eutrophic plateau lake with low TP (0.005-0.07 mg/L), which is mainly influenced by warming, high RUETP and their vertical migration characteristics. Therefore, we posit that although the obvious improvement of lake water quality is not directly proportional to the control efficacy of cyanobacterial blooms, the evolutionary shift in cyanobacteria population structure from Microcystis, which thrives under high nitrogen and phosphorus conditions, to filamentous cyanobacteria adapted to low nitrogen and phosphorus levels may serve as a significant indicator of water quality amelioration. Therefore, we suggest that the risk of filamentous cyanobacteria blooms in the meso-eutrophic plateau lake should be given attention, particularly in light of improving water quality and global warming, to ensure drinking water safety.

Comparison of Non-Covalent and Covalent Interactions between Lactoferrin and Chlorogenic Acid.

Adding polyphenols to improve the absorption of functional proteins has become a hot topic. Chlorogenic acid is a natural plant polyphenol with anti-inflammatory, antioxidant, and anticancer properties. Bovine lactoferrin is known for its immunomodulatory, anticancer, antibacterial, and iron-chelating properties. Therefore, the non-covalent binding of chlorogenic acid (CA) and bovine lactoferrin (BLF) with different concentrations under neutral conditions was studied. CA was grafted onto lactoferrin molecules by laccase catalysis, free radical grafting, and alkali treatment. The formation mechanism of non-covalent and covalent complexes of CA-BLF was analyzed by experimental test and theoretical prediction. Compared with the control BLF, the secondary structure of BLF in the non-covalent complex was rearranged and unfolded to provide more active sites, the tertiary structure of the covalent conjugate was changed, and the amino group of the protein participated in the covalent reaction. After adding CA, the covalent conjugates have better functional activity. These lactoferrin-polyphenol couplings can carry various bioactive compounds to create milk-based delivery systems for encapsulation.

ISIT-QA: In Silico Imaging Trial to Evaluate a Low-Count Quantitative SPECT Method Across Multiple Scanner-Collimator Configurations for 223Ra-Based Radiopharmaceutical Therapies.

Personalized dose-based treatment planning requires accurate and reproducible noninvasive measurements to ensure safety and effectiveness. Dose estimation using SPECT is possible but challenging for alpha (α)-particle-emitting radiopharmaceutical therapy (α-RPT) because of complex γ-emission spectra, extremely low counts, and various image-degrading artifacts across a plethora of scanner-collimator configurations. Through the incorporation of physics-based considerations and skipping of the potentially lossy voxel-based reconstruction step, a recently developed projection-domain low-count quantitative SPECT (LC-QSPECT) method has the potential to provide reproducible, accurate, and precise activity concentration and dose measures across multiple scanners, as is typically the case in multicenter settings. To assess this potential, we conducted an in silico imaging trial to evaluate the LC-QSPECT method for a 223Ra-based α-RPT, with the trial recapitulating patient and imaging system variabilities. Methods: A virtual imaging trial titled In Silico Imaging Trial for Quantitation Accuracy (ISIT-QA) was designed with the objectives of evaluating the performance of the LC-QSPECT method across multiple scanner-collimator configurations and comparing performance with a conventional reconstruction-based quantification method. In this trial, we simulated 280 realistic virtual patients with bone-metastatic castration-resistant prostate cancer treated with 223Ra-based α-RPT. The trial was conducted with 9 simulated SPECT scanner-collimator configurations. The primary objective of this trial was to evaluate the reproducibility of dose estimates across multiple scanner-collimator configurations using LC-QSPECT by calculating the intraclass correlation coefficient. Additionally, we compared the reproducibility and evaluated the accuracy of both considered quantification methods across multiple scanner-collimator configurations. Finally, the repeatability of the methods was evaluated in a test-retest study. Results: In this trial, data from 268 223RaCl2 treated virtual prostate cancer patients, with a total of 2,903 lesions, were used to evaluate LC-QSPECT. LC-QSPECT provided dose estimates with good reproducibility across the 9 scanner-collimator configurations (intraclass correlation coefficient > 0.75) and high accuracy (ensemble average values of recovery coefficients ranged from 1.00 to 1.02). Compared with conventional reconstruction-based quantification, LC-QSPECT yielded significantly improved reproducibility across scanner-collimator configurations, accuracy, and test-retest repeatability ([Formula: see text] Conclusion: LC-QSPECT provides reproducible, accurate, and repeatable dose estimations in 223Ra-based α-RPT as evaluated in ISIT-QA. These findings provide a strong impetus for multicenter clinical evaluations of LC-QSPECT in dose quantification for α-RPTs.

Real-time imaging and quantitative analysis of internal gap formation in bulk-fill and conventional resin composites: An OCT evaluation.

BACKGROUND: This study used optical coherence tomography (OCT) to observe real-time internal gap formation in both bulk-fill and conventional resin composites. It aimed to provide a quantitative analysis of variations, addressing the inconclusive nature of microleakage assessment caused by differences in testing methods. METHODS: Fifty extracted third molars prepared with Class I cavities, were divided into five groups (n = 10). Conventional resin Filtek Z350 XT (FZX) was applied with a double-layer filling of 2 mm per layer. Bulk-fill resins X-tra fil (XTF), Filtek Bulk Fill Posterior Restorative (FBP), Surefil SDR Flow + (SDR), and Filtek Flowable Restorative (FFR) were applied with a single-layer filling of 4 mm. Real-time OCT imaging was conducted during light curing. Post-curing, the entire sample was OCT-scanned. Following this, ImageJ software was used to measure the gap (G1 %). Subsequently, thermal cycling (TC) (5000 times, 5 °C-55 °C) was applied, followed by OCT scanning to calculate the gap (G2 %) and ΔG%. Data were analyzed using two-way repeated measures ANOVA, Kruskal-Wallis test, and Duncan's test (α=0.05). RESULTS: There was no significant difference in G1 % among the groups (p > 0.05). Following TC, FZX exhibited the highest G2 %, succeeded by FFR, FBP, XTF, and SDR, with SDR demonstrating the lowest G2 % (p < 0.05). FZX showed the highest ΔG% (p < 0.05), while SDR exhibited the lowest ΔG% (p < 0.05). CONCLUSION: OCT proves to be a promising tool for detecting microleakage. TC exerted a more significant negative impact on conventional resin. Surefil SDR Flow + displayed the least microleakage, both before and after TC.

InPACT: a computational method for accurate characterization of intronic polyadenylation from RNA sequencing data.

Alternative polyadenylation can occur in introns, termed intronic polyadenylation (IPA), has been implicated in diverse biological processes and diseases, as it can produce noncoding transcripts or transcripts with truncated coding regions. However, a reliable method is required to accurately characterize IPA. Here, we propose a computational method called InPACT, which allows for the precise characterization of IPA from conventional RNA-seq data. InPACT successfully identifies numerous previously unannotated IPA transcripts in human cells, many of which are translated, as evidenced by ribosome profiling data. We have demonstrated that InPACT outperforms other methods in terms of IPA identification and quantification. Moreover, InPACT applied to monocyte activation reveals temporally coordinated IPA events. Further application on single-cell RNA-seq data of human fetal bone marrow reveals the expression of several IPA isoforms in a context-specific manner. Therefore, InPACT represents a powerful tool for the accurate characterization of IPA from RNA-seq data.

Erratum: Author correction to "Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy" [Acta Pharm Sin B (2022) 4224-4234].

[This corrects the article DOI: 10.1016/j.apsb.2022.06.016.].

An atlas of cell-type-specific interactome networks across 44 human tumor types.

BACKGROUND: Biological processes are controlled by groups of genes acting in concert. Investigating gene-gene interactions within different cell types can help researchers understand the regulatory mechanisms behind human complex diseases, such as tumors. METHODS: We collected extensive single-cell RNA-seq data from tumors, involving 563 patients with 44 different tumor types. Through our analysis, we identified various cell types in tumors and created an atlas of different immune cell subsets across different tumor types. Using the SCINET method, we reconstructed interactome networks specific to different cell types. Diverse functional data was then integrated to gain biological insights into the networks, including somatic mutation patterns and gene functional annotation. Additionally, genes with prognostic relevance within the networks were also identified. We also examined cell-cell communications to investigate how gene interactions modulate cell-cell interactions. RESULTS: We developed a data portal called CellNetdb for researchers to study cell-type-specific interactome networks. Our findings indicate that these networks can be used to identify genes with topological specificity in different cell types. We also found that prognostic genes can deconvolved into cell types through analyzing network connectivity. Additionally, we identified commonalities and differences in cell-type-specific networks across different tumor types. Our results suggest that these networks can be used to prioritize risk genes. CONCLUSIONS: This study presented CellNetdb, a comprehensive repository featuring an atlas of cell-type-specific interactome networks across 44 human tumor types. The findings underscore the utility of these networks in delineating the intricacies of tumor microenvironments and advancing the understanding of molecular mechanisms underpinning human tumors.

Study on Modeling and Evaluating Alfalfa Yield and Optimal Water Use Efficiency in the Agro-Pastoral Ecotone of Northern China.

The agro-pastoral ecotone in northern China is the main production area of agriculture and animal husbandry, in which agricultural development relies entirely on groundwater. Due to the increasing water consumption of groundwater year by year, groundwater resources are becoming increasingly scarce. The substantial water demand and low germination rate in the first year are the main characteristics of alfalfa (Medicago sativa L.) yield in the agro-pastoral ecotone in northern China. Due to unscientific irrigation, water resources are seriously wasted, which restricts the development of local agriculture and animal husbandry. The study constructed the Dssat-Forages-Alfalfa model and used soil water content, leaf area index, and yield data collected with in situ observation experiments in 2022 and 2023 to calibrate and validate the parameters. The study found ARE < 10%, ENRMS < 15%, and R2 ≥ 0.85. The model simulation accuracy was acceptable. The study revealed that the water consumption at the surface soil layer (0-20 cm) was more than 6~12% and 13~31% than that at the 20-40 cm and 40-60 cm soil layers, respectively. The study showed when the irrigation quota was 30 mm, the annual yield of alfalfa (Medicago sativa L.) (7435 kg/ha) was consistent with that of the irrigation quota of 33 mm, and increased by 3.99% to 5.34% and 6.86% to 10.67% compared with that of irrigation quotas of 27 mm and 24 mm, respectively. To ensure the germination rate of alfalfa (Medicago sativa L.), it is recommended to control the initial soil water content at 0.8 θfc~1.0 θfc, with an irrigation quota of 30 mm, which was the best scheme for water-use efficiency and economic yield. The study aimed to provide technological support for the rational utilization of groundwater and the scientific improvement of alfalfa yield in the agro-pastoral ecotone in northern China.