GWAS and post-GWAS functional study reveal regulatory mechanism of piglet diarrhea.

Objective: Piglet diarrhea poses a serious threat to piglet health and the livestock economy, and is one of the most pressing problems in animal husbandry. This study aims to investigate the genetic factors involved in piglet diarrhea and to identify key genes that regulate this condition. Methods: We screened 600 diarrheal piglets based on unique diarrhea scores for resequencing and conducted a genome-wide association study (GWAS). Through this process, we identified 308 single nucleotide polymorphisms (SNPs) and annotated 151 candidate genes. Extensive functional validation and systematic analysis were performed on key candidate genes KSR1, SKAP1, SLC35F6, and OR12. Results: The study found that the four key genes were involved in the regulation of piglet diarrhea through various mechanisms. OR12 affects the levels of ZO-1 and claudin-1. Changes in the expression levels of KSR1 could alter the expression of IL1-ß, IL6, and TNF-α, as well as cell migration and proliferation. SKAP1 could affect the expression of CD3 and CD4, and influence the migration and proliferation ability of cells. SLC35F6 is involved in cell apoptosis through the Bcl2/BAX/caspase3 pathway and can also affect mitochondrial membrane potential. Conclusion: The results of this study provide strong support for breeding programs aimed at disease resistance and offer potential solutions to the problem of piglet diarrhea.

Transcriptome analysis of liver and ileum reveals potential regulation of long non-coding RNA in pigs with divergent feed efficiency.

Objective: LncRNA plays a significant role in regulating feed efficiency. This study aims to explore the key long non-coding RNAs, associated genes, and pathways in pigs with extreme feed efficiencies. Methods: We screened pigs with extremely high and low RFI through a 12-week animal growth trial and then conducted transcriptome analysis on their liver and ileum tissues. We analyzed the differential expressed lncRNAs, miRNAs, and mRNAs through target gene prediction and functional analysis. And we identified key lncRNAs and their potential regulatory genes associated with feed efficiency through the construction of competitive endogenous RNA network. Results: Differentially expressed lncRNAs were pinpointed in the liver, revealing 23 crucial target genes primarily associated with GTP metabolism and glycolipid biosynthesis. In the ileum, a screening identified 92 pivotal target genes, mainly linked to lipid and small molecule metabolism. Moreover, LOC106504303 and LOC102160805 emerged as potentially significant lncRNAs respectively, playing roles in mitochondrial oxidative phosphorylation in the liver, and lipid and cholesterol metabolism in the ileum. Conclusion: The lncRNAs regulate energy metabolism and biosynthesis in the liver, and the digestive absorption capacity in the small intestine, affecting the feed efficiency of pigs.

A novel prognostic risk score model based on RNA editing level in lower-grade glioma.

BACKGROUND: Lower-grade glioma (LGG) refers to WHO grade 2 and 3 gliomas. Surgery combined with radiotherapy and chemotherapy can significantly improve the prognosis of LGG patients, but tumor progression is still unavoidable. As a form of posttranscriptional regulation, RNA editing (RE) has been reported to be involved in tumorigenesis and progression and has been intensively studied recently. METHODS: Survival data and RE data were subjected to univariate and multivariate Cox regression analysis and lasso regression analysis to establish an RE risk score model. A nomogram combining the risk score and clinicopathological features was built to predict the 1-, 3-, and 5-year survival probability of patients. The relationship among ADAR1, SOD2 and SOAT1 was verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) RESULTS: A risk model associated with RE was constructed and patients were divided into different risk groups based on risk scores. The model demonstrated strong prognostic capability, with the area under the ROC curve (AUC) values of 0.882, 0.938, and 0.947 for 1-, 3-, and 5-year survival predictions, respectively. Through receiver operating characteristic curve (ROC) curves and calibration curves, it was verified that the constructed nomogram had better performance than age, grade, and risk score in predicting patient survival probability. Apart from this functional analysis, the results of correlation analyses between risk differentially expressed genes (RDEGs) and RE help us to understand the underlying mechanism of RE in LGG. ADAR may regulate the expression of SOD2 and SOAT1 through gene editing. CONCLUSION: In conclusion, this study establishes a novel and accurate 17-RE model and a nomogram for predicting the survival probability of LGG patients. ADAR may affect the prognosis of glioma patients by influencing gene expression.

Bifunctional iron-catalyzed alkyne Z-selective hydroalkylation and tandem Z-E inversion via radical molding and flipping.

The challenging synthesis of thermodynamic-unfavored cis-olefins through catalytic cross-coupling reactions requires the synergistic interaction of substrate-activating units and configuration-regulating catalysts. Successfully hitting these two birds with one stone, we herein develop a convenient photoredox access to Z-alkenes from alkynes and light alkanes with a bifunctional iron-catalyzed system possessing both C(sp3)-H activation and configuration-controlling abilities. The protocol exhibits 100% atom utilization, mild conditions, a broad substrate scope, and compatibility with multitudinous functional groups. The detailed reaction mechanism and the origin of geometry regulation are well investigated by experimental and computational studies. Progressively, a catalytic amount of diaryl disulfides is introduced for consecutive photoinduced Z-E isomerization via reversible radical addition and flipping. Big steric hindrance substituents assembled on the disulfide emerge necessity for suppressing double-bond migration. This tandem strategy paves a promising way for stereoselective alkene construction and will bring significant inspiration for the development of transition metal photocatalysis.

Hydrogen-Bond-Assisted Electrocatalytic Semi-Oxidation of 5-Hydroxymethylfurfural into 2,5-Diformylfuran by Operando Dissociated N-Oxyl Mediator.

The conversion of 5-hydroxymethylfurfural (HMF) to 2,5-diformylfuran (DFF) is a promising approach for enhancing biomass utilization. Nevertheless, traditional methods using noble metal catalysts face challenges due to high costs and poor selectivity towards DFF. Herein, we developed a novel catalytic electrode integrating N-hydroxyphthalimide (NHPI) into a metal-organic framework on a hydrophilic carbon cloth. This design significantly enhances the selective adsorption of HMF due to stronger hydrogen-bond interaction between the electrode's hydrophilic surface and the C(sp3)-OH group in HMF compared to the C(sp2)=O in DFF. Additionally, the electro-driven dissociation of the NHPI-linker generates stabilized N-Oxyl radicals that promote selective semi-oxidation of HMF under neutral conditions. As a result, this approach achieves a high yield rate of 138.2 mol molcat-1 h-1 with a selectivity of 96.7% for the HMF-to-DFF conversion. This work introduces a novel strategy for designing catalytic electrodes with stabilized N-Oxyl radicals, and offers a promising method for electrocatalytic DFF synthesis, leveraging hydrogen-bond interaction between electrode surface and HMF.

Photoinduced Phosphoniumation of Aryl Halides and Arylthianthrenium Salts via an Electron Donor-Acceptor Complex.

Owing to their remarkable practicality and utility, phosphonium salts have attracted substantial interest and are widely applied in critical areas, such as medicine, materials science, and catalysis. Herein, we developed a facile and photocatalyst/metal-free synthetic strategy for the preparation of phosphonium salts utilizing aryl halides/arylthianthrenium salts as aryl radical precursors. This approach is disclosed to undergo an efficient light-induced electron donor-acceptor pathway, facilitating the synthesis of a structurally diverse range of phosphonium salts.

HSPA12A stimulates "Smurf1-Hif1α-aerobic glycolysis" axis to promote proliferation of renal tubular epithelial cells after hypoxia/reoxygenation injury.

Proliferation of renal tubular epithelial cells (TECs) is critical for the recovery after kidney ischemia/reperfusion (KI/R). However, there is still a lack of ideal therapies for promoting TEC proliferation. Heat shock protein A12A (HSPA12A) shows abundant expression in kidney in our previous studies. To investigate the role of HSPA12A in TEC proliferation after KI/R, an in vitro KI/R model was simulated by hypoxia (12 h) and reoxygenation (12 h) in human kidney tubular epithelial HK-2 cells. We found that, when hypoxia/reoxygenation (H/R) triggered HK-2 cell injury, HSPA12A expression was downregulated, and extracellular lactate, the readout of glycolysis, was also decreased. Loss and gain of functional studies showed that HSPA12A did not change cell viability after hypoxia but increased cell proliferation as well as glycolytic flux of HK-2 cells after H/R. When blocking glycolysis by 2-deoxy-D-glucose or oxamate, the HSPA12A promoted HK-2 cell proliferation was also abolished. Further analysis revealed that HSPA12A overexpression increased hypoxia-inducible factor 1α (Hif1α) protein expression and nuclear localization in HK-2 cells in response to H/R, whereas HSPA12A knockdown showed the opposite effects. Notably, pharmacological inhibition of Hif1α with YC-1 reversed the HSPA12A-induced increases of both glycolytic flux and proliferation of H/R HK-2 cells. Moreover, the HSPA12A increased Hif1α protein expression was not via upregulating its transcription but through increasing its protein stability in a Smurf1-dependent manner. The findings indicate that HSPA12A might serve as a promising target for TEC proliferation to help recovery after KI/R.

Roadmap on computational methods in optical imaging and holography [invited].

Computational methods have been established as cornerstones in optical imaging and holography in recent years. Every year, the dependence of optical imaging and holography on computational methods is increasing significantly to the extent that optical methods and components are being completely and efficiently replaced with computational methods at low cost. This roadmap reviews the current scenario in four major areas namely incoherent digital holography, quantitative phase imaging, imaging through scattering layers, and super-resolution imaging. In addition to registering the perspectives of the modern-day architects of the above research areas, the roadmap also reports some of the latest studies on the topic. Computational codes and pseudocodes are presented for computational methods in a plug-and-play fashion for readers to not only read and understand but also practice the latest algorithms with their data. We believe that this roadmap will be a valuable tool for analyzing the current trends in computational methods to predict and prepare the future of computational methods in optical imaging and holography. Supplementary Information: The online version contains supplementary material available at 10.1007/s00340-024-08280-3.

A Modular Three-Component Approach for Site-selective Tandem Arene Thiophosphorylation.

Thiophosphates serve as pivotal reagents within the realms of both organic and inorganic synthesis, with their most notable applications observed in agricultural chemistry. This manuscript delineates a modular three-component synthetic strategy for site-selective arene C-H thiophosphorylation with thianthrenium salt, 1,4-diazabicyclo[2.2.2]octane-sulfur dioxide (DABSO), and diarylphosphine oxides as substrates. This approach facilitates the metal-free and green synthesis of a diverse spectrum of S-aryl phosphorothioates through C-H functionalization and late-stage modification showcasing practicality and broad applicability.

Surface functionalized nanomaterial systems for targeted therapy of endocrine related tumors: a review of recent advancements.

The application of multidisciplinary techniques in the management of endocrine-related cancers is crucial for harnessing the advantages of multiple disciplines and their coordinated efforts in eliminating tumors. Due to the malignant characteristics of cancer cells, they possess the capacity to develop resistance to traditional treatments such as chemotherapy and radiotherapy. Nevertheless, despite diligent endeavors to enhance the prediction of outcomes, the overall survival rate for individuals afflicted with endocrine-related malignancy remains quite miserable. Hence, it is imperative to investigate innovative therapy strategies. The latest advancements in therapeutic tactics have offered novel approaches for the therapy of various endocrine tumors. This paper examines the advancements in nano-drug delivery techniques and the utilization of nanomaterials for precise cancer cures through targeted therapy. This review provides a thorough analysis of the potential of combined drug delivery strategies in the treatment of thyroid cancer, adrenal gland tumors, and pancreatic cancer. The objective of this study is to gain a deeper understanding of current therapeutic approaches, stimulate the development of new drug DDS, and improve the effectiveness of treatment for patients with these diseases. The intracellular uptake of pharmaceuticals into cancer cells can be significantly improved through the implantation of synthetic or natural substances into nanoparticles, resulting in a substantial reduction in the development of endocrine malignancies.

Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

CADS: A Self-supervised Learner via Cross-modal Alignment and Deep Self-distillation for CT Volume Segmentation.

Self-supervised learning (SSL) has long had great success in advancing the field of annotation-efficient learning. However, when applied to CT volume segmentation, most SSL methods suffer from two limitations, including rarely using the information acquired by different imaging modalities and providing supervision only to the bottleneck encoder layer. To address both limitations, we design a pretext task to align the information in each 3D CT volume and the corresponding 2D generated X-ray image and extend self-distillation to deep self-distillation. Thus, we propose a self-supervised learner based on Cross-modal Alignment and Deep Self-distillation (CADS) to improve the encoder's ability to characterize CT volumes. The cross-modal alignment is a more challenging pretext task that forces the encoder to learn better image representation ability. Deep self-distillation provides supervision to not only the bottleneck layer but also shallow layers, thus boosting the abilities of both. Comparative experiments show that, during pre-training, our CADS has lower computational complexity and GPU memory cost than competing SSL methods. Based on the pre-trained encoder, we construct PVT-UNet for 3D CT volume segmentation. Our results on seven downstream tasks indicate that PVT-UNet outperforms state-of-the-art SSL methods like MOCOv3 and DiRA, as well as prevalent medical image segmentation methods like nnUNet and CoTr. Code and pre-trained weight will be available at https://github.com/yeerwen/CADS.

In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals.

Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.

Towards safer robot-assisted surgery: A markerless augmented reality framework.

Robot-assisted surgery is rapidly developing in the medical field, and the integration of augmented reality shows the potential to improve the operation performance of surgeons by providing more visual information. In this paper, we proposed a markerless augmented reality framework to enhance safety by avoiding intra-operative bleeding, which is a high risk caused by collision between surgical instruments and delicate blood vessels (arteries or veins). Advanced stereo reconstruction and segmentation networks are compared to find the best combination to reconstruct the intra-operative blood vessel in 3D space for registration with the pre-operative model, and the minimum distance detection between the instruments and the blood vessel is implemented. A robot-assisted lymphadenectomy is emulated on the da Vinci Research Kit in a dry lab, and ten human subjects perform this operation to explore the usability of the proposed framework. The result shows that the augmented reality framework can help the users to avoid the dangerous collision between the instruments and the delicate blood vessel while not introducing an extra load. It provides a flexible framework that integrates augmented reality into the medical robotic platform to enhance safety during surgery.

Iron-Catalyzed Photoredox Alcohol α-C-H Alkylation and Tandem Intramolecular Cyclization: Facile Access to Multisubstituted 2,3-Dihydrofurans and γ-Butyrolactones.

Multisubstituted furans occupy a pivotal position within the realms of synthetic chemistry and pharmacological science due to their distinctive chemical configurations and inherent properties. We herein introduce a tandem difunctionalization protocol of alcohols for the efficient synthesis of multisubstituted 2,3-dihydrofurans and γ-butyrolactones through the combination of photocatalysis and iron catalysis under mild conditions. Photoredox alcohol α-C(sp3)-H activation and Pinner-type intramolecular cyclization are two key processes. This method features significant convenience, economic benefits, and environmental friendliness.

A qualitative exploration of e-cigarette prevention advertisements' effectiveness among college students in China.

INTRODUCTION: The rapid growth of e-cigarette usage among youth and young people has emerged as a significant public health concern. It is imperative to initiate effective vaping prevention campaigns and undertake relevant research to address this pressing issue. This research seeks to identify effective video advertisements to deter young people from starting to use e-cigarettes. It aims to offer evidence-based insights and recommendations for creating communication materials and designing messages for youth e-cigarette prevention efforts. METHODS: College students aged 18-24 years (n=40) participated in focus groups within this qualitative study. After viewing four stimulus videos, participants discussed what they perceived as effective and ineffective video characteristics, as well as suggestions for future videos. RESULTS: Effective video characteristics included the use of real-life testimonials, displaying specific health hazards, revealing harmful chemical ingredients and the deceptive nature of flavors, and positively perceived effectiveness. Participants generally found that videos with strong visual impact and graphics were more engaging and that approaches using fear and emotion were more effective. Ineffective characteristics included complex and exaggerated information, lack of empathy and irrelevance, insufficiently specific information, extreme and death-themed content, industry messages, as well as preachy tones, animations, metaphors, dull formats, excessive length, and scenes of e-cigarette use. CONCLUSIONS: Developing anti-e-cigarette campaign materials for youth necessitates target audience-focused qualitative research. This helps in deeply exploring and identifying effective themes and messages, as well as video characteristics and details while avoiding ineffective or even misleading messages and themes from young people's perspectives outside the United States. Future development of e-cigarette prevention videos for Chinese college students may consider incorporating localized real-life testimonial cases to convey specific harms, including self-efficacy information, and utilizing fear and emotional appeals.

TriLA: Triple-Level Alignment Based Unsupervised Domain Adaptation for Joint Segmentation of Optic Disc and Optic Cup.

Cross-domain joint segmentation of optic disc and optic cup on fundus images is essential, yet challenging, for effective glaucoma screening. Although many unsupervised domain adaptation (UDA) methods have been proposed, these methods can hardly achieve complete domain alignment, leading to suboptimal performance. In this paper, we propose a triple-level alignment (TriLA) model to address this issue by aligning the source and target domains at the input level, feature level, and output level simultaneously. At the input level, a learnable Fourier domain adaptation (LFDA) module is developed to learn the cut-off frequency adaptively for frequency-domain translation. At the feature level, we disentangle the style and content features and align them in the corresponding feature spaces using consistency constraints. At the output level, we design a segmentation consistency constraint to emphasize the segmentation consistency across domains. The proposed model is trained on the RIGA+ dataset and widely evaluated on six different UDA scenarios. Our comprehensive results not only demonstrate that the proposed TriLA substantially outperforms other state-of-the-art UDA methods in joint segmentation of optic disc and optic cup, but also suggest the effectiveness of the triple-level alignment strategy.

Tyrosine Mutation in the Characteristic Motif of the Amorphous Region of Spidroin for Self-Assembly Capability Enhancement.

Spidroin, with robust mechanical performance and good biocompatibility, could fulfill broad applications in material science and biomedical fields. Development of miniature spidroin has made abundant fiber production economically feasible, but the mechanical properties of artificial silk still fall short of natural silk. The mechanism behind mechanical properties of spidroin usually focuses on ß-microcrystalline regions; the effect of amorphous regions was barely studied. In this study, residue tyrosines (Y) were designed to replace asparagine (N)/glutamic acid (Q) in the characteristic motifs (GGX)n in amorphous regions for performance enhancement of spidroin; the mutants presented lower free energy and significantly exhibited stronger van der Waals and electrostatic interactions, which might result from π-π stacking interactions between the phenyl rings in the side chain of tyrosine. Additionally, the soluble expressions of wild-type spidroin and mutant spidroin were achieved when heterologously expressed in E. coli, with yields of 560 mg/L (2REP), 590 mg/L (2REPM), 240 mg/L (4REP), and 280 mg/L (4REPM). Significantly, secondary structure analysis confirmed that the mutant spidroin more avidly forms more ß-sheets than the wild-type spidroin, and aggregation morphology suggested that mutant spidroin displayed better self-assembly capacity and was easier to form artificial spider silk fibers; in particular, self-assembled 4REPM nanofibrils had an average modulus of 11.2 ± 0.35 GPa, about 2 times higher than self-assembled B. mori silk nanofibrils and almost the same as that of native spider dragline silk fibers (10-15 GPa). Thus, we first demonstrated a new influence mechanism of the amorphous region's characteristic motif on the self-assembly and material properties of spidroin. Our study provides a reference for the design of high-performance material proteins and their heterologous preparation.

Metabolomics and network pharmacology reveal the mechanism of antithrombotic effect of Asperosaponin VI.

Dipsaci Radix may possess antithrombotic properties, and one of its primary active ingredients is Asperosaponin VI. However, the antithrombotic effects and pharmacological mechanisms of Asperosaponin VI remain unclear. An in vivo experimental study has demonstrated the antithrombotic activity of Asperosaponin VI. Asperosaponin VI also exhibits anticoagulant properties. Asperosaponin VI significantly hindered collagen adrenergic-induced acute pulmonary thrombosis in mice and enhanced their survival rate. This hinders the formation of acute pulmonary embolisms induced by adenosine diphosphate (ADP) and decreases recovery time. A comprehensive strategy that combines metabolomics, network pharmacology, molecular docking, and experimental validation has the potential to reveal the antithrombotic mechanisms of Asperosaponin VI. Metabolomic evidence suggests that Asperosaponin VI may influence platelet aggregation and the production of anti-inflammatory metabolites through the regulation of pathways such as phenylalanine and arachidonic acid metabolism, thereby inhibiting thrombosis. Network pharmacology identified the pharmacological targets of Asperosaponin VI and indicated that it treats thrombi by partially regulating the signaling pathways related to inflammation and platelet aggregation. Asperosaponin VI showed strong binding affinity for F2, PTPRC, JUN, STAT3, SRC, AKT1. The antiplatelet aggregation activity of Asperosaponin VI was validated based on the metabolomic and network pharmacology results. Asperosaponin VI inhibits platelet aggregation induced by ADP, AA, and collagen. Therefore, Asperosaponin VI exerts antithrombotic effects through antiplatelet aggregation. Therefore, Asperosaponin VI is a promising antithrombotic agent.