Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China.

Background: Idiopathic scoliosis significantly affects the physical and mental health of children and adolescents, with varying prevalence rates in different regions. The occurrence of idiopathic scoliosis is associated with genetic regulation and biochemical factors, but the changes in exosome-derived miRNA profiles among idiopathic scoliosis patients remain unclear. This study aimed to determine the prevalence of idiopathic scoliosis in Yunnan Province, China, and identify key exosome-derived miRNAs in idiopathic scoliosis through a cohort study. Methods: From January 2018 to December 2020, a cross-sectional study on idiopathic scoliosis in children and adolescents was conducted in Yunnan Province. A total of 84,460 students from 13 cities and counties in Yunnan Province participated in a scoliosis screening program, with ages ranging from 7 to 19 years. After confirmation through screening and imaging results, patients with severe idiopathic scoliosis and normal control individuals were selected using propensity matching. Subsequently, plasma exosome-derived miRNA sequencing and RT-qPCR validation were performed separately. Based on the validation results, diagnostic performance analysis and target gene prediction were conducted for differential plasma exosome-derived miRNAs. Results: The overall prevalence of idiopathic scoliosis in children and adolescents in Yunnan Province was 1.10%, with a prevalence of 0.87% in males and 1.32% in females. The peak prevalence was observed at age 13. Among patients diagnosed with idiopathic scoliosis, approximately 12.8% had severe cases, and there were more cases of double curvature than of single curvature, with thoracolumbar curvature being the most common in the single-curvature group. Sequencing of plasma exosome-derived miRNAs associated with idiopathic scoliosis revealed 56 upregulated and 153 downregulated miRNAs. Further validation analysis confirmed that hsa-miR-27a-5p, hsa-miR-539-5p, and hsa-miR-1246 have potential diagnostic value. Conclusions: We gained insights into the epidemiological characteristics of idiopathic scoliosis in Yunnan Province and conducted further analysis of plasma exosome-derived miRNA changes in patients with severe idiopathic scoliosis. This study has provided new insights for the prevention and diagnosis of idiopathic scoliosis, paving the way for exploring clinical biomarkers and molecular regulatory mechanisms. However, further validation and elucidation of the detailed biological mechanisms underlying these findings will be required in the future.

The tricarboxylic acid cycle is inhibited under acute stress from carbonate alkalinity in the gills of Eriocheir sinensis.

Owing to population growth and environmental pollution, freshwater aquaculture has been rapidly shrinking in recent years. Aquaculture in saline-alkaline waters is a crucial strategy to meet the increasing demand for aquatic products. The Chinese mitten crab is an important economic food in China, but the molecular mechanism by which it tolerates carbonate alkalinity (CA) in water remains unclear. Here, we found that enzyme activities of the tricarboxylic acid (TCA) cycle in the gills, such as citrate synthase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase, were markedly reduced under CA stress induced by 40 mM NaHCO3. Secondly, the TCA cycle in the gills is inhibited under acute CA stress, according to proteomic and metabolomic analyses. The expressions of six enzymes, namely aconitate hydratase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, dihydrolipoyl dehydrogenase, succinate-CoA ligase, and malate dehydrogenase, were downregulated, resulting in the accumulation of phosphoenolpyruvic acid, citric acid, cis-aconitate, and α-ketoglutaric acid. Finally, we testified that if the TCA cycle is disturbed by malonate, the survival rate increases in CA water. To our knowledge, this is the first study to show that the TCA cycle in the gills is inhibited under CA stress. Overall, the results provide new insights into the molecular mechanism of tolerance to saline-alkaline water in crabs, which helped us expand the area for freshwater aquaculture and comprehensively understand the physiological characteristics of crab migration.

Focus on brain-lung crosstalk: preventing or treating the pathological vicious circle between the brain and the lung.

Recently, there has been increasing attention to bidirectional information exchange between the brain and lungs. Typical physiological data is communicated by channels like the circulation and sympathetic nervous system. However, communication between the brain and lungs can also occur in pathological conditions. Studies have shown that severe traumatic brain injury(TBI), cerebral hemorrhage, subarachnoid hemorrhage(SAH), and other brain diseases can lead to lung damage. Conversely, severe lung diseases such as acute respiratory distress syndrome(ARDS), pneumonia, and respiratory failure can exacerbate neuroinflammatory responses, aggravate brain damage, deteriorate neurological function, and result in poor prognosis. A brain or lung injury can have adverse effects on another organ through various pathways, including inflammation, immunity, oxidative stress, neurosecretory factors, microbiome and oxygen. Researchers have increasingly concentrated on possible links between the brain and lungs. However, there has been little attention given to how the interaction between the brain and lungs affects the development of brain or lung disorders, which can lead to clinical states that are susceptible to alterations and can directly affect treatment results. This review described the relationships between the brain and lung in both physiological and pathological conditions, detailing the various pathways of communication such as neurological, inflammatory, immunological, endocrine, and microbiological pathways. Meanwhile, this review provides a comprehensive summary of both pharmacological and non-pharmacological interventions for diseases related to the brain and lungs. It aims to support clinical endeavors in preventing and treating such ailments and serve as a reference for the development of relevant medications.

Exploring Bitter and Sweet: The Application of Large Language Models in Molecular Taste Prediction.

The perception of bitter and sweet tastes is a crucial aspect of human sensory experience. Concerns over the long-term use of aspartame, a widely used sweetener suspected of carcinogenic risks, highlight the importance of developing new taste modifiers. This study utilizes Large Language Models (LLMs) such as GPT-3.5 and GPT-4 for predicting molecular taste characteristics, with a focus on the bitter-sweet dichotomy. Employing random and scaffold data splitting strategies, GPT-4 demonstrated superior performance, achieving an impressive 86% accuracy under scaffold partitioning. Additionally, ChatGPT was employed to extract specific molecular features associated with bitter and sweet tastes. Utilizing these insights, novel molecular compounds with distinct taste profiles were successfully generated. These compounds were validated for their bitter and sweet properties through molecular docking and molecular dynamics simulation, and their practicality was further confirmed by ADMET toxicity testing and DeepSA synthesis feasibility. This research highlights the potential of LLMs in predicting molecular properties and their implications in health and chemical science.

A contrastive learning approach to integrate spatial transcriptomics and histological images.

The rapid growth of spatially resolved transcriptomics technology provides new perspectives on spatial tissue architecture. Deep learning has been widely applied to derive useful representations for spatial transcriptome analysis. However, effectively integrating spatial multi-modal data remains challenging. Here, we present ConGcR, a contrastive learning-based model for integrating gene expression, spatial location, and tissue morphology for data representation and spatial tissue architecture identification. Graph convolution and ResNet were used as encoders for gene expression with spatial location and histological image inputs, respectively. We further enhanced ConGcR with a graph auto-encoder as ConGaR to better model spatially embedded representations. We validated our models using 16 human brains, four chicken hearts, eight breast tumors, and 30 human lung spatial transcriptomics samples. The results showed that our models generated more effective embeddings for obtaining tissue architectures closer to the ground truth than other methods. Overall, our models not only can improve tissue architecture identification's accuracy but also may provide valuable insights and effective data representation for other tasks in spatial transcriptome analyses.

Co-expression network analysis and identification of core genes in the interaction between wheat and Puccinia striiformis f. sp. tritici.

The epidemic of stripe rust, caused by the pathogen Puccinia striiformis f. sp. tritici (Pst), would reduce wheat (Triticum aestivum) yields seriously. Traditional experimental methods are difficult to discover the interaction between wheat and Pst. Multi-omics data analysis provides a new idea for efficiently mining the interactions between host and pathogen. We used 140 wheat-Pst RNA-Seq data to screen for differentially expressed genes (DEGs) between low susceptibility and high susceptibility samples, and carried out Gene Ontology (GO) enrichment analysis. Based on this, we constructed a gene co-expression network, identified the core genes and interacted gene pairs from the conservative modules. Finally, we checked the distribution of Nucleotide-binding and leucine-rich repeat (NLR) genes in the co-expression network and drew the wheat NLR gene co-expression network. In order to provide accessible information for related researchers, we built a web-based visualization platform to display the data. Based on the analysis, we found that resistance-related genes such as TaPR1, TaWRKY18 and HSP70 were highly expressed in the network. They were likely to be involved in the biological processes of Pst infecting wheat. This study can assist scholars in conducting studies on the pathogenesis and help to advance the investigation of wheat-Pst interaction patterns.

A Vacancy-Engineering Ferroelectric Nanomedicine for Cuproptosis/Apoptosis Co-Activated Immunotherapy.

Low efficacy of immunotherapy due to the poor immunogenicity of most tumors and their insufficient infiltration by immune cells highlights the importance of inducing immunogenic cell death and activating immune system for achieving better treatment outcomes. Herein, ferroelectric Bi2CuO4 nanoparticles with rich copper vacancies (named BCO-VCu) are rationally designed and engineered for ferroelectricity-enhanced apoptosis, cuproptosis, and the subsequently evoked immunotherapy. In this structure, the suppressed recombination of the electron-hole pairs by the vacancies and the band bending by the ferroelectric polarization lead to high catalytic activity, triggering reactive oxygen species bursts and inducing apoptosis. The cell fragments produced by apoptosis serve as antigens to activate T cells. Moreover, due to the generated charge by the ferroelectric catalysis, this nanomedicine can act as "a smart switch" to open the cell membrane, promote nanomaterial endocytosis, and shut down the Cu+ outflow pathway to evoke cuproptosis, and thus a strong immune response is triggered by the reduced content of adenosine triphosphate. Ribonucleic acid transcription tests reveal the pathways related to immune response activation. Thus, this study firstly demonstrates a feasible strategy for enhancing the efficacy of immunotherapy using single ferroelectric semiconductor-induced apoptosis and cuproptosis.

Remediation of Metal Oxide Nanotoxicity with a Functional Amyloid.

Understanding the environmental health and safety of nanomaterials (NanoEHS) is essential for the sustained development of nanotechnology. Although extensive research over the past two decades has elucidated the phenomena, mechanisms, and implications of nanomaterials in cellular and organismal models, the active remediation of the adverse biological and environmental effects of nanomaterials remains largely unexplored. Inspired by recent developments in functional amyloids for biomedical and environmental engineering, this work shows their new utility as metallothionein mimics in the strategically important area of NanoEHS. Specifically, metal ions released from CuO and ZnO nanoparticles are sequestered through cysteine coordination and electrostatic interactions with beta-lactoglobulin (bLg) amyloid, as revealed by inductively coupled plasma mass spectrometry and molecular dynamics simulations. The toxicity of the metal oxide nanoparticles is subsequently mitigated by functional amyloids, as validated by cell viability and apoptosis assays in vitro and murine survival and biomarker assays in vivo. As bLg amyloid fibrils can be readily produced from whey in large quantities at a low cost, the study offers a crucial strategy for remediating the biological and environmental footprints of transition metal oxide nanomaterials.

Positional cloning and characterization reveal the role of TaSRN-3D and TaBSR1 in the regulation of seminal root number in wheat.

Seminal roots play a critical role in water and nutrient absorption, particularly in the early developmental stages of wheat. However, the genes responsible for controlling SRN in wheat remain largely unknown. Genetic mapping and functional analyses identified a candidate gene (TraesCS3D01G137200, TaSRN-3D) encoding a Ser/Thr kinase glycogen synthase kinase 3 (STKc_GSK3) that regulated SRN in wheat. Additionally, experiments involving hormone treatment, nitrate absorption and protein interaction were conducted to explore the regulatory mechanism of TaSRN-3D. Results showed that the TaSRN-3D4332 allele inhibited seminal roots initiation and development, while loss-of-function mutants showed significantly higher seminal root number (SRN). Exogenous application of epi-brassinolide could increase the SRN in a HS2-allelic background. Furthermore, chlorate sensitivity and 15N uptake assays revealed that a higher number of seminal roots promoted nitrate accumulation. TaBSR1 (BIN2-related SRN Regulator 1, orthologous to OsGRF4/GL2 in rice) acts as an interactor of TaSRN-3D and promotes TaBSR1 degradation to reduce SRN. This study provides valuable insights into understanding the genetic basis and regulatory network of SRN in wheat, highlighting their roles as potential targets for root-based improvement in wheat breeding.

pathCLIP: Detection of Genes and Gene Relations from Biological Pathway Figures through Image-Text Contrastive Learning.

In biomedical literature, biological pathways are commonly described through a combination of images and text. These pathways contain valuable information, including genes and their relationships, which provide insight into biological mechanisms and precision medicine. Curating pathway information across the literature enables the integration of this information to build a comprehensive knowledge base. While some studies have extracted pathway information from images and text independently, they often overlook the correspondence between the two modalities. In this paper, we present a pathway figure curation system named pathCLIP for identifying genes and gene relations from pathway figures. Our key innovation is the use of an image-text contrastive learning model to learn coordinated embeddings of image snippets and text descriptions of genes and gene relations, thereby improving curation. Our validation results, using pathway figures from PubMed, showed that our multimodal model outperforms models using only a single modality. Additionally, our system effectively curates genes and gene relations from multiple literature sources. Two case studies on extracting pathway information from literature of non-small cell lung cancer and Alzheimer's disease further demonstrate the usefulness of our curated pathway information in enhancing related pathways in the KEGG database.

Corrigendum: Effect of intravenous immunoglobulin therapy on the prognosis of patients with severe fever with thrombocytopenia syndrome and neurological complications.

[This corrects the article DOI: 10.3389/fimmu.2023.1118039.].

Co-exposure of polystyrene nanoplastics and copper induces development toxicity and intestinal mitochondrial dysfunction in vivo and in vitro.

Nanoplastics (NPs) have raised concerns about the combined toxicity to living organisms due to their ability to adsorb heavy metals. There is still uncertainty, however, whether NPs combined with heavy metals exert adverse effects on intestinal microenvironment, especially the intestinal cells and microbiota. Herein, the combined effects of 500 nm spherical-shaped polystyrene nanoplastics (PSNPs) and copper ions (Cu2+) on intestinal cells and gut microbiota were assessed using HCT-116 cells and zebrafish models. The combined exposure of PSNPs (10 mg/L) and Cu2+ (0.5 mg/L) induced more severer hatching interference of zebrafish embryos, deformation, and mortality. In larval stage, PSNPs (10 mg/L) accumulated and carried more Cu2+ in the gastrointestinal tract (GIT) of zebrafish after co-exposure for 5 days. Excessive neutrophil recruitment and oxidative stress in GIT of zebrafish larvae were observed. The mechanism of the combined toxicity was revealed by transmission electron microscopy (TEM) showing the injuries of GIT, transcriptome and 16S rDNA gene sequencing showing the toxicity pathways, including oxidative phosphorylation and respiratory electron transport chain, as well as microbial community analysis showing the induced microbiota dysbiosis. In vitro tests using HCT-116 cells showed that PSNPs (10 mg/L) and Cu2+ (0.5 mg/L) increased cell death while decreasing ATP concentration and mitochondrial membrane potential after 48 h exposure. These findings may provide new insights into the combined toxicity of nanoplastics and heavy metals in the intestinal microenvironment.

RIP1 kinase inactivation protects against LPS-induced acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome (ARDS) is characterized by lung tissue oedema and inflammatory cell infiltration, with limited therapeutic interventions available. Receptor-interacting protein kinase 1 (RIPK1), a critical regulator of cell death and inflammation implicated in many diseases, is not fully understood in the context of ARDS. In this study, we employed RIP1 kinase-inactivated (Rip1K45A/K45A) mice and two distinct RIPK1 inhibitors to investigate the contributions of RIP1 kinase activity in lipopolysaccharide (LPS)-induced ARDS pathology. Our results indicated that RIPK1 kinase inactivation, achieved through both genetic and chemical approaches, significantly attenuated LPS-induced ARDS pathology, as demonstrated by reduced polymorphonuclear neutrophil percentage (PMN%) in alveolar lavage fluid, expression of inflammatory and fibrosis-related factors in lung tissues, as well as histological examination. Results by tunnel staining and qRT-PCR analysis indicated that RIPK1 kinase activity played a role in regulating cell apoptosis and inflammation induced by LPS administration in lung tissue. In summary, employing both pharmacological and genetic approaches, this study demonstrated that targeted RIPK1 kinase inactivation attenuates the pathological phenotype induced by LPS inhalation in an ARDS mouse model. This study enhances our understanding of the therapeutic potential of RIPK1 kinase modulation in ARDS, providing insights for the pathogenesis of ARDS.

Integrating Protein Structure Prediction and Bayesian Optimization for Peptide Design.

Peptide design, with the goal of identifying peptides possessing unique biological properties, stands as a crucial challenge in peptide-based drug discovery. While traditional and computational methods have made significant strides, they often encounter hurdles due to the complexities and costs of laboratory experiments. Recent advancements in deep learning and Bayesian Optimization have paved the way for innovative research in this domain. In this context, our study presents a novel approach that effectively combines protein structure prediction with Bayesian Optimization for peptide design. By applying carefully designed objective functions, we guide and enhance the optimization trajectory for new peptide sequences. Benchmarked against multiple native structures, our methodology is tailored to generate new peptides to their optimal potential biological properties.

Electrospun Poly-l-Lactic Acid Membranes Promote M2 Macrophage Polarization by Regulating the PCK2/AMPK/mTOR Signaling Pathway.

Electrospun membranes are widely used in tissue engineering. Regretfully, there is limited research on how its morphological characteristics precisely regulate macrophage activation and immune response. Therefore, electrospun poly-l-lactic acid (PLLA) membranes with different alignments (align and random) and diameters (nanoscale and microscale) are prepared to investigate the effects of different surface morphologies on M2 macrophage polarization. Additionally, transcriptome, proteome, and phosphoproteome sequencings are combined to examine the underlying regulatory mechanisms. The results show that the electrospun PLLA membranes with different surface morphologies have good biocompatibility and can regulate the phenotype and function of macrophages by changing the micromorphology of the matrix surface. Especially, macrophages cultured on the electrospun membranes of the A600 group exhibit higher M2 macrophage polarization than the other three groups. Furthermore, the findings demonstrate that electrospun PLLA membranes enhance AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling activation by upregulating the expression of integrin phosphoenolpyruvate carboxykinase 2 (PCK2), which is critical for M2 macrophage polarization. Taken together, electrospun PLLA membranes promote M2 macrophage polarization by regulating the PCK2/AMPK/mTOR signaling pathway. This research can provide further theoretical bases for scaffold design, immunoregulatory mechanisms, and clinical application based on electrospinning technology in the future.

Evolutionary genomics of climatic adaptation and resilience to climate change in alfalfa.

Given the escalating impact of climate change on agriculture and food security, gaining insights into the evolutionary dynamics of climatic adaptation and uncovering climate-adapted variation empower the breeding of climate-resilience crops to face future climate change. Alfalfa (Medicago sativa subsp. sativa), the queen of forages with remarkable adaptability across diverse global environments, is an excellent model for investigating species' responses to climate change. We conducted population genomic analyses to unravel alfalfa's climatic adaptation and genetic susceptibility to future climate change, utilizing genome resequencing data from 702 accessions of 24 Medicago species. We found that interspecific genetic exchange has fueled the gene pool of alfalfa, particularly enriching defense and stress response genes. Inter-subspecific introgression between Medicago sativa subsp. falcata (subsp. falcata) and alfalfa not only aids alfalfa's climatic adaptation but also introduces genetic burden. A total of 1671 genes were associated with climatic adaptation, and 5.7% of them were introgression from subsp. falcata. Integrating climate-associated variants and climate data, we identified vulnerable populations to future climate change, particularly in higher latitudes of the northern hemisphere, serving as a clarion call for targeted conservation initiatives and breeding efforts. Moreover, we unveil pre-adaptive populations demonstrating heightened resilience to climate fluctuations, illuminating a pathway for future breeding strategies. This study enhances our understanding of alfalfa's local adaptation and facilitates breeding of climate-resilient cultivars, contributing to effective agricultural strategies facing future climate change.

Venetoclax combined chemotherapy versus chemotherapy alone for acute myeloid leukemia: a systematic review and meta-analysis.

Objective: To compare the efficacy and safety of venetoclax (VEN) in combination with chemotherapy (chemo) versus chemo alone in the treatment of acute myeloid leukemia (AML). Method: To compare the efficacy and/or safety of VEN+chemo versus chemotherapy alone for AML, PubMed, Embase, Web of Science, and the Cochrane Library were used to searching up to June 2023. Comparisons included complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), overall response rate (ORR), and adverse events (AEs). Result: A total of 9 articles were included, including 3124 patients. The baseline characteristics between two patient groups were similar. The combined analysis showed that compared with the group receiving chemo alone, the VEN+chemo group exhibited higher rates of CR, CRi, MLFS and ORR. Additionally, the VEN+chemo group had longer event-free survival (EFS) and overall survival (OS) durations. The incidence rates of AEs and serious AEs (SAEs) were similar between the two groups, but the early 30-day mortality rate was lower in the VEN+chemo group than in the chemo alone group. Conclusion: The VEN+chemo therapy demonstrates significant efficacy and safety profile in AML patients. However, more prospective studies are needed in the future to provide more accurate and robust evidence for treatment selection in patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023439288, identifier CRD42023439288.

Rapid and Green Fabrication of Nanozyme with Geminal CuN3O Configuration for Efficient Catecholase-Mimicking.

Fabrication of nanozyme with catecholase-like catalytic activity faces the great challenge of merging outstanding activity with low cost as well as simple, rapid, and low-energy-consumed production, restricting its industrial applications. Herein, an inexpensive yet robust nanozyme (i.e., DT-Cu) via simple one-step coordination between diaminotriazole (DT) and CuSO4 within 1 h in water at room temperature is constructed. The asymmetric dicopper site with CuN3O configuration for each copper as well as Cu─O bond length of ≈1.83 Å and Cu···Cu distance of ≈3.5 Å in DT-Cu resemble those in catechol oxidase (CO), which ensure its prominent intrinsic activity, outperforming most CO-mimicking nanozymes and artificial homogeneous catalysts. The use of inexpensive DT/CuSO4 in this one-pot strategy endows DT-Cu with only ≈20% cost of natural CO per activity unit. During catalysis, O2 experienced a 4e-dominated reduction process accompanied by the formation of 1O2 and H2O2 intermediates and the product of H2O. Benefiting from the low cost as well as the distinctive structure and superior intrinsic activity, DT-Cu presents potential applications ranging from biocatalysis to analytical detection of biomolecules such as epinephrine and beyond.

Creep constitutive modeling of the shear strength of the permafrost-concrete interface considering the stress level at -1°C.

The shear creep characteristics of the contact surface between the permafrost and the structure play an important role in the study of the law of deformation and the measures for the prevention and control of pile foundations. In order to study the creep law and the development tendency of the contact surface between permafrost and concrete, it is necessary to establish an accurate creep model. In this study, based on the Nishihara model, a nonlinear element and damage factor D were introduced to establish an intrinsic model of permafrost-concrete contact surfaces considering the effect of shear stress. Creep tests with graded loading of concrete and frozen silt with different roughness at -1°C were conducted using a large stress-controlled shear apparatus. The adequacy of the model was checked using the test data and the regularity of the parameters of the model was investigated. The results show that the creep curves of the contact surface obtained with the improved Nishihara model agree well with the test results and can better describe the whole process of creep of the contact surface of frozen concrete. The analysis of the experimental data shows that: the roughness of the concrete has an inhibiting effect on the creep deformation of the contact surface, When the roughness R varies from 0 mm to 1.225 mm, the specimen corresponds to a long-term strength of 32.84 kPa to 34.57 kPa. For the same roughness and creep time, the creep deformation of the contact surface is more significant with the increasing shear stress τ. The results of the study can provide a theoretical basis for the design and numerical simulation of pile foundations in permafrost regions.