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Abstract Posttraumatic stress disorder (PTSD) is associated with glutamatergic neuron hyperactivation in the basolateral amygdala (BLA) brain area, while GABAergic interneurons in the BLA modulate glutamatergic neuron excitability. Studies have shown that propofol exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid. The neuronal mechanism by which propofol anesthesia modulates fear memory is currently unknown. Here, we used optogenetics and chemogenetics to suppress glutamatergic neurons or activate GABAergic interneurons in the BLA to assess alterations in neuronal excitation-inhibition balance and investigate fear memory. The excitability of glutamatergic neurons in the BLA was significantly reduced by the suppression of glutamatergic neurons or activation of GABAergic interneurons, while propofol-mediated enhancement of fear memory was attenuated. We suggest that propofol anesthesia could reduce the excitability of GABAergic neurons through activation of GABAA receptors, subsequently increasing the excitability of glutamatergic neurons in the mice BLA; the effect of propofol on enhancing mice fear memory might be mediated by strengthening glutamatergic neuronal excitability and decreasing the excitability of GABAergic neurons in the BLA; neuronal excitation-inhibition imbalance in the BLA might be important in mediating the enhancement of fear memory induced by propofol.

Abstract The prolonged war in Ukraine is having a strong impact on all sectors of the Ukrainian society, including biomedical research. Although the material and psychological conditions are challenging, the country and its researchers are courageously managing to continue their activities. This perspective paper describes the multiple challenges faced by Ukrainian biomedical researchers during wartime and outlines strategies to support and enhance collaboration with the global scientific community. Ukraine has a rich scientific history and modern expertise in biomedical research, and developing more international collaborations with Ukraine can have mutual benefits for all involved parties.

Abstract Cellular bioenergetics and mitochondrial dynamics are crucial for the secretion of insulin by pancreatic beta cells in response to elevated levels of blood glucose. To elucidate the interactions between energy production and mitochondrial fission/fusion dynamics, we combine live-cell mitochondria imaging with biophysical-based modeling and graph-based network analysis. The aim is to determine the mechanism that regulates mitochondrial morphology and balances metabolic demands in pancreatic beta cells. A minimalistic differential equation-based model for beta cells is constructed that includes glycolysis, oxidative phosphorylation, calcium dynamics, and fission/fusion dynamics, with ATP synthase flux and proton leak flux as main regulators of mitochondrial dynamics. The model shows that mitochondrial fission occurs in response to hyperglycemia, starvation, ATP synthase inhibition, uncoupling, and diabetic conditions, in which the rate of proton leakage exceeds the rate of mitochondrial ATP synthesis. Under these metabolic challenges, the propensities of tip-to-tip fusion events simulated from the microscopy images of the mitochondrial networks are lower than those in the control group and prevent the formation of mitochondrial networks. The study provides a quantitative framework that couples bioenergetic regulation with mitochondrial dynamics, offering insights into how mitochondria adapt to metabolic challenges.

Frozen shoulder (FS) manifests as progressively worsening pain and a reduction in shoulder range of motion (ROM). Salvianolic acid B (SaB) is recently expected to be used in the treatment of fibrosis diseases including FS. We firstly demonstrate that SaB can effectively hinder the progression of oxidative stress, inflammation, and pathological fibrosis within the synovial tissue in FS, potentially leading to the reduction or reversal of capsule fibrosis and joint stiffness. For further clinical application, we design and synthesize a novel, superior, antioxidant and antibacterial CSMA-PBA/OD-DA (CPDA) hydrogel for the delivery of SaB. In vitro experiments demonstrate that the CPDA hydrogel exhibits excellent biocompatibility and rheological properties, rendering it suitable for intra-articular injections. Upon injection into the contracted joint cavity of FS model rat, the SaB-CPDA hydrogel accelerate the recovery of ROM and exhibit superior anti-fibrosis effect, presenting the promise for the treatment of FS in vivo.

Dracocephalum moldavica is widely used as an ornamental, medicine, and perfume in industry. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) is widely and accurately utilized for gene expression evaluations. Selecting optimal reference genes is essential for normalizing RT-qPCR results. However, the identification of suitable reference genes in D. moldavica has not been documented. A total of 12 reference genes in D. moldavica were identified by PEG6000 (15%) treatment under hypertonia conditions in different tissues (roots, stem, leaves, flower, seeds and sepal) and during three stages of flower development, then used to validate the expression stability. There were four algorithms (delta Ct, geNorm, NormFinder, and BestKeeper) used to analyze the stability. Finally, the RefFinder program was employed to evaluate the candidate reference genes’ stability. The results showed that ACTIN, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and EF1α (elongation factor-1α) were stable reference genes under the PEG6000 treatment. Heat shock protein 70 (HSP70) was the most stable gene across different flower development stages. ADP-ribosylation factor (ARF) was the most stable gene in different tissues and total samples. This study provides reliable gene expression studies for future research in D. moldavica.

Stroke is recognized as a network communication disorder. Advances in neuroimaging technologies have enhanced our comprehension of dynamic cerebral alterations. However, different levels of motor function impairment after stroke may have different patterns of brain reorganization. Abnormal and adaptive patterns of brain activity in mild-to-moderate motor function impairments after stroke remain still underexplored. We aim to identify dynamic patterns of network remodeling in stroke patients with mild-to-moderate impairment of motor function. fMRI data were obtained from 30 stroke patients and 31 healthy controls to establish a spatiotemporal multilayer modularity model. Then, graph-theoretic measures, including modularity, flexibility, cohesion, and disjointedness, were calculated to quantify dynamic reconfiguration. Our findings reveal that the post-stroke brain exhibited higher modular organization, as well as heightened disjointedness, compared to HCs. Moreover, analyzing from the network level, we found increased disjointedness and flexibility in the Default mode network (DMN), indicating that brain regions tend to switch more frequently and independently between communities and the dynamic changes were mainly driven by DMN. Notably, modified functional dynamics positively correlated with motor performance in patients with mild-to-moderate motor impairment. Collectively, our research uncovered patterns of dynamic community reconstruction in multilayer networks following stroke. Our findings may offer new insights into the complex reorganization of neural function in post-stroke brain.

As a master regulator of seed development, Leafy Cotyledon 1 (LEC1) promotes chlorophyll (Chl) biosynthesis in Arabidopsis, but the mechanism underlying this remains poorly understood. Here, we found that loss of function of OsNF-YB7, a LEC1 homolog of rice, leads to chlorophyllous embryo, indicating that OsNF-YB7 plays an opposite role in Chl biosynthesis in rice compared with that in Arabidopsis. OsNF-YB7 regulates the expression of a group of genes responsible for Chl biosynthesis and photosynthesis by directly binding to their promoters. In addition, OsNF-YB7 interacts with Golden 2-Like 1 (OsGLK1) to inhibit the transactivation activity of OsGLK1, a key regulator of Chl biosynthesis. Moreover, OsNF-YB7 can directly repress OsGLK1 expression by recognizing its promoter in vivo, indicating the involvement of OsNF-YB7 in multiple regulatory layers of Chl biosynthesis in rice embryo. We propose that OsNF-YB7 functions as a transcriptional repressor to regulate Chl biosynthesis in rice embryo.

Abstract Transcriptional regulation plays a crucial role in determining cell fate and disease, yet inferring the key regulators from gene expression data remains a significant challenge. Existing methods for estimating transcription factor (TF) activity often rely on static TF-gene interaction databases and cannot adapt to changes in regulatory mechanisms across different cell types and disease conditions. Here, we present a new algorithm - Transcriptional Inference using Gene Expression and Regulatory data (TIGER) - that overcomes these limitations by flexibly modeling activation and inhibition events, up-weighting essential edges, shrinking irrelevant edges towards zero through a sparse Bayesian prior, and simultaneously estimating both TF activity levels and changes in the underlying regulatory network. When applied to yeast and cancer TF knock-out datasets, TIGER outperforms comparable methods in terms of prediction accuracy. Moreover, our application of TIGER to tissue- and cell-type-specific RNA-seq data demonstrates its ability to uncover differences in regulatory mechanisms. Collectively, our findings highlight the utility of modeling context-specific regulation when inferring transcription factor activities.

Abstract New concept for the development of supramolecular assemblies from intricate interactions between different classes of biomacromolecules (polysaccharides, proteins and lipids) is yet to come, due to their intrinsic chemical and structural complexity and incompatibility. Herein, we report an interaction mechanism among multiple biomacromolecules, and the structural and digestive properties of their assemblies using amylose (AM), lauric acid (LA), and β‐lactoglobulin (βLG) as exemplars. AM, LA, and βLG interact to form a water‐soluble ternary complex through van der Waals forces between AM and LA and high affinity binding between AM and βLG, which can further assemble into uniform‐sized, semi‐crystalline nanospheres under certain thermodynamic conditions. These nanospheres are substantially resistant to amylolysis, thus can be well utilized by gut microbiota, including increasing short‐chain fatty acid levels and shaping bacterial communities. Illustrating the complexation of AM, LA, and βLG and their assemblies from disorder to order, this work offers potential rationale of assemblies for multiple biomacromolecules driven by non‐covalent interactions and substantial potentials for supramolecular biomaterials development.

Meiosis is a critical process in sexual reproduction, and errors during this cell division can significantly impact fertility. Successful meiosis relies on the coordinated action of numerous genes involved in DNA replication, strand breaks, and subsequent rejoining. DNA topoisomerase enzymes play a vital role by regulating DNA topology, alleviating tension during replication and transcription. To elucidate the specific function of DNA topoisomerase 1α ( $AtTOP1 \alpha$AtTOP1α ) in male reproductive development of Arabidopsis thaliana, we investigated meiotic cell division in Arabidopsis flower buds. Combining cytological and biochemical techniques, we aimed to reveal the novel contribution of $AtTOP1 \alpha$AtTOP1α to meiosis. Our results demonstrate that the absence of $AtTOP1 \alpha$AtTOP1α leads to aberrant chromatin behavior during meiotic division. Specifically, the top1α1 mutant displayed altered heterochromatin distribution and clustered centromere signals at early meiotic stages. Additionally, this mutant exhibited disruptions in the distribution of 45s rDNA signals and a reduced frequency of chiasma formation during metaphase I, a crucial stage for genetic exchange. Furthermore, the atm-2×top1α1 double mutant displayed even more severe meiotic defects, including incomplete synapsis, DNA fragmentation, and the presence of polyads. These observations collectively suggest that $AtTOP1 \alpha$AtTOP1α plays a critical role in ensuring accurate meiotic progression, promoting homologous chromosome crossover formation, and potentially functioning in a shared DNA repair pathway with ATAXIA TELANGIECTASIA MUTATED (ATM) in Arabidopsis microspore mother cells.

Background Myocardial ischemia–reperfusion injury (MIRI) refers to severe damage to the ischemic myocardium following the restoration of blood flow, and it is a major complication of reperfusion therapy for myocardial infarction. Notably, drugs such as metoprolol have been utilized to reduce ischemia–reperfusion injury. Tanshinone IIA is a major constituent extracted from Salvia miltiorrhiza Bunge. Recently, tanshinone IIA has been studied extensively in animal models for controlling MIRI. Therefore, we conducted a meta-analysis on the application of tanshinone IIA in rat models with MIRI to evaluate the therapeutic effects of tanshinone IIA. Methods A comprehensive search was conducted across PubMed, Web of Science, Embase, the Cochrane Library, the China National Knowledge Infrastructure database, the Wanfang database, and the Chinese Scientific Journal Database to gather studies on tanshinone IIA intervention in rat models with MIRI.We employed SYRCLE’s risk of bias tool to assess study quality. The primary outcome indicators were superoxide dismutase (SOD) and malondialdehyde (MDA). Myocardial infarction area was a secondary outcome indicator. This study was registered at PROSPERO (registration number CRD 42022344447). Results According to the inclusion and exclusion criteria, 15 eligible studies were selected from 295 initially identified studies. In rat models with MIRI, tanshinone IIA significantly increased SOD levels while reducing MDA levels and myocardial infarction area. Moreover, the duration of myocardial ischemia influenced the effectiveness of tanshinone IIA. However, additional high-quality research studies are needed to establish the efficacy and definitive guidelines for the use of tanshinone IIA. Animal studies demonstrated that tanshinone IIA exerted a significant therapeutic effect when the ischemia duration was less than 40 minutes. Tanshinone IIA was found to be more effective when administered via intravenous, intraperitoneal, and intragastric routes at doses above 5 mg/kg. Additionally, treatment with tanshinone IIA at all stages—prior to myocardial ischemia, after ischemia but before reperfusion, prior to ischemia and after reperfusion, and after reperfusion—showed satisfactory results. Conclusions Tanshinone IIA enhanced SOD activity and reduced MDA levels, thereby ameliorating oxidative stress damage during MIRI. Additionally, it reduced the myocardial infarction area, indicating its effectiveness in mitigating MIRI-induced damage in rats and demonstrating a myocardial protective effect. These findings contribute valuable insights for developing MIRI treatment strategies.

Daylily (Hemerocallis citrina) is a perennial herb of the genus Hemerocallis of Liliaceae. It is also an economically important crop and is widely cultivated. Daylily has nutritional, medicinal and ornamental values. The research literature shows that daylily is a high-quality food raw material rich in soluble sugars, ascorbic acid, flavonoids, dietary fiber, carotenoids, mineral elements, polyphenols and other nutrients, which are effective in clearing heat and diuresis, resolving bruises and stopping bleeding, strengthening the stomach and brain, and reducing serum cholesterol levels. This article reviews the main nutrients of daylily and summarizes the drying process of daylily. In addition, due to the existence of active ingredients, daylily also has a variety of biological activities that are beneficial to human health. This article also highlights the nutritional quality of daylily, the research progress of dried vegetable rehydration technology and dried daylily. In the end, the undeveloped molecular mechanism and functional research status of daylily worldwide are introduced in order to provide reference for the nutritional quality research and dried processing industry of daylily.

This study aimed to clarify the role of pituitary tumor-transforming gene 1 (PTTG1) in proliferation, migration, invasion, and aerobic glycolysis of pancreatic cancer cells, and evaluate the potential of PTTG1 as a therapeutic target. PTTG1 expression in pancreatic cancers was analyzed using the GEPIA databank. In the Panc1 cell with the PTTG1 knockdown or Mia-PaCa2 cells with PTTG1 overexpression, the cell proliferation was evaluated using cell viability curves and colony formation, and wound heal assay and transwell assay were performed to evaluate the migration and invasion, respectively. Furthermore, a western blot was performed to evaluate the expressions of PTTG1, proliferating cell nuclear antigen, E-cadherin, N-cadherin, and c-myc. Meanwhile, the glucose uptake, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR) were analyzed. Our results showed that PTTG1 expression is upregulated in pancreatic cancer, which promoted cell proliferation. Low PTTG1 contributed to higher disease-free survival and overall survival. In Panc1 cell, PTTG1 knockdown resulted in reduced cell viability and colony formation. The migration and invasion abilities of the cells were also reduced in Panc1 with PTTG1 knockdown. Correspondingly, PTTG1 knockdown decreased c-myc expression, glucose uptake, ECAR, and OCR in Panc1 cells. In Mia-PaCa2 cells, PTTG1 overexpression promoted cell proliferation, aerobic glycolysis, and translocation of β-catenin to the nucleus by regulating c-myc. In conclusion, PTTG1 induces proliferation, migration, and invasion, and promotes aerobic glycolysis in pancreatic cancer cells via regulating c-myc, demonstrating the potential of PTTG1 as a therapeutic target.

Abstract Background Congenital heart defects (CHDs) are the most common birth defects. Assessment of the incidence, distribution, disease spectrum, and genetic deficits of fetal CHDs in China is urgently needed. Methods A national echocardiography screening program for fetal CHDs was implemented in 92 prenatal screening–diagnostic centers in China. Findings A total of 18,171 fetal CHD cases were identified from 2,452,249 pregnancies, resulting in 7·4/1,000 as the national incidence rate of fetal CHD. The incidences of fetal CHD in the six geographical regions, the southern, central, eastern, southwestern, northern, and northwestern, were 7·647 (CI: 7·383–7·915), 7·839 (CI: 7·680–8·000), 7·647 (CI: 7·383–7·915), 7·562 (CI: 7·225–7·907), 5·618 (CI: 5·337–5·906), and 4·716 (CI: 4·341–5·108), respectively, per 1,000 pregnancies. Overall, ventricular septal defect was the most common fetal CHD, accounting for 17.04% of screened pregnancies nationwide, and tetralogy of Fallot, the most common anomaly in the major defect of fetal CHD, was the second most common, accounting for 9.72%. A total of 76.24% cases of fetal CHD were found to be an isolated intracardiac single defect. The remaining 23.76% of cases of fetal CHD had multiple heart defects. Among all extracardiac malformations, the central nervous system (CNS) was the most common tissue with extracardiac anomalies associated with CHD, accounting for 22.89% of fetal CHD cases. Chromosomal karyotyping identified trisomy 18 as the most common chromosomal abnormality in fetal CHD. We also documented that CHD-containing syndromes could be identified with a comprehensive approach integrating prenatal ultrasound, MRI, pathological autopsy, and cytogenetics and molecular genetics. Conclusion Implementation of prenatal echocardiography as a practically feasible platform to screen fetal CHD will reduce the financial and emotional burden of CHD, which may facilitate intrauterine and neonatal intervention of CHD.

Akebia trifoliata is an economically important, self-incompatible fruit tree in the Lardizabalaceae family. Asexual propagation is the main strategy used to maintain excellent agronomic traits. However, the generation of adventitious roots during asexual propagation is very difficult. To study the important role of the WUSCHEL-related homeobox (WOX) transcription factor in adventitious root growth and development, we characterized this transcription factor family in the whole genome of A. trifoliata. A total of 10 AktWOXs were identified, with the following characteristics: length (657~11,328 bp), exon number (2~5), isoelectric point (5.65~9.03), amino acid number (176~361 AA) and molecular weight (20.500~40.173 kDa), and their corresponding expression sequence could also be detectable in the public transcriptomic data for A. trifoliata fruit. A total of 10 AktWOXs were classified into modern (6), intermediate (2) and ancient clades (2) and all AktWOXs had undergone strong purifying selection during evolution. The expression profile of AktWOXs during A. trifoliata adventitious root formation indicated that AktWOXs play an important role in the regulation of adventitious root development. Overall, this is the first study to identify and characterize the WOX family in A. trifoliata and will be helpful for further research on A. trifoliata adventitious root formation.

Amid the vigorous development of the high-speed rail (HSR) network, local governments in China generally consider the construction of HSR as a crucial task in their regional development strategies. Currently, most provincial capitals and prefecture-level cities in the eastern and central regions of China already have operational HSR services. This study aims to examine a key question: has the objective of local governments to promote urban development through the construction of HSR been effective? The research selects cities along the Beijing–Shanghai, Beijing–Guangzhou, and Harbin–Dalian HSR lines as the study subjects. Based on the principles of proximity and similarity, cities with operational HSR and those without are chosen as the experimental group and the control group, respectively. Following the double difference (difference-in-differences) approach, an advantage index is proposed to systematically evaluate the impact of HSR operation on urban development from three dimensions: population aggregation, economic development, and expansion of construction land. Furthermore, the evaluation results are systematically clustered to identify city types that exhibit different promotional effects in various dimensions. The research findings indicate the following: (1) The promotion effect of HSR on the development of small to medium-sized cities is more reflected in economic growth and construction land growth. (2) The promotion effect of HSR on the development of large cities is more reflected in the growth of the employment population. (3) For smaller or economically less-developed cities, HSR may be detrimental to the aggregation of resident and employment populations. (4) Cities with moderate size and good economic development have the opportunity to use HSR to promote population aggregation. On this basis, combined with the findings above, strategies to promote the coordinated development of high-speed rail construction and urban systems are discussed.

The emergence of AIGC has significantly improved design efficiency, enriched creativity, and promoted innovation in the design industry. However, whether the content generated from its own database meets the preferences of target users still needs to be determined through further testing. This study investigates the appeal of AI-generated stylized products to users, utilizing 12 images as stimuli in conjunction with eye-tracking technology. The stimulus is composed of top-selling gender-based stylized Bluetooth earphones from the Taobao shopping platform and the gender-based stylized earphones generated by the AIGC software GPT4.0, categorized into three experimental groups. An eye-tracking experiment was conducted in which 44 participants (22 males and 22 females, mean age = 21.75, SD = 2.45, range 18–27 years) observed three stimuli groups. The eye movements of the participants were measured while viewing product images. The results indicated that variations in stimuli category and gender caused differences in fixation durations and counts. When presenting a mix of the two types of earphones, the AIGC-generated earphones and earphones from the Taobao shopping platform, the two gender groups both showed a significant effect in fixation duration with F (2, 284) = 3.942, p = 0.020 < 0.05, and η = 0.164 for the female group and F (2, 302) = 8.824, p < 0.001, and η = 0.235 for the male group. They all had a longer fixation duration for the AI-generated earphones. When presenting exclusively the two types of AI-generated gender-based stylized earphones, there was also a significant effect in fixation duration with F (2, 579) = 4.866, p = 0.008 < 0.05, and η = 0.129. The earphones generated for females had a longer fixation duration. Analyzing this dataset from a gender perspective, there was no significant effect when the male participants observed the earphones, with F (2, 304) = 1.312 and p = 0.271, but there was a significant difference in fixation duration when the female participants observed the earphones (F (2, 272) = 4.666, p = 0.010 < 0.05, and η = 0.182). The female participants had a longer fixation duration towards the earphones that the AI generated for females.

Background Promoter hypermethylation of the tumor suppressor gene is one of the well-studied causes of cancer development. The drugs that reverse the process by driving demethylation could be a candidate for anticancer therapy. This study was designed to investigate the effects of arsenic disulfide on PTPL1 methylation in diffuse large B cell lymphoma (DLBCL). Methods We knocked down the expression of PTPL1 in two DLBCL cell lines (i.e., DB and SU-DHL-4 cells) using siRNA. Then the DLBCL proliferation was determined in the presence of PTPL1 knockdown. The methylation of PTPL1 in DLBCL cells was analyzed by methylation specific PCR (MSPCR). The effect of arsenic disulfide on the PTPL1 methylation was determined in DLBCL cell lines in the presence of different concentrations of arsenic disulfide (5 µM, 10 µM and 20 µM), respectively. To investigate the potential mechanism on the arsenic disulfide-mediated methylation, the mRNA expression of DNMT1, DNMT3B and MBD2 was determined. Results PTPL1 functioned as a tumor suppressor gene in DLBCL cells, which was featured by the fact that PTPL1 knockdown promoted the proliferation of DLBCL cells. PTPL1 was found hypermethylated in DLBCL cells. Arsenic disulfide promoted the PTPL1 demethylation in a dose-dependent manner, which was related to the inhibition of DNMTs and the increase of MBD2. Conclusion Experimental evidence shows that PTPL1 functions as a tumor suppressor gene in DLBCL progression. PTPL1 hyper-methylation could be reversed by arsenic disulfide in a dose-dependent manner.

Polycomb group (PcG) proteins are a subset of epigenetic factors that are highly conserved throughout evolution. In mammals, PcG proteins can be classified into two muti-proteins complexes: Polycomb repressive complex 1 (PRC1) and PRC2. Increasing evidence has demonstrated that PcG complexes play critical roles in the regulation of gene expression, genomic imprinting, chromosome X-inactivation, and chromatin structure. Accordingly, the dysfunction of PcG proteins is tightly orchestrated with abnormal developmental processes. Here, we summarized and discussed the current knowledge of the biochemical and molecular functions of PcG complexes, especially the PRC1 and PRC2 in mammalian development including embryonic development and tissue development, which will shed further light on the deep understanding of the basic knowledge of PcGs and their functions for reproductive health and developmental disorders.

Abstract To enhance the AlphaFold-Multimer-based protein complex structure prediction, we developed a quaternary structure prediction system (MULTICOM) to improve the input fed to AlphaFold-Multimer and evaluate and refine its outputs. MULTICOM samples diverse multiple sequence alignments (MSAs) and templates for AlphaFold-Multimer to generate structural predictions by using both traditional sequence alignments and Foldseek-based structure alignments, ranks structural predictions through multiple complementary metrics, and refines the structural predictions via a Foldseek structure alignment-based refinement method. The MULTICOM system with different implementations was blindly tested in the assembly structure prediction in the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) in 2022 as both server and human predictors. MULTICOM_qa ranked 3rd among 26 CASP15 server predictors and MULTICOM_human ranked 7th among 87 CASP15 server and human predictors. The average TM-score of the first predictions submitted by MULTICOM_qa for CASP15 assembly targets is ~0.76, 5.3% higher than ~0.72 of the standard AlphaFold-Multimer. The average TM-score of the best of top 5 predictions submitted by MULTICOM_qa is ~0.80, about 8% higher than ~0.74 of the standard AlphaFold-Multimer. Moreover, the Foldseek Structure Alignment-based Multimer structure Generation (FSAMG) method outperforms the widely used sequence alignment-based multimer structure generation.

Disulfidptosis is a newly discovered cellular programmed cell death mode. Presently, a considerable number of genes related to disulfidptosis remain undiscovered, and its significance in hepatocellular carcinoma remains unrevealed. We have developed a powerful analytical method called RF-GSEA for identifying potential genes associated with disulfidptosis. This method draws inspiration from gene regulation networks and graph theory, and it is implemented through a combination of random forest regression model and Gene Set Enrichment Analysis. Subsequently, to validate the practical application value of this method, we applied it to hepatocellular carcinoma. Based on the RF-GSEA method, we developed a disulfidptosis-related signature. Lastly, we looked into how the disulfidptosis-related signature is connected to HCC prognosis, the tumor microenvironment, the effectiveness of immunotherapy, and the sensitivity of chemotherapy drugs. The RF-GSEA method identified a total of 220 disulfidptosis-related genes, from which 7 were selected to construct the disulfidptosis-related signature. The high-disulfidptosis-related score group had a worse prognosis compared to the low-disulfidptosis-related score group and showed lower infiltration levels of immune-promoting cells. The high-disulfidptosis-related score group had a higher likelihood of benefiting from immunotherapy compared to the low-disulfidptosis-related score group. The RF-GSEA method is a powerful tool for identifying disulfidptosis-related genes. The disulfidptosis-related signature effectively predicts HCC prognosis, immunotherapy response, and drug sensitivity.

Tea plants are a perennial crop with significant economic value. Chlorophyll, a key factor in tea leaf color and photosynthetic efficiency, is affected by the photoperiod and usually exhibits diurnal and seasonal variations. In this study, high-throughput transcriptomic analysis was used to study the chlorophyll metabolism, under different photoperiods, of tea plants. We conducted a time-series sampling under a skeleton photoperiod (6L6D) and continuous light conditions (24 L), measuring the chlorophyll and carotenoid content at a photoperiod interval of 3 h (24 h). Transcriptome sequencing was performed at six time points across two light cycles, followed by bioinformatics analysis to identify and annotate the differentially expressed genes (DEGs) involved in chlorophyll metabolism. The results revealed distinct expression patterns of key genes in the chlorophyll biosynthetic pathway. The expression levels of CHLE (magnesium-protoporphyrin IX monomethyl ester cyclase gene), CHLP (geranylgeranyl reductase gene), CLH (chlorophyllase gene), and POR (cytochrome P450 oxidoreductase gene), encoding enzymes in chlorophyll synthesis, were increased under continuous light conditions (24 L). At 6L6D, the expression levels of CHLP1.1, POR1.1, and POR1.2 showed an oscillating trend. The expression levels of CHLP1.2 and CLH1.1 showed the same trend, they both decreased under light treatment and increased under dark treatment. Our findings provide potential insights into the molecular basis of how photoperiods regulate chlorophyll metabolism in tea plants.

Polyvalent passive vaccines can act fast in resisting various bacteria with good efficacy, and they have application value in aquaculture. This study prepared live and inactivated Vibrio fluvialis mouse antisera (L-VF-antiserum and I-VF-antiserum), and administered them to goldfish (Carassius auratus) infected with V. fluvialis and Aeromonas hydrophila. The passive protective rates of live and inactivated mouse antisera against V. fluvialis were 60% (p < 0.05) and 40% (p < 0.05), and their passive cross-protective rates against A. hydrophila were 42.86% (p < 0.05) and 35.71% (p < 0.05), respectively. Furthermore, the two mouse antisera could recognize the bacteria in vitro; the content of bacteria in the C. auratus kidney decreased (p < 0.05), the phagocytic activity of C. auratus leukocytes was enhanced (p < 0.05), and the expression of inflammatory genes and activity of antioxidant factors decreased (p < 0.05). Moreover, the kidney, spleen, and intestinal tissue structures were intact, and the apoptosis and DNA damage were decreased (p < 0.05) among the kidney cells. The live V. fluvialis antiserum contained more antibodies against the outer membrane proteins of V. fluvialis than the inactivated mouse antiserum. The immunoprotective abilities of the live V. fluvialis antiserum were higher than those of the inactivated antiserum, and the antiserum of live V. fluvialis immunity demonstrated potential application value as a polyvalent passive immune vaccine in fish.

Sepsis is now defined as a life-threatening syndrome of organ dysfunction triggered by a dysregulated host response to infection, posing significant challenges in critical care. The main objective of this review is to evaluate the potential of emerging biomarkers for early diagnosis and accurate prognosis in sepsis management, which are pivotal for enhancing patient outcomes. Despite advances in supportive care, traditional biomarkers like C-reactive protein and procalcitonin have limitations, and recent studies have identified novel biomarkers with increased sensitivity and specificity, including circular RNAs, HOXA distal transcript antisense RNA, microRNA-486-5p, protein C, triiodothyronine, and prokineticin 2. These emerging biomarkers hold promising potential for the early detection and prognostication of sepsis. They play a crucial role not only in diagnosis but also in guiding antibiotic therapy and evaluating treatment effectiveness. The introduction of point-of-care testing technologies has brought about a paradigm shift in biomarker application, enabling swift and real-time patient evaluation. Despite these advancements, challenges persist, notably concerning biomarker variability and the lack of standardized thresholds. This review summarizes the latest advancements in sepsis biomarker research, spotlighting the progress and clinical implications. It emphasizes the significance of multi-biomarker strategies and the feasibility of personalized medicine in sepsis management. Further verification of biomarkers on a large scale and their integration into clinical practice are advocated to maximize their efficacy in future sepsis treatment.

Angelica dahurica var. formosana (ADF), which belongs to the Umbelliferae family, is one of the original plants of herbal raw material Angelicae Dahuricae Radix. ADF roots represent an enormous biomass resource convertible for disease treatment and bioproducts. But, early bolting of ADF resulted in lignification and a decrease in the coumarin content in the root, and roots lignification restricts its coumarin for commercial utility. Although there have been attempts to regulate the synthesis ratio of lignin and coumarin through biotechnology to increase the coumarin content in ADF and further enhance its commercial value, optimizing the biosynthesis of lignin and coumarin remains challenging. Based on gene expression analysis and phylogenetic tree profiling, AdNAC20 as the target for genetic engineering of lignin and coumarin biosynthesis in ADF was selected in this study. Early-bolting ADF had significantly greater degrees of root lignification and lower coumarin contents than that of the normal plants. In this study, overexpression of AdNAC20 gene plants were created using transgenic technology, while independent homozygous transgenic lines with precise site mutation of AdNAC20 were created using CRISPR/Cas9 technology. The overexpressing transgenic ADF plants showed a 9.28% decrease in total coumarin content and a significant 12.28% increase in lignin content, while knockout mutant plants showed a 16.3% increase in total coumarin content and a 33.48% decrease in lignin content. Furthermore, 29,671 differentially expressed genes (DEGs) were obtained by comparative transcriptomics of OE-NAC20, KO-NAC20, and WT of ADF. A schematic diagram of the gene network interacting with AdNAC20 during the early-bolting process of ADF was constructed by DEG analysis. AdNAC20 was predicted to directly regulate the transcription of several genes with SNBE-like motifs in their promoter, such as MYB46, C3H, and CCoAOMT. In this study, AdNAC20 was shown to play a dual pathway function that positively enhanced lignin formation but negatively controlled coumarin formation. And the heterologous expression of the AdNAC20 gene at Arabidopsis thaliana proved that the AdNAC20 gene also plays an important role in the process of bolting and flowering.

The improvement in the utilization rate and nutritional value of soybean meal (SBM) represents a significant challenge in the feed industry. This study conducted a 50 kg SBM fermentation based on the 300 g small-scale fermentation of SBM in early laboratory research, to explore the combined effects of lactic acid bacteria (LAB) and acid protease on fermentation quality, chemical composition, microbial population, and macromolecular protein degradation during fermentation and aerobic exposure of SBM in simulated actual production. The results demonstrated that the increase in crude protein content and reduction in crude fiber content were considerably more pronounced after fermentation for 30 days (d) and subsequent aerobic exposure, compared to 3 d. It is also noteworthy that the treated group exhibited a greater degree of macromolecular protein degradation relative to the control and 30 d of fermentation relative to 3 d. Furthermore, after 30 d of fermentation, adding LAB and protease significantly inhibited the growth of undesired microbes including coliform bacteria and aerobic bacteria. In the mixed group, the microbial diversity decreased significantly, and Firmicutes replaced Cyanobacteria for bacteria in both groups’ fermentation.

Abstract The increasing incidence of bacterial infections caused by multidrug-resistant (MDR) Gram-negative bacteria has deepened the need for new effective treatments. Antibiotic adjuvant strategy is a more effective and economical approach to expand the lifespan of currently used antibiotics. Herein, we uncover that alcohol-abuse drug disulfiram (DSF) and derivatives thereof are potent antibiotic adjuvants, which dramatically potentiate the antibacterial activity of carbapenems and colistin against New Delhi metallo-β-lactamase (NDM)- and mobilized colistin resistance (MCR)-expressing Gram-negative pathogens, respectively. Mechanistic studies indicate that DSF improves meropenem efficacy by specifically inhibiting NDM activity. Moreover, the robust potentiation of DSF to colistin is due to its ability to exacerbate the membrane-damaging effects of colistin and disrupt bacterial metabolism. Notably, the passage and conjugation assays reveal that DSF minimizes the evolution and spread of meropenem and colistin resistance in clinical pathogens. Finally, their synergistic efficacy in animal models was evaluated and DSF-colistin/meropenem combination could effectively treat MDR bacterial infections in vivo. Taken together, our works demonstrate that DSF and its derivatives are versatile and potent colistin and carbapenems adjuvants, opening a new horizon for the treatment of difficult-to-treat infections.

Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD.

Abstract Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi’s sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p

Summary: The titer of viruses that persist and propagate in their insect vector must be high enough for transmission yet not harm the insect, but the mechanism of this dynamic balance is unclear. Here, expression of inosine monophosphate dehydrogenase (LsIMPDH), a rate-limiting enzyme for guanosine triphosphate (GTP) synthesis, is shown to be downregulated by increased levels of N6-methyladenosine (m6A) on LsIMPDH mRNA in rice stripe virus (RSV)-infected small brown planthoppers (SBPHs; Laodelphax striatellus), the RSV vector, which decreases GTP content, thus limiting viral proliferation. Moreover, planthopper methyltransferase-like protein 3 (LsMETTL3) and m6A reader protein LsYTHDF3 are found to catalyze and recognize the m6A on LsIMPDH mRNA, respectively, and cooperate in destabilizing LsIMPDH transcripts. Co-silencing assays show that negative regulation of viral proliferation by both LsMETTL3 and LsYTHDF3 is partially dependent on LsIMPDH. This distinct mechanism limits virus replication in an insect vector, providing a potential gene target to block viral transmission.

Background In observational studies, sepsis and circulating levels of cytokines have been associated with unclear causality. This study used Mendelian randomization (MR) to identify the causal direction between circulating cytokines and sepsis in a two-sample study. Methods An MR analysis was performed to estimate the causal effect of 41 cytokines on sepsis risk. The inverse-variance weighted random-effects method, the weighted median-based method, and MR-Egger were used to analyze the data. Heterogeneity and pleiotropy were assessed using MR-Egger regression and Cochran’s Q statistic. Results Genetically predicted beta-nerve growth factor (OR = 1.12, 95% CI [1.037–1.211], P = 0.004) increased the risk of sepsis, while RANTES (OR = 0.92, 95% CI [0.849–0.997], P = 0.041) and fibroblast growth factor (OR = 0.869, 95% CI [0.766–0.986], P = 0.029) reduced the risk of sepsis. These findings were robust in extensive sensitivity analyses. There was no clear association between the other cytokines and sepsis risk. Conclusion The findings of this study demonstrate that beta-nerve growth factor, RANTES, and fibroblast growth factor contribute to sepsis risk. Investigations into potential mechanisms are warranted.

The cruising propulsion process of the bionic robotic fish under the swinging tail motion presents a strong periodic dynamic response, and accurate prediction of its performance is the key to the overall design. Taking the two-jointed bionic robotic dolphin as the research object, five kinds of movement modes were designed, and the coupled analysis model of the propulsion motion of the bionic robotic dolphin was established based on the hydrodynamic and Lagrangian dynamics methods, and the hydrodynamic performance of different movement modes and its linear propulsion dynamic response process were investigated. The results show that the coupled analysis method proposed in the paper can accurately obtain the motion response parameters of the robotic dolphin as well as the forces and moments of each joint, and the speed error with the hydrodynamic simulation is controlled within 5%. The research method and results have good application value to guide the selection design and performance prediction of bionic robotic fish.

Abstract Background Ferroptosis is a unique cell death, dependent on iron and phospholipid peroxidation, involved in massive processes of physiopathology. Tremendous attention has been caught in oncology, particularly for those therapy-resistant cancers in the mesenchymal state prone to metastasis due to their exquisite vulnerability to ferroptosis. Therefore, a therapeutical ferroptosis inducer is now underway to be exploited. Results A natural compound, hinokitiol (hino), has been considered to be an iron chelator. We have a novel finding that hino complexed with iron to form Fe(hino)3 can function as a ferroptosis inducer in vitro. The efficiency, compared with the same concentration of iron, increases nearly 1000 folds. Other iron chelators, ferroptosis inhibitors, or antioxidants can inhibit Fe(hino)3-induced ferroptosis. The complex Fe(hino)3 efficacy is further confirmed in orthotopic triple-negative breast cancer (TNBC) tumor models that Fe(hino)3 significantly boosted lipid peroxidation to induce ferroptosis and significantly reduced the sizes of TNBC cell-derived tumors. The drug’s safety was also evaluated, and no detrimental side effects were found with the tested dosage. Conclusions When entering cells, the chelated iron by hinokitiol as a complex Fe(hino)3 is proposed to be redox-active to vigorously promote the production of free radicals via the Fenton reaction. Thus, Fe(hino)3 is a ferroptosis inducer and, therapeutically, exhibits anti-TNBC activity.

Abstract Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x‐box binding protein 1 (XBP1s) may constitute a novel therapeutic target; here we report XBP1s expression and biological activity in GBM. Tumor samples from patients with GBM (n = 85) and low‐grade glioma (n = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low‐grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient‐derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC‐3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O6‐methylguanine‐DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC‐3946 and the long‐term inhibitory effect of MKC‐3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.

The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research.

One previously undescribed alkaloid, named penifuranone A (1), and three known compounds (2–4) were isolated from the mangrove endophytic fungus Penicillium crustosum SCNU-F0006. The structure of the new alkaloid (1) was elucidated based on extensive spectroscopic data analysis and single-crystal X-ray diffraction analysis. Four natural isolates and one new synthetic derivative of penifuranone A, compound 1a, were screened for their antimicrobial, antioxidant, and anti-inflammatory activities. Bioassays revealed that penifuranone A (1) exhibited strong anti-inflammatory activity in vitro by inhibiting nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells with an IC50 value of 42.2 μM. The docking study revealed that compound 1 exhibited an ideal fit within the active site of the murine inducible nitric oxide synthase (iNOS), establishing characteristic hydrogen bonds.

Obstructive Sleep Apnea (OSA), a sleep disorder with high prevalence, is normally accompanied by affective, autonomic, and cognitive abnormalities, and is deemed to be linked to functional brain alterations. To investigate alterations in brain functional connectivity properties in patients with OSA, a comparative analysis of global and local topological properties of brain networks was conducted between patients with OSA and healthy controls (HCs), utilizing functional near-infrared spectroscopy (fNIRS) imaging. A total of 148 patients with OSA and 150 healthy individuals were involved. Firstly, quantitative alterations in blood oxygen concentration, changes in functional connectivity, and variations in graph theory-based network topological characteristics were assessed. Then, with Mann–Whitney statistics, this study compared whether there are significant differences in the above characteristics between patients with OSA and HCs. Lastly, the study further examined the correlation between the altered characteristics and the apnea hypopnea index (AHI) using linear regression. Results revealed a higher mean and standard deviation of hemoglobin concentration in the superior temporal gyrus among patients with OSA compared to HCs. Resting-state functional connectivity (RSFC) exhibited a slight increase between the superior temporal gyrus and other specific areas in patients with OSA. Notably, neither patients with OSA nor HCs demonstrated significant small-world network properties. Patients with OSA displayed an elevated clustering coefficient (p < 0.05) and local efficiency (p < 0.05). Additionally, patients with OSA exhibited a tendency towards increased nodal betweenness centrality (p < 0.05) and degree centrality (p < 0.05) in the right supramarginal gyrus, as well as a trend towards higher betweenness centrality (p < 0.05) in the right precentral gyrus. The results of multiple linear regressions indicate that the influence of the AHI on RSFC between the right precentral gyrus and right superior temporal gyrus (p < 0.05), as well as between the right precentral gyrus and right supramarginal gyrus (p < 0.05), are statistically significant. These findings suggest that OSA may compromise functional brain connectivity and network topological properties in affected individuals, serving as a potential neurological mechanism underlying the observed abnormalities in brain function associated with OSA.

A widely used organophosphate flame retardant (OPFR), triphenyl phosphate (TPP), is frequently detected in various environmental media and humans. However, there is little known on the human corneal epithelium of health risk when exposed to TPP. In this study, human normal corneal epithelial cells (HCECs) were used to investigate the cell viability, morphology, apoptosis, and mitochondrial membrane potential after they were exposed to TPP, as well as their underlying molecular mechanisms. We found that TPP decreased cell viability in a concentration-dependent manner, with a half maximal inhibitory concentration (IC50) of 220 μM. Furthermore, TPP significantly induced HCEC apoptosis, decreased mitochondrial membrane potential in a dose-dependent manner, and changed the mRNA levels of the apoptosis biomarker genes (Cyt c, Caspase-9, Caspase-3, Bcl-2, and Bax). The results showed that TPP induced cytotoxicity in HCECs, eventually leading to apoptosis and changes in mitochondrial membrane potential. In addition, the caspase-dependent mitochondrial pathways may be involved in TPP-induced HCEC apoptosis. This study provides a reference for the human corneal toxicity of TPP, indicating that the risks of OPFR to human health cannot be ignored.

Pumpkin (Cucurbita maxima) is an important vegetable crop of the Cucurbitaceae plant family. The fruits of pumpkin are often used as directly edible food or raw material for a number of processed foods. In nature, mature pumpkin fruits differ in size, shape, and color. The Atlantic Giant (AG) cultivar has the world’s largest fruits and is described as the giant pumpkin. AG is well-known for its large and bright-colored fruits with high ornamental and economic value. At present, there are insufficient studies that have focused on the formation factors of the AG cultivar. To address these knowledge gaps, we performed comparative transcriptome, proteome, and metabolome analysis of fruits from the AG cultivar and a pumpkin with relatively small fruit (Hubbard). The results indicate that up-regulation of gene-encoded expansins contributed to fruit cell expansion, and the increased presence of photoassimilates (stachyose and D-glucose) and jasmonic acid (JA) accumulation worked together in terms of the formation of large fruit in the AG cultivar. Notably, perhaps due to the rapid transport of photoassimilates, abundant stachyose that was not converted into glucose in time was detected in giant pumpkin fruits, implying that a unique mode of assimilate unloading is in existence in the AG cultivar. The potential molecular regulatory network of photoassimilate metabolism closely related to pumpkin fruit expansion was also investigated, finding that three MYB transcription factors, namely CmaCh02G015900, CmaCh01G018100, and CmaCh06G011110, may be involved in metabolic regulation. In addition, neoxanthin (a type of carotenoid) exhibited decreased accumulation that was attributed to the down-regulation of carotenoid biosynthesis genes in AG fruits, which may lead to pigmentation differences between the two pumpkin cultivars. Our current work will provide new insights into the potential formation factors of giant pumpkins for further systematic elucidation.

EEG, which can provide brain alteration information via recording the electrical activity of neurons in the cerebral cortex, has been widely used in neurophysiology. However, conventional wet electrodes in EEG monitoring typically suffer from inherent limitations, including the requirement of skin pretreatment, the risk of superficial skin infections, and signal performance deterioration that may occur over time due to the air drying of the conductive gel. Although the emergence of dry electrodes has overcome these shortcomings, their electrode–skin contact impedance is significantly high and unstable, especially in hair-covered areas. To address the above problems, an active claw-shaped dry electrode is designed, moving from electrode morphological design, slurry preparation, and coating to active electrode circuit design. The active claw-shaped dry electrode, which consists of a claw-shaped electrode and active electrode circuit, is dedicated to offering a flexible solution for elevating electrode fittings on the scalp in hair-covered areas, reducing electrode–skin contact impedance and thus improving the quality of the acquired EEG signal. The performance of the proposed electrodes was verified by impedance, active electrode circuit, eyes open-closed, steady-state visually evoked potential (SSVEP), and anti-interference tests, based on EEG signal acquisition. Experimental results show that the proposed claw-shaped electrodes (without active circuit) can offer a better fit between the scalp and electrodes, with a low electrode–skin contact impedance (18.62 KΩ@1 Hz in the hairless region and 122.15 KΩ@1 Hz in the hair-covered region). In addition, with the active circuit, the signal-to-noise ratio (SNR) of the acquiring EEG signal was improved and power frequency interference was restrained, therefore, the proposed electrodes can yield an EEG signal quality comparable to wet electrodes.

Non-adherent culture is critical for the transdifferentiation of stem cells from mesoderm to neuroectoderm. Sphere culture has been reported to directly induce the adipose tissue cells to neural stem cells. Here we aimed to evaluate continuous non-adherent culture on the transdifferentiation potential of human adipose-derived stem cells (ASCs) into retinal lineage. Human ASCs were induced into retinal lineage by the treatment of noggin, dickkopf-related protein 1, and IGF-1 (NDI) under adherent and non-adherent culture. The NDI induction treatment with the adherent culture for 21 days promoted robust expression of retinal markers in the induced ASCs as compared to those without NDI induction on the adherent culture. With continuous non-adherent culture for 21 days, human ASCs could highly express retinal marker genes even without NDI induction treatment as compared to those on the adherent culture. The combination of continuous non-adherent culture with the NDI induction did not show a significant upregulation of the retinal marker expression as compared to either NDI induction with the adherent culture or continuous non-adherent culture without NDI induction treatment. In summary, both non-adherent culture and NDI induction medium could independently promote the transdifferentiation of human ASCs into retinal lineage. Yet, their combination did not produce an enhancement effect.

Mutations in mitochondrial DNA (mtDNA) contribute to a variety of serious multi-organ human diseases, which are strictly inherited from the maternal germline. However, there is currently no curative treatment. Attention has been focused on preventing the transmission of mitochondrial diseases through mitochondrial replacement (MR) therapy, but levels of mutant mtDNA can often unexpectedly undergo significant changes known as mitochondrial genetic drift. Here, we proposed a novel strategy to perform spindle-chromosomal complex transfer (SCCT) with maximal residue removal (MRR) in metaphase II (MII) oocytes, thus hopefully eliminated the transmission of mtDNA diseases. With the MRR procedure, we initially investigated the proportions of mtDNA copy numbers in isolated karyoplasts to those of individual oocytes. Spindle-chromosomal morphology and copy number variation (CNV) analysis also confirmed the safety of this method. Then, we reconstructed oocytes by MRR-SCCT, which well developed to blastocysts with minimal mtDNA residue and normal chromosomal copy numbers. Meanwhile, we optimized the manipulation order between intracytoplasmic sperm injection (ICSI) and SCC transfer and concluded that ICSI-then-transfer was conducive to avoid premature activation of reconstructed oocytes in favor of normal fertilization. Offspring of mice generated by embryos transplantation in vivo and embryonic stem cells derivation further presented evidences for competitive development competence and stable mtDNA carryover without genetic drift. Importantly, we also successfully accomplished SCCT in human MII oocytes resulting in tiny mtDNA residue and excellent embryo development through MRR manipulation. Taken together, our preclinical mouse and human models of the MRR-SCCT strategy not only demonstrated efficient residue removal but also high compatibility with normal embryo development, thus could potentially be served as a feasible clinical treatment to prevent the transmission of inherited mtDNA diseases.

Summary: Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit “non-classic” characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.

Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identified as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-flurorouracil. However, 6-PGDH knockdown did not affect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro findings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy.

Abstract Macrophages in tumors (tumor-associated macrophages, TAMs), a major population within most tumors, play key homeostatic functions by stimulating angiogenesis, enhancing tumor cell growth, and suppressing antitumor immunity. Resetting TAMs by simple, efficacious and safe approach(s) is highly desirable to enhance antitumor immunity and attenuate tumor cell malignancy. Previously, we used tumor cell-derived microparticles to package chemotherapeutic drugs (drug-MPs), which resulted in a significant treatment outcome in human malignant pleural effusions via neutrophil recruitments, implicating that drug-MPs might reset TAMs, considering the inhibitory effects of M2 macrophages on neutrophil recruitment and activation. Here, we show that drug-MPs can function as an antitumor immunomodulator by resetting TAMs with M1 phenotype and IFN-β release. Mechanistically, drug molecules in tumor MPs activate macrophage lysosomal P450 monooxygenases, resulting in superoxide anion formation, which further amplifies lysosomal ROS production and pH value by activating lysosomal NOX2. Consequently, lysosomal Ca2+ signaling is activated, thus polarizing macrophages towards M1. Meanwhile, the drug molecules are delivered from lysosomes into the nucleus where they activate DNA sensor hnRNPA2B1 for IFN-β production. This lysosomal-nuclear machinery fully arouses the antitumor activity of macrophages by targeting both lysosomal pH and the nuclear innate immunity. These findings highlight that drug-MPs can act as a new immunotherapeutic approach by revitalizing antitumor activity of macrophages. This mechanistic elucidation can be translated to treat malignant ascites by drug-MPs combined with PD-1 blockade.

Abstract Light and phytohormone are external and internal cues that regulate plant growth and development throughout their life cycle. BBXs (B-box domain proteins) are a group of zinc finger proteins that not only directly govern the transcription of target genes but also associate with other factors to create a meticulous regulatory network to precisely regulate numerous aspects of growth and developmental processes in plants. Recent studies demonstrate that BBXs play pivotal roles in light-controlled plant growth and development. Besides, BBXs have been documented to regulate phytohormone-mediated physiological procedures. In this review, we summarize and highlight the multi-faced role of BBXs, with a focus in photomorphogenesis, photoperiodic flowering, shade avoidance, abiotic stress, and phytohormone-mediated growth and development in plant.

A synthetic peptide LI14 demonstrates potent antibacterial activity against drug-resistant bacteria in vitro and in vivo by inducing membrane damage and disrupting membrane potential leading to metabolic perturbation.

Abstract Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases (CVD). Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants, have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health. First, this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health. We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health. The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations. The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling. Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects. Moreover, we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD. We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise. We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.

Summary: Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.