Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke.

The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3's role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO-induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3's effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.

Biodegradable Lipid-Modified Poly(Guanidine Thioctic Acid)s: A Fortifier of Lipid Nanoparticles to Promote the Efficacy and Safety of mRNA Cancer Vaccines.

Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.

Supramolecular Lipid Nanoparticles Based on Host-Guest Recognition: A New Generation Delivery System of mRNA Vaccines For Cancer Immunotherapy.

Dendritic cell (DC) maturation is a crucial process for antigen presentation and the initiation of T cell-mediated immune responses. Toll-like receptors play pivotal roles in stimulating DC maturation and promoting antigen presentation. Here, a novel message RNA (mRNA) cancer vaccine is reported that boosts antitumor efficacy by codelivering an mRNA encoding tumor antigen and a TLR7/8 agonist (R848) to DC using supramolecular lipid nanoparticles (SMLNP) as a delivery platform, in which a new ionizable lipid (N2-3L) remarkably enhances the translation efficiency of mRNA and a ß-cyclodextrin (ß-CD)-modified ionizable lipid (Lip-CD) encapsulates R848. The incorporation of R848 adjuvant into the mRNA vaccine through noncovalent host-guest complexation significantly promotes DC maturation and antigen presentation after vaccination, thus resulting in superior antitumor efficacy in vivo. Moreover, the antitumor efficacy is further boosted synergized with immune checkpoint blockade by potentiating the anticancer capability of cytotoxic T lymphocytes infiltrated in tumor sites. This work indicates that SMLNP shows brilliant potential as next-generation delivery system in the development of mRNA vaccines with high efficacy.

Development of Mannosylated Lipid Nanoparticles for mRNA Cancer Vaccine with High Antigen Presentation Efficiency and Immunomodulatory Capability.

Insufficient accumulation of lipid nanoparticles (LNPs)-based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor-mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs-Man). Intramuscular injection of mRNA vaccine (STLNPs-Man@mRNAOVA ) results in a four-fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs-Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one-fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs-Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T-lymphocyte-associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.

Multi-node knowledge graph assisted distributed fault detection for large-scale industrial processes based on graph attention network and bidirectional LSTMs.

Modern industrial processes are characterized by extensive, multiple operation units, and strong coupled correlation of subsystems. Fault detection of large-scale processes is still a challenging problem, especially for tandem plant-wide processes in multiple fields such as water treatment process. In this paper, a novel distributed graph attention network-bidirectional long short-term memory (D-GATBLSTM) fault detection model is proposed for large-scale industrial processes. Firstly, a multi-node knowledge graph (MNKG) is constructed using a joint data and knowledge driven strategy. Secondly, for large-scale industrial process, a global feature extractor of graph attention networks (GATs) is constructed, on the basis of which, sub-blocks are decomposed based on MNKG. Then, local feature extractors of bidirectional long short-term memory (Bi-LSTM) for each sub-block are constructed, in which correlations among multiple sub-blocks are considered. Finally, a multi-subblock fusion collaborative prediction model is constructed and the comprehensive fault detection results are given by the grid search method. The effectiveness of our D-GATBLSTM is exemplified in a secure water treatment process case, where it outperforms baseline models compared, with 27% improvement in precision, 15% increase in recall, and overall F-score enhancement of 0.22.

Enhancement, integration, expansion: Activating representation of detailed features for occluded person re-identification.

A proposed method, Enhancement, integration, and Expansion, aims to activate the representation of detailed features for occluded person re-identification. Region and context are two important and complementary features, and integrating them in an occluded environment can effectively improve the robustness of the model. Firstly, a self-enhancement module is designed. Based on the constructed multi-stream architecture, rich and meaningful feature interference is introduced in the feature extraction stage to enhance the model's ability to perceive noise. Next, a collaborative integration module similar to cascading cross-attention is proposed. By studying the intrinsic interaction patterns of regional and contextual features, it adaptively fuses features across streams and enhances the diverse and complete representation of internal information. The module is not only robust to complex occlusions, but also mitigates the feature interference problem due to similar appearances or scenes. Finally, a matching expansion module that enhances feature discriminability and completeness is proposed. Providing more stable and accurate features for recognition. Compared with state-of-the-art methods on two occluded and holistic datasets, the proposed method is proved to be advanced and the effectiveness of the module is proved by extensive ablation studies.

Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury.

The Class-I histone deacetylases (HDACs) mediate microglial inflammation and neurological dysfunction after traumatic brain injury (TBI). However, whether the individual Class-I HDACs play an indispensable role in TBI pathogenesis remains elusive. HDAC2 has been shown to upregulate pro-inflammatory genes in myeloid cells under brain injuries such as intracerebral hemorrhage, thereby worsening outcomes. Thus, we hypothesized that HDAC2 drives microglia toward a pro-inflammatory neurotoxic phenotype in a murine model of controlled cortical impact (CCI). Our results revealed that HDAC2 expression was highly induced in CD16/CD32+ pro-inflammatory microglia 3 and 7d after TBI. Surprisingly, microglia-targeted HDAC2 knockout (HDAC2 miKO) mice failed to demonstrate a beneficial phenotype after CCI/TBI compared to their wild-type (WT) littermates. HDAC2 miKO mice exhibited comparable levels of grey and white matter injury, efferocytosis, and sensorimotor and cognitive deficits after CCI/TBI as WT mice. RNA sequencing of isolated microglia 3d after CCI/TBI indicated the elevation of a panel of pro-inflammatory cytokines/chemokines in HDAC2 miKO mice over WT mice, and flow cytometry showed further elevated brain infiltration of neutrophils and B cells in HDAC2 miKO mice. Together, this study does not support a detrimental role for HDAC2 in microglial responses after TBI and calls for investigation into alternative mechanisms.

Effects of Differentially Expressed mRNAs Screened Based on GEO Database on Inflammatory Infiltration of Nasal Mucosa in Mice with Allergic Rhinitis.

Objective: To identify messenger RNAs (mRNAs) with differential expression in allergic rhinitis (AR) based on an online database, Gene Expression Omnibus (GEO), to provide a new research direction for future diagnosis and treatment of AR. Methods: The GSE44037 dataset from the CEO database was selected to obtain differentially expressed mRNAs (DEmRNAs) in AR. The keywords involved in these DEmRNAs were enriched and analyzed, and ECM1 and CCL2 were selected for subsequent analysis. In addition, BALB/c mice were purchased and randomized to control (normal feeding), model (AR modeling), si-CCL2 (AR modeling + CCL2 suppression by lentivirus vector), nc-CCL2 (AR modeling + CCL2 empty vector), si-ECM1 (AR modeling + ECM1 suppression by lentivirus vector), and nc-ECM1 (AR modeling + ECM1 empty vector) groups. The frequencies of sneezing and nasal rubbing were recorded in each group. Besides, levels of CCL2, ECM1, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hs-CRP) were quantified, and the inflammatory infiltration of nasal mucosa (NM) was observed. Results: Twenty-six DEmRNAs were acquired from the GSE44037 dataset, among which only CCL2 and ECM1 were found to be associated with keywords such as "immune response" and "inflammatory response" through enrichment analysis. In animal experiments, CCL2 presented lower mRNA expression in model mice than in control mice, while ECM1 showed higher mRNA expression (P < .05). The frequencies of sneezing and nose rubbing and the levels of inflammatory factors were significantly increased in si-CCL2 mice compared with model mice, while were significantly decreased in si-ECM1 mice (P < .05). The NM inflammatory infiltration was serious in the si-CCL2 group and significantly improved in the si-ECM1 group. Conclusions: Low expression of CCL2 and high expression of ECM1 in AR are strongly linked to the pathological progression of AR, and these two genes are expected to be new research directions for AR diagnosis and treatment.

Laser welding simulation of large-scale assembly module of stainless steel side-wall.

Due to the advantageous characteristics of laser welding technology, it is being increasingly used for constructing stainless steel rail vehicles. It can improve the appearance of a vehicle, enable designs with a relatively high degree of flatness, and ensure higher-quality connections between different parts of a vehicle. Moreover, it can improve the strength and stiffness of the components of the vehicle. In this study, a large-scale assembly module of a stainless steel side-wall was considered as the research object. The combined heat source model of a Gaussian heat source and a cylindrical volume heat source was used to obtain the heat source parameters of laser welding to match the experimental data. Based on the thermal cycle curve method (TCCM), the influence of the number of weld segments and mesh divisions of the local model on the efficiency and accuracy of laser welding simulations was investigated. Thereafter, the research results were applied to the welding simulation of the whole side-wall module. The shape of the molten pool obtained using the combined heat source was closer to that of the experiments (error < 10%), demonstrating the accuracy and effectiveness of the developed the heat source model for laser welding simulation. For local model laser welding using the TCCM, a coarse mesh was used, and the weld was divided into four segments, and highly accurate results were obtained. This calculation time was only 5.97% of that of a moving heat source in case of the thermo-elastic-plastic method (TEPM). Residual stress and welding deformation of the stainless steel side-wall module were calculated according to actual process parameters and the results of local model simulation. Residual stress was discontinuously distributed at the weld segments, and it only slightly influenced the overall stress distribution. The maximum residual stress (462.15 MPa) occurred at the weld of the large crossbeam. Welding eight small and two large crossbeams influenced the deformation change and the maximum deformation (1.26 mm) appeared in the middle position of the left side-wall. The findings of this study show that the TCCM has high calculation accuracy and is sufficiently economical for predicting laser welding of large structures.

Interleukin-4 mitigates anxiety-like behavior and loss of neurons and fiber tracts in limbic structures in a microglial PPARγ-dependent manner after traumatic brain injury.

Traumatic brain injury (TBI) is commonly followed by intractable psychiatric disorders and long-term changes in affect, such as anxiety. The present study sought to investigate the effect of repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles on affective symptoms after TBI in mice. Adult male C57BL/6 J mice (10-12 weeks of age) were subjected to controlled cortical impact (CCI) and assessed by a battery of neurobehavioral tests up to 35 days after CCI. Neuron numbers were counted in multiple limbic structures, and the integrity of limbic white matter tracts was evaluated using ex vivo diffusion tensor imaging (DTI). As STAT6 is a critical mediator of IL-4-specific transcriptional activation, STAT6 knockout mice were used to explore the role of endogenous IL-4/STAT6 signaling axis in TBI-induced affective disorders. We also employed microglia/macrophage (Mi/Mϕ)-specific PPARγ conditional knockout (mKO) mice to test if Mi/Mϕ PPARγ critically contributes to IL-4-afforded beneficial effects. We observed anxiety-like behaviors up to 35 days after CCI, and these measures were exacerbated in STAT6 KO mice but mitigated by repetitive IL-4 delivery. We discovered that IL-4 protected against neuronal loss in limbic structures, such as the hippocampus and the amygdala, and improved the structural integrity of fiber tracts connecting the hippocampus and amygdala. We also observed that IL-4 boosted a beneficial Mi/Mϕ phenotype (CD206+/Arginase 1+/PPARγ+ triple-positive) in the subacute injury phase, and that the numbers of Mi/Mϕ appositions with neurons were robustly correlated with long-term behavioral performances. Remarkably, PPARγ-mKO completely abolished IL-4-afforded protection. Thus, CCI induces long-term anxiety-like behaviors in mice, but these changes in affect can be attenuated by transnasal IL-4 delivery. IL-4 prevents the long-term loss of neuronal somata and fiber tracts in key limbic structures, perhaps due to a shift in Mi/Mϕ phenotype. Exogenous IL-4 therefore holds promise for future clinical management of mood disturbances following TBI.

Neuron-targeted Knockout of APE1 Forces Premature Cognitive Impairment and Synaptic Dysfunction in Adult Mice.

Adaptable and consistent neural function relies at least in part on the ongoing repair of oxidative damage that can accumulate in the brain over a lifespan. To determine whether forebrain neuron-targeted knockout of AP endonuclease 1 (APE1), a critical enzyme in the base excision DNA repair pathway, contributes to neuronal impairments, we generated APE1 conditional knockout mice under the control of the CamKIIα promotor (APE1 cKO). Spatial learning and memory were tested using the Morris water maze. Synaptic markers, including synapsin, vGLUT, GABA1, and GAD were immunostained and quantified. Dendritic morphology and number were characterized using Golgi staining. Long-term potentiation (LTP) was measured in slices from the 6-month-old brain. APE1 cKO mice did not significantly differ from WT mice in the learning phase of the Morris water maze, but performed significantly worse during the memory phase of the Morris water maze. vGLUT, GABA1, and GAD immunostaining was significantly decreased in APE1 cKO mice without concomitant changes in the number of synapsin-positive structures, suggesting that neural networks may be impaired but not at the level of total presynaptic structures. Dendrites were reduced both in number and length of spines in APE1 cKO mice. APE1 cKO brain slices exhibited decreased LTP induction compared to WT brain slices. Together, these data indicate that the conditional loss of APE1 in forebrain neurons leads to a phenotype consistent with expedited brain aging.

STAT1 contributes to microglial/macrophage inflammation and neurological dysfunction in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop therapies that can mitigate brain inflammation and improve the outcome after TBI. This study investigated the transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and brain inflammation burden after TBI. Such phenotype-modulating effects of fludarabine on post-TBI Mi/MΦ were reproduced by tamoxifen-induced, selective knockout of STAT1 in Mi/MΦ (STAT1 mKO). By propelling Mi/MΦ away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neurological deficits and brain lesion size after TBI. Importantly, short-term fludarabine treatment after TBI elicited long-lasting improvement of TBI outcomes, but this effect was lost on STAT1 mKO mice. Together, our study provided the first line of evidence that STAT1 causatively determines the proinflammatory phenotype of brain Mi/MΦ after TBI. We also showed promising preclinical data supporting the use of fludarabine as a novel immunomodulating therapy to TBI.SIGNIFICANCE STATEMENTThe functional phenotype of microglia and macrophages (Mi/MΦ) critically influences brain inflammation and the outcome after traumatic brain injury (TBI); however, no therapies have been developed to modulate Mi/MΦ functions to treat TBI. Here we report for the first time that the transcription factor STAT1 is a key mediator of proinflammatory Mi/MΦ responses in the post-TBI brain, the specific deletion of which ameliorates neuroinflammation and improves long-term functional recovery after TBI. We also show excellent efficacy of a selective STAT1 inhibitor fludarabine against TBI-induced functional deficits and brain injury using a mouse model, presenting STAT1 as a promising therapeutic target for TBI.

In Situ Observation and Phase-Field Simulation Framework of Duplex Stainless-Steel Slab during Solidification.

The melting and solidification process of S32101 duplex stainless steel (DSS) was investigated using high-temperature confocal microscopy (HTCM). The method of concentric HTCM was employed to study microstructure evolution during the solidification process of S32101 DSS. This method could artificially create a meniscus-shaped solid-liquid interface, which dramatically improved the quality of in situ observations. During the heating stage, γ-austenite transformed to δ-ferrite, and this transformation manifested itself in the form of grain boundaries (GBs) moving. The effects of cooling rate on the solidification pattern and microstructure were revealed in the present research. An enhanced cooling rate led to a finer microstructure, and the solidification pattern changed from cellular to dendritic growth. As the temperature decreased, the commencement and growth of precipitates were observed. In this paper, the experimental data, including parameters such as temperature, cooling rate, and growth mode, were used as the benchmark for the simulation. A simulation framework using Micress linked to a 1D heat transfer model enabling consistent analysis of solidification dynamics in DSS across the whole cast slab was established. Simulating the dendrite growth and elemental segregation of DSS at specific cooling rates shows that this framework can be a powerful tool for solving practical production problems.

Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury.

BACKGROUND: Histone deacetylases (HDACs) are believed to exacerbate traumatic brain injury (TBI) based on studies using pan-HDAC inhibitors. However, the HDAC isoform responsible for the detrimental effects and the cell types involved remain unknown, which may hinder the development of specific targeting strategies that boost therapeutic efficacy while minimizing side effects. Microglia are important mediators of post-TBI neuroinflammation and critically impact TBI outcome. HDAC3 was reported to be essential to the inflammatory program of in vitro cultured macrophages, but its role in microglia and in the post-TBI brain has not been investigated in vivo. METHODS: We generated HDAC3LoxP mice and crossed them with CX3CR1CreER mice, enabling in vivo conditional deletion of HDAC3. Microglia-specific HDAC3 knockout (HDAC3 miKO) was induced in CX3CR1CreER:HDAC3LoxP mice with 5 days of tamoxifen treatment followed by a 30-day development interval. The effects of HDAC3 miKO on microglial phenotype and neuroinflammation were examined 3-5 days after TBI induced by controlled cortical impact. Neurological deficits and the integrity of white matter were assessed for 6 weeks after TBI by neurobehavioral tests, immunohistochemistry, electron microscopy, and electrophysiology. RESULTS: HDAC3 miKO mice harbored specific deletion of HDAC3 in microglia but not in peripheral monocytes. HDAC3 miKO reduced the number of microglia by 26%, but did not alter the inflammation level in the homeostatic brain. After TBI, proinflammatory microglial responses and brain inflammation were markedly alleviated by HDAC3 miKO, whereas the infiltration of blood immune cells was unchanged, suggesting a primary effect of HDAC3 miKO on modulating microglial phenotype. Importantly, HDAC3 miKO was sufficient to facilitate functional recovery for 6 weeks after TBI. TBI-induced injury to axons and myelin was ameliorated, and signal conduction by white matter fiber tracts was significantly enhanced in HDAC3 miKO mice. CONCLUSION: Using a novel microglia-specific conditional knockout mouse model, we delineated for the first time the role of microglial HDAC3 after TBI in vivo. HDAC3 miKO not only reduced proinflammatory microglial responses, but also elicited long-lasting improvement of white matter integrity and functional recovery after TBI. Microglial HDAC3 is therefore a promising therapeutic target to improve long-term outcomes after TBI.

Microglia: Active participants in brain capillary function.

A recent study by Bisht, Okojie, and Sharma, et al. characterizes a population of capillary-associated microglia (CAM) whose cell bodies are positioned along small blood vessels in the healthy mouse brain. Through elegant, longitudinal intravital imaging of brain vasculature and CAMs, the authors have uncovered the significance of microglia in cerebral blood flow regulation. Further investigation into the functions of this CAM population and how they interact with surrounding cells within the neurovascular unit will improve our understanding of vascular regulation and cerebrovascular diseases.

Development of a high-throughput SNP array for sea cucumber (Apostichopus japonicus) and its application in genomic selection with MCP regularized deep neural networks.

High-throughput single nucleotide polymorphism (SNP) genotyping assays are powerful tools for genetic studies and genomic breeding applications for many species. Though large numbers of SNPs have been identified in sea cucumber (Apostichopus japonicus), but, as yet, no high-throughput genotyping platform is available for this species. In this study, we designed and developed a high-throughput 24 K SNP genotyping array named HaishenSNP24K for A. japonicus, based on the multi-objective-local optimization (MOLO) algorithm and HD-Marker genotyping method. The SNP array exhibited a relatively high genotyping call rate (> 96%), genotyping accuracy (>95%) and exhibited highly polymorphic in sea cucumber populations. In addition, we also assessed its application in genomic selection (GS). Deep neural networks (DNN) that can capture the complicated interactions of genes have been proposed as a promising tool in GS for SNP-based genomic prediction of complex traits in animal breeding. To overcome the problem of over-fitting when using the HaishenSNP24K array as high-dimensional DNN input, we developed minmax concave penalty (MCP) regularization for sparse deep neural networks (DNN-MCP) that finds an optimal sparse structure of a DNN by minimizing the square error subject to the non-convex penalty MCP on the parameters (weights and biases). Compared to two linear models, namely RR-GBLUP and Bayes B, and the nonlinear model DNN, DNN-MCP has greatly improved the genomic prediction ability for three quantitative traits (e.g., wet weight, dry weight and survival time) in the sea cucumber population. To the best of our knowledge, this is the first work to develop a high-throughput SNP array for A. japonicus and a new model DNN-MCP for genomic prediction of complex traits in GS. The present results provide evidence that supports the HaishenSNP24K array with DNN-MCP will be valuable for genetic studies and molecular breeding in A. japonicus.

Intervention mechanism of self-degradation of ready-to-eat sea cucumber by adding green tea extract and gallic acid.

Gallic acid (GA) and green tea extract (GT) could retard the self-degradation of ready-to-eat sea cucumber (RSC). The physical and chemical properties of RSC were changed after cross-linking. Cross-linkers could retard the conversion of α-helix like structure to random coil. Besides, the peptides of cross-linked RSC were easily broken at the sites of G, E, A, L, S, H, Y, V and I after stored for 30 d. The self-degradation rate of RSC before and after cross-linking was determined by synthetic typical peptides. After cross-linked by GA, the relative peak heights of NQ, NL and GLQ increased by 20.59%, 11.14% and 31.49%, indicating that GA could effectively retard the degradation of the peptides during storage. Moreover, hydrogen bond was confirmed as the main force to maintain the stability of RSC body wall before and after cross-linking.

Phagocytic microglia and macrophages in brain injury and repair.

AIMS: Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, and is a key element in the evolution of central nervous system (CNS) disorders. Microglia and macrophages are the professional phagocytes of the CNS. By clearing toxic cellular debris and reshaping the extracellular matrix, microglia/macrophages help pilot the brain repair and functional recovery process. However, CNS resident and invading immune cells can also magnify tissue damage by igniting runaway inflammation and phagocytosing stressed-but viable-neurons. DISCUSSION: Microglia/macrophages help mediate intercellular communication and react quickly to the "find-me" signals expressed by dead/dying neurons. The activated microglia/macrophages then migrate to the injury site to initiate the phagocytic process upon encountering "eat-me" signals on the surfaces of endangered cells. Thus, healthy cells attempt to avoid inappropriate engulfment by expressing "do not-eat-me" signals. Microglia/macrophages also have the capacity to phagocytose immune cells that invade the injured brain (e.g., neutrophils) and to regulate their pro-inflammatory properties. During brain recovery, microglia/macrophages engulf myelin debris, initiate synaptogenesis and neurogenesis, and sculpt a favorable extracellular matrix to support network rewiring, among other favorable roles. Here, we review the multilayered nature of phagocytotic microglia/macrophages, including the molecular and cellular mechanisms that govern microglia/macrophage-induced phagocytosis in acute brain injury, and discuss strategies that tap into the therapeutic potential of this engulfment process. CONCLUSION: Identification of biological targets that can temper neuroinflammation after brain injury without hindering the essential phagocytic functions of microglia/macrophages will expedite better medical management of the stroke recovery stage.

Aquaculture Molecular Breeding Platform (AMBP): a comprehensive web server for genotype imputation and genetic analysis in aquaculture.

It is of vital importance to understand the population structure, dissect the genetic bases of performance traits, and make proper strategies for selection in breeding programs. However, there is no single webserver covering the specific needs in aquaculture. We present Aquaculture Molecular Breeding Platform (AMBP), the first web server for genetic data analysis in aquatic species of farming interest. AMBP integrates the haplotype reference panels of 18 aquaculture species, which greatly improves the accuracy of genotype imputation. It also supports multiple tools to infer genetic structures, dissect the genetic architecture of performance traits, estimate breeding values, and predict optimum contribution. All the tools are coherently linked in a web-interface for users to generate interpretable results and evaluate statistical appropriateness. The webserver supports standard VCF and PLINK (PED, MAP) files, and implements automated pipelines for format transformation and visualization to simplify the process of analysis. As a demonstration, we applied the webserver to Pacific white shrimp and Atlantic salmon datasets. In summary, AMBP constitutes comprehensive resources and analytical tools for exploring genetic data and guiding practical breeding programs. AMBP is available at http://mgb.qnlm.ac.

Rheological properties, thermal stability and conformational changes of collagen from sea cucumber (Apostichopus japonicas).

Sea cucumber collagen (SCC) properties affected the thermal processing of sea cucumber. SCC showed the shear-thinning and pseudo-plastic properties, and the viscosity and frequency of viscoelastic crossover were decreased gradually with the temperature from 15 to 30 °C. Differential scanning calorimetry of SCC confirmed that it was thermolabile with the increase of temperatures, acid or NaCl concentrations. As the temperature increasing, the triple helix of SCC disappeared with the decrease of the relative proportion of P2 structures by circular dichroism spectrometry and Fourier transform infrared spectroscopy, and shearing could accelerate the change. Intramolecular changes investigated by molecular dynamics simulation showed the average number of hydrogen bonds decreased from 47 (20 °C) to 42 (80 °C), indicating triple helix of SCC was triggered to uncoil within 250 ns. These results could provide a scientific basis for processing of sea cucumbers.