Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

Host MOV10 is induced to restrict herpes simplex virus 1 lytic infection by promoting type I interferon response.

Moloney leukemia virus 10 protein (MOV10) is an interferon (IFN)-inducible RNA helicase implicated in antiviral activity against RNA viruses, yet its role in herpesvirus infection has not been investigated. After corneal inoculation of mice with herpes simplex virus 1 (HSV-1), we observed strong upregulation of both MOV10 mRNA and protein in acutely infected mouse trigeminal ganglia. MOV10 suppressed HSV-1 replication in both neuronal and non-neuronal cells, and this suppression required the N-terminus, but not C-terminal helicase domain of MOV10. MOV10 repressed expression of the viral gene ICP0 in transfected cells, but suppressed HSV-1 replication independently of ICP0. MOV10 increased expression of type I IFN in HSV-1 infected cells with little effect on IFN downstream signaling. Treating the cells with IFN-α or an inhibitor of the IFN receptor eliminated MOV10 suppression of HSV-1 replication. MOV10 enhanced IFN production stimulated by cytoplasmic RNA rather than DNA. IKKε co-immunoprecipitated with MOV10 and was required for MOV10 restriction of HSV-1 replication. Mass spectrometry identified ICP27 as a viral protein interacting with MOV10. Co-immunoprecipitation results suggested that this interaction depended on the RGG box of ICP27 and both termini of MOV10. Overexpressed ICP27, but not its RGG-Box deletion mutant, rendered MOV10 unable to regulate HSV-1 replication and type I IFN production. In summary, MOV10 is induced to restrict HSV-1 lytic infection by promoting the type I IFN response through an IKKε-mediated RNA sensing pathway, and its activity is potentially antagonized by ICP27 in an RGG box dependent manner.

Increase in Agricultural-Derived NHx and Decrease in Coal Combustion-Derived NOx Result in Atmospheric Particulate N-NH4+ Surpassing N-NO3- in the South China Sea.

The atmospheric deposition of anthropogenic active nitrogen significantly influences marine primary productivity and contributes to eutrophication. The form of nitrogen deposition has been evolving annually, alongside changes in human activities. A disparity arises between observation results and simulation conclusions due to the limited field observation and research in the ocean. To address this gap, our study undertook three field cruises in the South China Sea in 2021, the largest marginal sea of China. The objective was to investigate the latest atmospheric particulate inorganic nitrogen deposition pattern and changes in nitrogen sources, employing nitrogen-stable isotopes of nitrate (δ15N-NO3-) and ammonia (δ15N-NH4+) linked to a mixing model. The findings reveal that the N-NH4+ deposition generally surpasses N-NO3- deposition, attributed to a decline in the level of NOx emission from coal combustion and an upswing in the level of NHx emission from agricultural sources. The disparity in deposition between N-NH4+ and N-NO3- intensifies from the coast to the offshore, establishing N-NH4+ as the primary contributor to oceanic nitrogen deposition, particularly in ocean background regions. Fertilizer (33 ± 21%) and livestock (20 ± 6%) emerge as the primary sources of N-NH4+. While coal combustion continues to be a significant contributor to marine atmospheric N-NO3-, its proportion has diminished to 22 (Northern Coast)-35% (background area) due to effective NOx emission controls by the countries surrounding the South China Sea, especially the Chinese Government. As coal combustion's contribution dwindles, the significance of vessel and marine biogenic emissions grows. The daytime higher atmospheric N-NO3- concentration and lower δ15N-NO3- compared with nighttime further underscore the substantial role of marine biogenic emissions.

Regulatory T cell expansion promotes white matter repair after stroke.

Recent research highlights the function of regulatory T cells (Tregs) in white matter integrity in CNS diseases. Approaches that expand the number of Tregs have been utilized to improve stroke recovery. However, it remains unclear if Treg augmentation preserves white matter integrity early after stroke or promotes white matter repair. This study evaluates the effect of Treg augmentation on white matter injury and repair after stroke. Adult male C57/BL6 mice randomly received Treg or splenocyte (2 million, iv) transfer 2 h after transient (60 min) middle cerebral artery occlusion (tMCAO). Immunostaining showed improved white matter recovery after tMCAO in Treg-treated mice compared to mice received splenocytes. In another group of mice, IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or isotype IgG were administered (i.p) for 3 consecutive days starting 6 h after tMCAO, and repeated on day 10, 20 and 30. The IL-2/IL-2Ab treatment boosted the number of Tregs in blood and spleen and increased Treg infiltration into the ischemic brain. Longitudinal in vivo and ex vivo diffusion tensor imaging analysis revealed an increase in fractional anisotropy 28d and 35d, but not 14d, after stroke in IL-2/IL-2Ab-treated mice compared to isotype-treated mice, suggesting a delayed improvement in white matter integrity. IL-2/IL-2Ab also improved sensorimotor functions (rotarod test and adhesive removal test) 35d after stroke. There were correlations between white matter integrity and behavior performance. Immunostaining confirmed the beneficial effects of IL-2/IL-2Ab on white matter structures 35d after tMCAO. IL-2/IL-2Ab treatment starting as late as 5d after stroke still improved white matter integrity 21d after tMCAO, suggesting long-term salutary effects of Tregs on the late-stage tissue repair. We also found that IL-2/IL-2Ab treatment reduced the number of dead/dying OPCs and oligodendrocytes in the brain 3d after tMCAO. To confirm the direct effect of Tregs on remyelination, Tregs were cocultured with lysophosphatidyl choline (LPC)-treated organotypic cerebella. LPC exposure for 17 h induced demyelination in organotypic cultures, followed by gradual spontaneous remyelination upon removal of LPC. Co-culture with Tregs accelerated remyelination in organotypic cultures 7d after LPC. In conclusion, Boosting the number of Tregs protects oligodendrocyte lineage cells early after stroke and promotes long-term white matter repair and functional recovery. IL-2/IL-2Ab represents a feasible approach of Treg expansion for stroke treatment.

Mooring Stone-Like Arg114 Pulls Diverse Bulged Peptides: First Insight into African Swine Fever Virus-Derived T Cell Epitopes Presented by Swine Major Histocompatibility Complex Class I.

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), which is a devastating pig disease threatening the global pork industry. However, currently, no commercial vaccines are available. During the pig immune response, major histocompatibility complex class I (MHC-I) molecules select viral peptide epitopes and present them to host cytotoxic T lymphocytes, thereby playing critical roles in eliminating viral infections. Here, we screened peptides derived from ASFV and determined the molecular basis of ASFV-derived peptides presented by the swine leukocyte antigen 1*0101 (SLA-1*0101). We found that peptide binding in SLA-1*0101 differs from the traditional mammalian binding patterns. Unlike the typical B and F pockets used by the common MHC-I molecule, SLA-1*0101 uses the D and F pockets as major peptide anchor pockets. Furthermore, the conformationally stable Arg114 residue located in the peptide-binding groove (PBG) was highly selective for the peptides. Arg114 draws negatively charged residues at positions P5 to P7 of the peptides, which led to multiple bulged conformations of different peptides binding to SLA-1*0101 and creating diversity for T cell receptor (TCR) docking. Thus, the solid Arg114 residue acts as a "mooring stone" and pulls the peptides into the PBG of SLA-1*0101. Notably, the T cell recognition and activation of p72-derived peptides were verified by SLA-1*0101 tetramer-based flow cytometry in peripheral blood mononuclear cells (PBMCs) of the donor pigs. These results refresh our understanding of MHC-I molecular anchor peptides and provide new insights into vaccine development for the prevention and control of ASF. IMPORTANCE The spread of African swine fever virus (ASFV) has caused enormous losses to the pork industry worldwide. Here, a series of ASFV-derived peptides were identified, which could bind to swine leukocyte antigen 1*0101 (SLA-1*0101), a prevalent SLA allele among Yorkshire pigs. The crystal structure of four ASFV-derived peptides and one foot-and-mouth disease virus (FMDV)-derived peptide complexed with SLA-1*0101 revealed an unusual peptide anchoring mode of SLA-1*0101 with D and F pockets as anchoring pockets. Negatively charged residues are preferred within the middle portion of SLA-1*0101-binding peptides. Notably, we determined an unexpected role of Arg114 of SLA-1*0101 as a "mooring stone" which pulls the peptide anchoring into the PBG in diverse "M"- or "n"-shaped conformation. Furthermore, T cells from donor pigs could activate through the recognition of ASFV-derived peptides. Our study sheds light on the uncommon presentation of ASFV peptides by swine MHC-I and benefits the development of ASF vaccines.

UV-Blocking and Light-Responsive Poly (ϵ-Caprolactone)/ZIF-8 Multifunctional Composite Films for Efficient Antibacterial Activities.

Antibacterial photodynamic therapy (APDT) has received considerable attention owing to its superiority. ZIF-8 was used to address the poor stability of the photosensitizer Rose Bengal (RB) encapsulation to synthesize RB@ZIF-8 NPs, which were doped into a composite film with poly (ϵ-caprolactone) (PCL) and polyvinyl alcohol-quaternary ammonium chitosan (PVA-QCS) as substrates to form composite films (PQZ). The composite films exhibited excellent photodynamic sterilization and good resistance to bacterial adhesion. The tensile strength of the film increased to 43.4 MPa, which was approximately 1.8 times that of the PCL film. With the addition of SiO2 and RB@ZIF-8 NPs, the film exhibited water repellency and UV-blocking properties. RAW264.7 cells were selected using the MTT method to confirm that the composite films had excellent biocompatibility and had no significant inhibitory effect on cell growth and reproduction. PQZ multifunctional composite films show potential as novel APDT antimicrobial materials for food packaging.

Peptide Presentations of Marsupial MHC Class I Visualize Immune Features of Lower Mammals Paralleled with Bats.

Marsupials are one of three major mammalian lineages that include the placental eutherians and the egg-laying monotremes. The marsupial brushtail possum is an important protected species in the Australian forest ecosystem. Molecules encoded by the MHC genes are essential mediators of adaptive immune responses in virus-host interactions. Yet, nothing is known about the peptide presentation features of any marsupial MHC class I (MHC I). This study identified a series of possum MHC I Trvu-UB*01:01 binding peptides derived from wobbly possum disease virus (WPDV), a lethal virus of both captive and feral possum populations, and unveiled the structure of marsupial peptide/MHC I complex. Notably, we found the two brushtail possum-specific insertions, the 3-aa Ile52Glu53Arg54 and 1-aa Arg154 insertions are located in the Trvu-UB*01:01 peptide binding groove (PBG). The 3-aa insertion plays a pivotal role in maintaining the stability of the N terminus of Trvu-UB*01:01 PBG. This aspect of marsupial PBG is unexpectedly similar to the bat MHC I Ptal-N*01:01 and is shared with lower vertebrates from elasmobranch to monotreme, indicating an evolution hotspot that may have emerged from the pathogen-host interactions. Residue Arg154 insertion, located in the α2 helix, is available for TCR recognition, and it has a particular influence on promoting the anchoring of peptide WPDV-12. These findings add significantly to our understanding of adaptive immunity in marsupials and its evolution in vertebrates. Our findings have the potential to impact the conservation of the protected species brushtail possum and other marsupial species.

Predicting Breast Cancer Subtypes Using Magnetic Resonance Imaging Based Radiomics With Automatic Segmentation.

OBJECTIVE: The aim of the study is to demonstrate whether radiomics based on an automatic segmentation method is feasible for predicting molecular subtypes. METHODS: This retrospective study included 516 patients with confirmed breast cancer. An automatic segmentation-3-dimensional UNet-based Convolutional Neural Networks, trained on our in-house data set-was applied to segment the regions of interest. A set of 1316 radiomics features per region of interest was extracted. Eighteen cross-combination radiomics methods-with 6 feature selection methods and 3 classifiers-were used for model selection. Model classification performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULTS: The average dice similarity coefficient value of the automatic segmentation was 0.89. The radiomics models were predictive of 4 molecular subtypes with the best average: AUC = 0.8623, accuracy = 0.6596, sensitivity = 0.6383, and specificity = 0.8775. For luminal versus nonluminal subtypes, AUC = 0.8788 (95% confidence interval [CI], 0.8505-0.9071), accuracy = 0.7756, sensitivity = 0.7973, and specificity = 0.7466. For human epidermal growth factor receptor 2 (HER2)-enriched versus non-HER2-enriched subtypes, AUC = 0.8676 (95% CI, 0.8370-0.8982), accuracy = 0.7737, sensitivity = 0.8859, and specificity = 0.7283. For triple-negative breast cancer versus non-triple-negative breast cancer subtypes, AUC = 0.9335 (95% CI, 0.9027-0.9643), accuracy = 0.9110, sensitivity = 0.4444, and specificity = 0.9865. CONCLUSIONS: Radiomics based on automatic segmentation of magnetic resonance imaging can predict breast cancer of 4 molecular subtypes noninvasively and is potentially applicable in large samples.

Marine biomaterials in biomedical nano/micro-systems.

Marine resources in unique marine environments provide abundant, cost-effective natural biomaterials with distinct structures, compositions, and biological activities compared to terrestrial species. These marine-derived raw materials, including polysaccharides, natural protein components, fatty acids, and marine minerals, etc., have shown great potential in preparing, stabilizing, or modifying multifunctional nano-/micro-systems and are widely applied in drug delivery, theragnostic, tissue engineering, etc. This review provides a comprehensive summary of the most current marine biomaterial-based nano-/micro-systems developed over the past three years, primarily focusing on therapeutic delivery studies and highlighting their potential to cure a variety of diseases. Specifically, we first provided a detailed introduction to the physicochemical characteristics and biological activities of natural marine biocomponents in their raw state. Furthermore, the assembly processes, potential functionalities of each building block, and a thorough evaluation of the pharmacokinetics and pharmacodynamics of advanced marine biomaterial-based systems and their effects on molecular pathophysiological processes were fully elucidated. Finally, a list of unresolved issues and pivotal challenges of marine-derived biomaterials applications, such as standardized distinction of raw materials, long-term biosafety in vivo, the feasibility of scale-up, etc., was presented. This review is expected to serve as a roadmap for fundamental research and facilitate the rational design of marine biomaterials for diverse emerging applications.

Intelligent Vehicle Path Tracking Control Method Based on Curvature Optimisation.

In this study, an intelligent vehicle (IV) path tracking control method based on curvature optimisation is proposed to reduce the comprehensive performance conflict of the system. This system conflict is caused by the mutual restriction between the path tracking accuracy and the body stability during the movement of the intelligent automobile. First, the working principle of the new IV path tracking control algorithm is briefly introduced. Then, a three-degrees-of-freedom vehicle dynamics model and a preview error model considering vehicle roll are established. In addition, a path tracking control method based on curvature optimisation is designed to solve the deterioration of vehicle stability even when the path tracking accuracy of the IV is improved. Finally, the effectiveness of the IV path tracking control system is validated through simulations and the Hardware in the Loop (HIL) test with various conditions forms. Results clearly show that the optimisation amplitude of the IV lateral deviation is up to 84.10%, and the stability is improved by approximately 2% under the vx = 10 m/s and ρ = 0.15 m-1 condition; the optimisation amplitude of the lateral deviation is up to 66.80%, and the stability is improved by approximately 4% under the vx = 10 m/s and ρ = 0.2 m-1 condition; the body stability is improved by 20-30% under the vx = 15 m/s and ρ = 0.15 m-1 condition, and the boundary conditions of body stability are triggered. The curvature optimisation controller can effectively improve the tracking accuracy of the fuzzy sliding mode controller. The body stability constraint can also ensure the smooth running of the vehicle in the optimisation process.

The Effect of Cooling Rates on Thermal, Crystallization, Mechanical and Barrier Properties of Rotational Molding Polyamide 11 as the Liner Material for High-Capacity High-Pressure Vessels.

The rapid development of hydrogen fuel cells has been paralleled by increased demand for lightweight type IV hydrogen storage vessels with high hydrogen storage density, which raises the performance requirements of internal plastic liners. An appropriate manufacturing process is important to improve the quality of polymer liners. In this paper, DSC, WAXD, a universal testing machine and a differential pressure gas permeameter were used to investigate the effect of the cooling rate of the rotational molding polyamide 11 on the thermal, crystallization, mechanical and barrier properties. The cooling rate is formulated according to the cooling rate that can be achieved in actual production. The results suggest that two PA11 liner materials initially exhibited two-dimensional (circular) growth under non-isothermal crystallization conditions and shifted to one-dimensional space growth due to spherulite collision and crowding during the secondary crystallization stage. The slower the cooling process, the greater the crystallinity of the specimen. The increase in crystallinity significantly improved the barrier properties of the two PA11 liner materials, and the gas permeability coefficient was 2-3-fold higher than at low crystallinity. Moreover, the tensile strength, the tensile modulus, the flexural strength, and the flexural modulus increased, and the elongation at break decreased as the crystallinity increased.

Epidemiological characteristics and cerebrospinal fluid cytokine profiles of enterovirus encephalitis in children in Hangzhou, China.

Enteroviruses (EVs) are common causes of viral encephalitis in children. To better understand the epidemiological and pathological characteristics of EV encephalitis, we enrolled suspected encephalitis patients younger than 15 years old in Hangzhou, China, from October 2016 to September 2019 for cerebrospinal fluid (CSF) collection and analyses. A total of 7735 CSF samples were collected, among which 330 (4.27%) were positive for the EV genome. The positivity rate was significantly higher in boys than girls (χ2 =  5.68, p =  0.02). The monthly case numbers peaked from June to August (80.30%). Among the different age groups, the 0-2 months age group showed the highest number of cases (28.48% of all cases). The 6-7 years (10.82%) and 9-10 years (9.29%) age groups showed the highest EV-positivity rates among suspected encephalitis cases. Sixty-two EV-positive and 53 control CSF samples were collected for Bio-Plex Pro human cytokine assays that simultaneously tested 48 cytokines. Principle component analyses showed significant separation between EV-positive and control samples, but insignificant separation between children and newborns. The levels of 28 cytokines and chemokines were significantly elevated in the EV-positive group including many proinflammatory and a few anti-inflammatory cytokines, as well as chemokines belonging to the CC and CXC subfamilies. Only one cytokine, stem cell growth factor-ß, showed a decrease in the EV-positive group. Thus, this study revealed age, sex, and seasonal preferences for EV encephalitis incidences in children and identified many cytokines dysregulated during EV encephalitis.

Manipulating upconversion luminescence intensity in a single crystal particle with a waveguide structure.

Lanthanide (Ln)-doped upconversion luminescence (UCL) materials have attracted worldwide attention due to their unique photophysical characteristics. However, how to effectively improve their UCL efficiency has always been an important scientific issue. Here, we design and fabricate ß-NaYF4 microtubes (MTs) with a natural hexagonal shape in the cross section and wedge shape on both top vertexes, which can be regarded as an optical waveguide. The UCL property of a single ß-NaYF4:Yb3+,Er3+(or Tm3+) MT is systematically investigated based on waveguide-excitation modes. It is found that the excitation light can be efficiently coupled in the ß-NaYF4:Yb3+,Er3+(or Tm3+) MT by modulating the angle between the wedge-shape end plane of MT and the microscope slide. In addition, it is clearly observed that the excitation light can be confined and propagate in the MT by introducing a 633 nm laser, which is mainly due to the natural waveguide structure with a stronger confinement and propagation effect of light, thereby enhancing light-to-MT interactions. The current work provides a powerful solution to build high-efficiency Ln-doped UCL materials, which may have potential applications in the optical communication and biomedical fields.

An indirect approach for reference intervals establishment of immunoglobulin A, G and M: the combination of laboratory database and statistics.

Immunoglobulins are affected by sex, age and region, so it is necessary to establish suitable reference intervals (RIs) for clinical diagnosis. Various statistical methods were used to calculate RIs, but there has been a lack of comparison among the methods. Research based on immunoglobulin RIs establishment with various methods would provide a methodological basis for further research. A total of 16,525 individuals were enrolled in the study. Individuals were selected in the medical examination center of First Hospital of Jilin University from 2014 to 2020. The lambda-mu-sigma (LMS) method was performed to evaluate the dynamic changes in analytes. RIs were calculated by parametric, non-parametric, Hoffman method and Bhattacharya method. Sex and age partitions were found for immunoglobulins G and immunoglobulin M. The levels of IgM showed no difference with age in males, but showed differences after 50 years of age in females. Circulating immunoglobulin A concentrations showed an increasing trend with age, and immunoglobulin M showed a fluctuating trend with age. Obvious difference (>5%) was commonly found among the four methods, however, the RIs established by the four methods all passed the verification with a high passing rate. Sex and age differences should be considered for immunoglobulins G and immunoglobulin M in clinical practice. The feasibility of the four indirect methods was proven, which would provides a methodological reference for further studies and benefit the application of clinical data.

Optimization of the Laminate Structure of a Composite Cylinder Based on the Combination of Response Surface Methodology (RSM) and Finite Element Analysis (FEA).

This study optimized the laminate structure of a composite cylinder under the constraint of minimum layup thickness. Based on the progressive damage theory, a finite element model of the cylinder was established, and the NOL ring tensile test was used to verify the accuracy of the damage theory. The winding angle, the number of layers, and the helical/hoop ratio (the stacking sequence) were selected as the optimization factors, and the burst pressure value was used to evaluate the quality of the laminate structure. Then the orthogonal experiments were designed by RSM. Combined with FEA, the function model of the burst pressure of the gas cylinder and each optimization factor was established to obtain the optimal layering scheme, satisfying the minimum burst pressure. In addition, finite element analysis was used to verify the optimal scheme, demonstrating that the error of the burst pressure predicted by the quadratic model established by the response surface design was not more than 5%. This study provides a faster and more efficient optimization method for the optimization design of composite gas cylinder layers.

Proteomic Signature of Urosepsis: From Discovery in a Rabbit Model to Validation in Humans.

Urosepsis after upper urinary tract endoscopic lithotripsy (UUTEL) may cause uroseptic shock with high mortality, which can be prevented if early diagnosis and timely intervention are implemented with help of a diagnostic protein panel. The plasma of five rabbits of uroseptic shock and five controls was subjected to exploratory proteomics to search biomarker candidates from proteomic profiles related to uroseptic shock. Then, plasma from 21 nonsepsis and 20 urosepsis patients according to European diagnostic criteria of sepsis was enrolled in the validation study via targeted proteomics. Changes in a massive number of plasma proteins, mainly enriched in immune regulation, coagulation, structural repair, and transport activity, were observed in the rabbit model of septic shock. Fifteen proteins were identified as differential expression proteins between sepsis and nonsepsis patients. A diagnostic model composed of three proteins lipopolysaccharide-binding protein (LBP), clusterin (CLU), and vascular cell adhesion protein 1 (VCAM1) was developed for the early detection (2 hours postoperatively) of urosepsis after UUTEL, with a high area under the receiver operating characteristic (ROC) curve of 0.921. In conclusion, changes in the proteomic profile may reflect the underlying biological mechanisms during the development of urosepsis and produce diagnostic biomarkers for the early detection of urosepsis after UUTEL.

Response of Leucine-Rich Repeat Domain-Containing Protein in Haemaphysalis longicornis to Babesia microti Infection and Its Ligand Identification.

Haemaphysalis longicornis is a blood-feeding hard tick known for transmitting a variety of pathogens, including Babesia How the parasites in the imbibed blood become anchored in the midgut of ticks is still unknown. Leucine-rich repeat domain (LRR)-containing protein, which is associated with the innate immune reaction and conserved in many species, has been detected in H. longicornis and has previously been indicated in inhibiting the growth of Babesia gibsoni However, the detailed mechanism is unknown. In this study, one of the ligands for LRR from H. longicornis (HlLRR) was identified in Babesia microti, designated BmActin, using glutathione transferase (GST) pulldown experiments and immunofluorescence assays. Moreover, RNA interference of HlLRR led to a decrease in the BmActin mRNA expression in the midgut of fully engorged ticks which fed on B. microti-infected mice. We also found that the expression level of the innate immune molecules in H. longicornis, defensin, antimicrobial peptides (AMPs), and lysozyme, were downregulated after the knockdown of HlLRR. However, subolesin expression was upregulated. These results indicate that HlLRR not only recognizes BmActin but may also modulate innate immunity in ticks to influence Babesia growth, which will further benefit the development of anti-Babesia vaccines or drugs.

Ceria nanoparticles ameliorate white matter injury after intracerebral hemorrhage: microglia-astrocyte involvement in remyelination.

BACKGROUND: Intracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration. METHODS: ICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms. RESULTS: CeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia. CONCLUSION: The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.

miR-23a-3p regulated by LncRNA SNHG5 suppresses the chondrogenic differentiation of human adipose-derived stem cells via targeting SOX6/SOX5.

Cartilage generation and degradation are controlled by miRNAs. Our previous study showed miR-23a-3p was downregulated during chondrogenic differentiation in chondrogenic human adipose-derived mesenchymal stem cells (hADSCs). In the present study, we explored the function of miR-23a-3p in chondrogenesis differentiation. The role of miR-23a-3p in chondrogenic differentiation potential of hADSCs was assessed by Alcian blue staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. We show that miR-23a-3p suppressed the chondrogenic differentiation of hADSCs. LncRNA SNHG5 interacted with miR-23a-3p, and suppression or overexpression of SNHG5 correlates with inhibition and promotion of hADSC chondrogenic differentiation, respectively. We have determined that SNHG5 can sponge miR-23a-3p to regulate the expression of SOX6/SOX5, transcription factors that play essential roles in chondrocyte differentiation. Furthermore, the overexpression of SNHG5 activates the JNK/MAPK/ERK pathway. In conclusion, miR-23a-3p regulated by lncRNA SNHG5 suppresses the chondrogenic differentiation of human adipose-derived stem cells via targeting SOX6/SOX5.

Advanced gastric cancer: CT radiomics prediction and early detection of downstaging with neoadjuvant chemotherapy.

OBJECTIVES: To develop and evaluate machine learning models using baseline and restaging computed tomography (CT) for predicting and early detecting pathological downstaging (pDS) with neoadjuvant chemotherapy in advanced gastric cancer (AGC). METHODS: We collected 292 AGC patients who received neoadjuvant chemotherapy. They were classified into (a) primary cohort (206 patients with 3-4 cycles chemotherapy) for model development and internal validation, (b) testing cohort I (46 patients with 3-4 cycles chemotherapy) for evaluating models' predictive ability before and after the complete course, and (c) testing cohort II (n = 40) for model evaluation on its performance at early treatment. We extracted 1,231 radiomics features from venous phase CT at baseline and restaging. We selected radiomics models based on 28 cross-combination models and measured the areas under the curve (AUC). Our prediction radiomics (PR) model is designed to predict pDS outcomes using baseline CT. Detection radiomics (DR) model is applied to restaging CT for early pDS detection. RESULTS: PR model achieved promising outcomes in two testing cohorts (AUC 0.750, p = .009 and AUC 0.889, p = .000). DR model also showed a good predictive ability (AUC 0.922, p = .000 and AUC 0.850, p = .000), outperforming the commonly used RECIST method (NRI 39.5% and NRI 35.4%). Furthermore, the improved DR model with averaging outcome scores of PR and DR models showed boosted results in two testing cohorts (AUC 0.961, p = .000 and AUC 0.921, p = .000). CONCLUSIONS: CT-based radiomics models perform well on prediction and early detection tasks of pDS and can potentially assist surgical decision-making in AGC patients. KEY POINTS: • Baseline contrast-enhanced computed tomography (CECT)-based radiomics features were predictive of pathological downstaging, allowing accurate identification of non-responders before therapy. • Restaging CECT-based radiomics features were predictive to achieve pDS after and even at an early stage of neoadjuvant chemotherapy. • Combination of baseline and restaging CECT-based radiomics features was promising for early detection and preoperative evaluation of pathological downstaging of AGC.