Observations reveal vertical transport induced by submesoscale front.

Submesoscale fronts, with horizontal scale of 0.1-10 km, are key components of climate system by driving intense vertical transports of heat, salt and nutrients in the ocean. However, our knowledge on how large the vertical transport driven by one single submesoscale front can reach remains limited due to the lack of comprehensive field observations. Here, based on high-resolution in situ observations in the Kuroshio-Oyashio Extension region, we detect an exceptionally sharp submesoscale front. The oceanic temperature (salinity) changes sharply from 14 °C (34.55 psu) to 2 °C (32.7 psu) within 2 km across the front from south to north. Analysis reveals intense vertical velocities near the front reaching 170 m day-1, along with upward heat transport up to 1.4 × 10-2 °C m s-1 and salinity transport reaching 4 × 10-4 psu m s-1. The observed heat transport is much larger than the values reported in previous observations and is three times as that derived from current eddy-rich climate models, whereas the salinity transport enhances the nutrients concentration with prominent implications for marine ecosystem and fishery production. These observations highlight the vertical transport of submesoscale fronts and call for a proper representation of submesoscale processes in the next generation of climate models.

Anatomical Brushite-Coated Mg-Nd-Zn-Zr Alloy Cage Promotes Cervical Fusion: One-Year Results in Goats.

In this study, an anatomical brushite-coated Mg-Nd-Zn-Zr alloy cage was fabricated for cervical fusion in goats. The purpose of this study was to investigate the cervical fusion effect and degradation characteristics of this cage in goats. The Mg-Nd-Zn-Zr alloy cage was fabricated based on anatomical studies, and brushite coating was prepared. Forty-five goats were divided into three groups, 15 in each group, and subjected to C2/3 anterior cervical decompression and fusion with tricortical bone graft, Mg-Nd-Zn-Zr alloy cage, or brushite-coated Mg-Nd-Zn-Zr alloy cage, respectively. Cervical radiographs and computed tomography (CT) were performed 3, 6, and 12 months postoperatively. Blood was collected for biocompatibility analysis and Mg2+ concentration tests. The cervical spine specimens were obtained at 3, 6, and 12 months postoperatively for biomechanical, micro-CT, scanning electron microscopy coupled with energy dispersive spectroscopy, laser ablation-inductively coupled plasma-time-of-flight mass spectrometry, and histological analysis. The liver and kidney tissues were obtained for hematoxylin and eosin staining 12 months after surgery for biosafety analysis. Imaging and histological analysis showed a gradual improvement in interbody fusion over time; the fusion effect of the brushite-coated Mg-Nd-Zn-Zr alloy cage was comparable to that of the tricortical bone graft, and both were superior to that of the Mg-Nd-Zn-Zr alloy cage. Biomechanical testing showed that the brushite-coated Mg-Nd-Zn-Zr alloy cage achieved better stability than the tricortical bone graft at 12 months postoperatively. Micro-CT showed that the brushite coating significantly decreases the corrosion rate of the Mg-Nd-Zn-Zr alloy cage. In vivo degradation analysis showed higher Ca and P deposition in the degradation products of the brushite-coated Mg-Nd-Zn-Zr alloy cage, and no hyperconcentration of Mg was detected. Biocompatibility analysis showed that both cages were safe for cervical fusion surgery in goats. To conclude, the anatomical brushite-coated Mg-Nd-Zn-Zr alloy cage can promote cervical fusion in goats, and the brushite-coated Mg-Nd-Zn-Zr alloy is a potential material for developing absorbable fusion cages.

Mfat-1 ameliorates cachexia after hypoxic-ischemic brain damage in mice by protecting the hypothalamus-pituitary-adrenal axis.

AIMS: Cachexia, a metabolic syndrome, affects 21 % of patients suffering from ischemic encephalopathy. However, the specific mechanism and prevention measures are still unclear. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been proven to reduce inflammatory cytokine levels during ischemic events, but whether they have a protective effect against cachexia after hypoxic-ischemic brain damage (HIBD) remains unclear. MAIN METHODS: C57BL/6J wild-type and mfat-1 transgenic male mice were treated with and without HIBD. One day after HIBD, the epididymal white fat, gastrocnemius muscle and hypothalamus were weighed and analyzed the phenotypic changes. RNA sequencing was applied to gastrocnemius muscle to identify differential genes and pathways in HIBD groups. The effect of HPA axis on cachexia post-HIBD was examined via adrenalectomy, dexamethasone (0.1 mg/kg), and corticosterone injection (100 mg/kg). KEY FINDINGS: The results showed that the incidence of cachexia in mfat-1 mice, which produce high proportion of n-3 PUFAs, was significantly lower than that in wild-type mice post-HIBD. Cachexia-related factors, such as inflammation, muscle atrophy and lipid metabolism were significantly improved in mfat-1 HIBD. RNA sequencing revealed that catabolic and proteasome pathways were significantly downregulated. In hypothalamus, inflammatory cytokines, lipid peroxidation levels were reduced. Corticosterone, glucocorticoid receptor, and dexamethasone suppression test all showed that mfat-1 improved the dysfunction of the HPA axis post-HIBD. The present study elucidated for the first time that mfat-1 reduced HIBD-induced hyperactivation of the HPA axis in mice by reducing inflammation and oxidative stress and contributed to the reduction of metabolic imbalance in peripheral tissues. SIGNIFICANCE: Our study provides mechanistic information for the development of intervention strategies to prevent cachexia.

Phenylethanoid glycosides derived from Cistanche deserticola promote neurological functions and the proliferation of neural stem cells for improving ischemic stroke.

Phenylethanoid glycosides derived from Cistanche deserticola (PhGs) are plant-derived natural medicinal compounds that occur in many medicinal plants. This study aims to investigate whether PhGs treatment improves the stroke and its potential mechanisms. Adult male C57BL/6 J mice were administrated PhGs once daily for 7 days after MCAO surgery. The neurological score, and catwalk were evaluated on Day 1, 3 and 7 after ischemic stroke. Furthermore, triphenyl-2,3,5-tetrazoliumchloride (TTC) and hematoxylin-eosin (H&E) staining were used for evaluating the infarct volume and neuronal restoration. The effects of PhGs on NSCs proliferation were investigated in vitro and in vivo. Western blot was used to detect the proteins of Wnt/ß-catenin signaling pathway. This study found that PhGs effectively improved the neurological functions in ischemic stroke mice. TTC and H&E staining demonstrated that PhGs not only reduced infarct volume, but also improved neuronal restoration. The immunohistochemistry and 5-Ethynyl-2-deoxyuridine (EdU) incorporation assays revealed that PhGs promoted the proliferation of neural stem cells (NSCs) in subventricular zone (SVZ). In addition, transcriptome analysis of NSCs showed that the Wnt/ß-catenin signaling pathway was involved in the PhGs induced NSCs proliferation. Importantly, the related proteins in the Wnt/ß-catenin signaling pathway were changed after PhGs treatment, including ß-catenin, Wnt3a, GSK-3ß, c-Myc. PhGs treatment improved the stroke through enhancing endogenous NSCs proliferation via activating Wnt/ß-catenin signaling pathway. Due to its effect on the proliferation of NSCs, PhGs are a potential adjuvant therapeutic drug for post-stroke treatment.

North Atlantic subtropical mode water formation controlled by Gulf Stream fronts.

The North Atlantic Ocean hosts the largest volume of global subtropical mode waters (STMWs) in the world, which serve as heat, carbon and oxygen silos in the ocean interior. STMWs are formed in the Gulf Stream region where thermal fronts are pervasive and result in feedback with the atmosphere. However, their roles in STMW formation have been overlooked. Using eddy-resolving global climate simulations, we find that suppressing local frontal-scale ocean-to-atmosphere (FOA) feedback leads to STMW formation being reduced almost by half. This is because FOA feedback enlarges STMW outcropping, attributable to the mixed layer deepening associated with cumulative excessive latent heat loss due to higher wind speeds and greater air-sea humidity contrast driven by the Gulf Stream fronts. Such enhanced heat loss overshadows the stronger restratification induced by vertical eddies and turbulent heat transport, making STMW colder and heavier. With more realistic representation of FOA feedback, the eddy-present/rich coupled global climate models reproduce the observed STMWs much better than the eddy-free ones. Such improvement in STMW production cannot be achieved, even with the oceanic resolution solely refined but without coupling to the overlying atmosphere in oceanic general circulation models. Our findings highlight the need to resolve FOA feedback to ameliorate the common severe underestimation of STMW and associated heat and carbon uptakes in earth system models.

Virus-Like Nanotherapeutic for Spatiotemporally Enhancing Antigen Presentation and Cross-Presentation toward Potential Personalized Immunotherapy.

One of the major causes of immunotherapy resistance is the loss of major histocompatibility complex class I (MHC-I) molecules in tumor cells or the downregulation of the class I antigen presentation pathway. In this study, a novel virus-like nanotherapeutic (siRNA@HCM) is developed via encapsulating nanosized siRNA nanoparticles in a hybrid membrane comprising a personalized tumor cell membrane and a universal 293T membrane expressing the mutant vesicular stomatitis virus glycoprotein (mVSV-G). Upon intravenous administration, siRNA@HCM accumulates at the tumor site and provides two potent driving forces for antitumor immunity. First, mVSV-G induces the fusion of siRNA@HCM with tumor cell membranes and directly injects siRNAs into the cytoplasm, significantly improving tumor intrinsic MHC-I antigen presentation. Moreover, mVSV-G can promote the maturation of dendritic cells, thereby achieving highly efficient antigen cross-presentation. The results demonstrate that spatiotemporally enhancing tumor intrinsic antigen presentation and cross-presentation via siRNA@HCM can achieve satisfactory antitumor efficacy and excellent biocompatibility. Immune infiltration analysis shows that siRNA@HCM treatment turns cold tumors into hot tumors. In addition, it significantly promotes the therapeutic effect of programmed death-1 inhibitor. In summary, virus-like nanotherapeutics present a promising approach to enhance the antitumor immune response, with distinct advantages for potential personalized therapy and clinical applications.

Brushite-coated Mg-Nd-Zn-Zr alloy promotes the osteogenesis of vertebral laminae through IGF2/PI3K/AKT signaling pathway.

Biodegradable magnesium (Mg) alloys have been extensively investigated in orthopedic implants due to their suitable mechanical strength and high biocompatibility. However, no studies have reported whether Mg alloys can be used to repair lamina defects, and the biological mechanisms regulating osteogenesis are not fully understood. The present study developed a lamina reconstruction device using our patented biodegradable Mg-Nd-Zn-Zr alloy (JDBM), and brushite (CaHPO4·2H2O, Dicalcium phosphate dihydrate, DCPD) coating was developed on the implant. Through in vitro and in vivo experiments, we evaluated the degradation behavior and biocompatibility of DCPD-JDBM. In addition, we explored the potential molecular mechanisms by which it regulates osteogenesis. In vitro, ion release and cytotoxicity tests revealed that DCPD-JDBM had better corrosion resistance and biocompatibility. We found that DCPD-JDBM extracts could promote MC3T3-E1 osteogenic differentiation via the IGF2/PI3K/AKT pathway. The lamina reconstruction device was implanted on a rat lumbar lamina defect model. Radiographic and histological analysis showed that DCPD-JDBM accelerated the repair of rat lamina defects and exhibited lower degradation rate compared to uncoated JDBM. Immunohistochemical and qRT-PCR results showed that DCPD-JDBM promoted osteogenesis in rat laminae via IGF2/PI3K/AKT pathway. This study shows that DCPD-JDBM is a promising biodegradable Mg-based material with great potential for clinical applications.

Oceanic mesoscale eddies as crucial drivers of global marine heatwaves.

Marine heatwaves (MHWs) are prolonged extreme warm water events in the ocean, exerting devastating impacts on marine ecosystems. A comprehensive knowledge of physical processes controlling MHW life cycles is pivotal to improve MHW forecast capacity, yet it is still lacking. Here, we use a historical simulation from a global eddy-resolving climate model with improved representation of MHWs, and show that heat flux convergence by oceanic mesoscale eddies acts as a dominant driver of MHW life cycles over most parts of the global ocean. In particular, the mesoscale eddies make an important contribution to growth and decay of MHWs, whose characteristic spatial scale is comparable or even larger than that of mesoscale eddies. The effect of mesoscale eddies is spatially heterogeneous, becoming more dominant in the western boundary currents and their extensions, the Southern Ocean, as well as the eastern boundary upwelling systems. This study reveals the crucial role of mesoscale eddies in controlling the global MHW life cycles and highlights that using eddy-resolving ocean models is essential, albeit not necessarily fully sufficient, for accurate MHW forecasts.

Mfsd2a attenuated hypoxic-ischemic brain damage via protection of the blood-brain barrier in mfat-1 transgenic mice.

Previous studies have shown that mfat-1 transgenic mice have protective effects against some central nervous system (CNS) disorders, owing to the high docosahexaenoic acid (DHA) content enriched in their brains. However, whether this protective effect is connected to the blood-brain barrier (BBB) remains unclear. This study aims to investigate the mechanisms of the protective effect against hypoxic-ischemic brain damage (HIBD) of mfat-1 transgenic mice. mfat-1 mice not only demonstrated a significant amelioration of neurological dysfunction and neuronal damage but also partly maintained the physiological permeability of the BBB after HIBD. We initially showed this was associated with elevated major facilitator superfamily domain-containing 2a (Mfsd2a) expression on the BBB, resulting from more lysophosphatidylcholine (LPC)-DHA entering the brain. Wild-type (WT) mice showed a similar Mfsd2a expression trend after long-term feeding with an LPC-DHA-rich diet. Knockdown of Mfsd2a by siRNA intra-cerebroventricular (ICV) injection neutralized the protective effect against HIBD-induced BBB disruption in mfat-1 mice, further validating the protective function of Mfsd2a on BBB. HIBD-induced BBB high permeability was attenuated by Mfsd2a, primarily through a transcellular pathway to decrease caveolae-like vesicle-mediated transcytosis. Taken together, these findings not only reveal that mfat-1 transgenic mice have higher expression of Mfsd2a on the BBB, which partly sustains BBB permeability via vesicular transcytosis to alleviate the severity of HIBD, but also suggest that dietary intake of LPC-DHA may upregulate Mfsd2a expression as a novel therapeutic strategy for BBB dysfunction and survival in HIBD patients.

Growth of ocean thermal energy conversion resources under greenhouse warming regulated by oceanic eddies.

The concept of utilizing a large temperature difference (>20 °C) between the surface and deep seawater to generate electricity, known as the ocean thermal energy conversion (OTEC), provides a renewable solution to fueling our future. However, it remains poorly assessed how the OTEC resources will respond to future climate change. Here, we find that the global OTEC power potential is projected to increase by 46% around the end of this century under a high carbon emission scenario, compared to its present-day level. The augmented OTEC power potential due to the rising sea surface temperature is partially offset by the deep ocean warming. The offsetting effect is more evident in the Atlantic Ocean than Pacific and Indian Oceans. This is mainly attributed to the weakening of mesoscale eddy-induced upward heat transport, suggesting an important role of mesoscale eddies in regulating the response of thermal stratification and OTEC power potential to greenhouse warming.

Technical Notes for Establishing a Cervical Fusion Model in Goats Based on Distinctive Anatomy.

Goat is an adequate experimental model for cervical spine testing. However, studies on the anatomy of the cervical spine in goats are limited, and there is no uniform standard for establishing a single-segment anterior cervical discectomy and fusion (ACDF) model in goats. To address this issue, we investigated the cervical spine anatomy of goats and provided a technical basis for establishing a single-segment ACDF model in goats. We measured the imaging anatomical parameters using Mimics Medical 20.0 software. We then performed histological analysis of the cervical spine segment 2-3 (C2-3) segment of six goat cervical spine specimens. Based on the measurements and histological analysis, the fusion cage was designed to be wedge-shaped, the length of the plate was 25 mm, and the length of the screw was 15 mm. Based on the anatomical characteristics of goats, we believed that the C2-3 segment of goats was most suitable for a single-segment ACDF model in goats, and the decompression should be performed medial to the pterygoid joint on both sides, the thickness of the removed endplate was ∼0.6 mm, the cage implanted in the anterior two-thirds of the intervertebral space could maximize the contact area of the cage-endplate interface, and the location of the midline spur could position the implantation of the internal fixtures. Radiological examination at 12 weeks postoperatively suggested that the internal fixtures were in place and new bone formation was visible. These results demonstrated that these technical notes based on anatomical features were practical and could minimize damage to animals.

TLR4 aggravates microglial pyroptosis by promoting DDX3X-mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury.

BACKGROUND: Toll-like receptor 4 (TLR4) participates in the initiation of neuroinflammation in various neurological diseases, including central nervous system injuries. NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated microglial pyroptosis is crucial for the inflammatory response during secondary spinal cord injury (SCI). However, the underlying mechanism by which TLR4 regulates NLRP3 inflammasome activation and microglial pyroptosis after SCI remains uncertain. METHODS: We established an in vivo mouse model of SCI using TLR4-knockout (TLR4-KO) and wild-type (WT) mice. The levels of pyroptosis, tissue damage and neurological function recovery were evaluated in the three groups (Sham, SCI, SCI-TLR4-KO). To identify differentially expressed proteins, tandem mass tag (TMT)-based proteomics was conducted using spinal cord tissue between TLR4-KO and WT mice after SCI. For our in vitro model, mouse microglial BV2 cells were exposed to lipopolysaccharides (1 µg/ml, 8 h) and adenosine triphosphate (ATP) (5 mM, 2 h) to induce pyroptosis. A series of molecular biological experiments, including Western blot (WB), real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemical (IHC), chromatin immunoprecipitation (ChIP), Dual-Luciferase Reporter assay (DLA) and co-immunoprecipitation (Co-IP), were performed to explore the specific mechanism of microglial pyroptosis in vivo and in vitro. RESULTS: Our results indicated that TLR4 promoted the expression of dead-box helicase 3 X-linked (DDX3X), which mediated NLRP3 inflammasome activation and microglial pyroptosis after SCI. Further analysis revealed that TLR4 upregulated the DDX3X/NLRP3 axis by activating the JAK2/STAT1 signalling pathway, and importantly, STAT1 was identified as a transcription factor promoting DDX3X expression. In addition, we found that biglycan was increased after SCI and interacted with TLR4 to jointly regulate microglial pyroptosis through the JAK2/STAT1/DDX3X/NLRP3 axis after SCI. CONCLUSION: Our study preliminarily identified a novel mechanism by which TLR4 regulates NLRP3 inflammasome-mediated microglial pyroptosis in response to SCI-providing a novel and promising therapeutic target for SCI.

Extending systems factorial technology to errored responses.

Systems factorial technology (SFT) is a theoretically derived methodology that allows for strong inferences to be made about underlying processing architectures (e.g., whether processing occurs in a pooled, coactive fashion or in serial or in parallel). Measures of mental architecture using SFT have been restricted to the use of error-free response times (RTs). In this article, through formal proofs and demonstrations, we extended the measure of architecture, the survivor interaction contrast (SIC), to RTs conditioned on whether they are correct or incorrect. We show that so long as an ordering relation (between stimulus conditions of different difficulty) is preserved, we learn that the canonical SIC predictions result when exhaustive processing is necessary and sufficient for a response. We further prove that this ordering relation holds for the popular Wiener diffusion model for both correct and error RTs but fails under some classes of a Poisson counter model, which affords a strong potential experimental test of the latter class versus the others. Our exploration also serves to point to the importance of detailed studies of how errors are made in perceptual and cognitive tasks. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Artificial Nanoplatelets Depend on Size for Precisely Inducing Thrombosis in Tumor Vessels.

Due to the heterogeneity of a tumor, the tumor vascular interruption-based therapy has become an ideal treatment strategy. Herein, artificial nanoplatelets are reported to induce selective thrombosis in tumor vessels, which can achieve rapid and large-scale necrosis of tumor cells. For one, the nanoplatelets are exploited to specially release thrombin into target regions without affecting the established coagulation factors system. For another, the thrombin elicits vascular infarction to provide tumor-ablation effects. More importantly, the size-dependent effect of nanoplatelets (with diameters of 200, 400, and 800 nm) in vivo on blocking the tumor vessels is evaluated. The results show that the nanoplatelets from nanometer to submicron have achieved different biodistribution and therapeutic effects through the vascular transport. Notably, 400 nm scale nanoplatelets can induce thrombosis in tumor vessels and achieve 83% of the tumor elimination rate, thus manifesting the effectiveness of anti-tumor strategy compared with the other two scales of nanoplatelets (200 and 800 nm). These findings highlight the need of concern about nanoparticle size, providing a promising strategy for the future design of advanced vascular targeting reagents and the clinical translation of tumor vascular interruption-based therapy.

Protective effects on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice by alleviating neuroinflammation.

Acute hypoxic-ischemic brain damage (HIBD) mainly occurs in adults as a result of perioperative cardiac arrest and asphyxia. The benefits of n-3 polyunsaturated fatty acids (n-3 PUFAs) in maintaining brain growth and development are well documented. However, possible protective targets and underlying mechanisms of mfat-1 mice on HIBD require further investigation. The mfat-1 transgenic mice exhibited protective effects on HIBD, as indicated by reduced infarct range and improved neurobehavioral defects. RNA-seq analysis showed that multiple pathways and targets were involved in this process, with the anti-inflammatory pathway as the most significant. This study has shown for the first time that mfat-1 has protective effects on HIBD in mice. Activation of a G protein-coupled receptor 120 (GPR120)-related anti-inflammatory pathway may be associated with perioperative and postoperative complications, thus innovating clinical intervention strategy may potentially benefit patients with HIBD.

Multifunctional Parachute-like Nanomotors for Enhanced Skin Penetration and Synergistic Antifungal Therapy.

Fungal infections in skin are extremely stubborn and seriously threaten human health. In the process of antifungal treatment, it is a huge challenge that the stratum corneum of the skin and fungal biofilms form the drug transport barrier. Herein, a near-infrared (NIR) laser-propelled parachute-like nanomotor loaded with miconazole nitrate (PNM-MN) is fabricated to enhance transdermal drug delivery for synergistic antifungal therapy. Due to asymmetrically spatial distribution, PNM can generate a thermal gradient under NIR laser irradiation, thereby forming effective self-thermophoretic propulsion. The self-propulsion and photothermal effect of PNM play a major role in promoting fungal uptake and biofilm adhesion. Moreover, under laser irradiation, PNM-MN can obliterate plankton Candida albicans and mature biofilms by combining pharmacological therapy and photothermal therapy. More importantly, the drug effectively penetrated the skin to reach the infected site using the nanomotor with NIR laser irradiation. Moreover, PNM-MN with a NIR laser can eradicate fungal infections caused by C. albicans and facilitate the abscess ablation, showing a therapeutic effect in vivo better than that of PNM with a NIR laser or free MN groups, with negligible histological toxicity. Taken together, NIR laser-propelled PNM-MN, as an antifungal nanoagent, provides a promising strategy for transdermal delivery and antifungal therapy.

Impaired generation of mature neurons due to extended expression of Tlx by repressing Sox2 transcriptional activity.

As a master regulator of the dynamic process of adult neurogenesis, timely expression and regulation of the orphan nuclear receptor Tailless (Tlx) is essential. However, there is no study yet to directly investigate the essential role of precise spatiotemporal expressed Tlx. Here, we generated a conditional gain of Tlx expression transgenic mouse model, which allowed the extended Tlx expression in neural stem cells (NSCs) and their progeny by mating with a TlxCreERT2 mouse line. We demonstrate that extended expression of Tlx induced the impaired generation of mature neurons in adult subventricular zone and subgranular zone. Furthermore, we elucidated for the first time that this mutation decreased the endogenous expression of Sox2 by directly binding to its promoter. Restoration experiments further confirmed that Sox2 partially rescued these neuron maturation defects. Together, these findings not only highlight the importance of shutting-off Tlx on time in controlling NSC behavior, but also provide insights for further understanding adult neurogenesis and developing treatment strategies for neurological disorders.

Artificial M2 macrophages for disease-modifying osteoarthritis therapeutics.

Osteoarthritis (OA) is one of the most common joint diseases worldwide and the focus is shifting to disease prevention and the pharmaceutical and surgical treatment of early OA. However, at present few have proven ability to block or delay the progression of OA. Nevertheless, M2 macrophages present an anti-inflammatory function and promote cartilage repair, thereby alleviating OA in mice. However, it is a significant challenge to regulate the helpful secretion of M2 macrophages on demand toward disease-modifying osteoarthritis therapeutics. Here, artificial M2 macrophage (AM2M) with yolk-shell structure was proposed and fabricated to enhance the therapeutic efficacy of M2 macrophages in the treatment of OA. AM2M was composed of macrophage membrane as "shell" and inflammation-responsive nanogel as "yolk". The nanogel was prepared via physical interaction of gelatin and chondroitin sulfate (ChS) through ionic bond and hydrogen bond, achieving burst release to down-regulate inflammation during acute flares and sustainable release to repair cartilage during low inflammatory activity. Furthermore, AM2M exhibited the targeting and long-term residence in the inflamed area and blocked the immune stimulation of macrophages by ChS. Therefore, our fabrication provided a new insight that artificial M2 macrophages are expected to break a vicious and self-perpetuating cycle of OA.

Screening and Identification of the First Non-CRISPR/Cas9-Treated Chinese Miniature Pig With Defective Porcine Endogenous Retrovirus pol Genes.

Pig to human xenotransplantation is considered to be a possible approach to alleviate the shortage of human allografts. Porcine endogenous retrovirus (PERV) is the most significant pathogen in xenotransplantation. We screened for pigs that consistently did not transmit human-tropic replication competent PERVs (HTRC PERVs), namely, non-transmitting pigs. Then, we conducted whole-genome resequencing and full-length transcriptome sequencing to further investigate the sequence characteristics of one non-transmitting pig. Using in vitro transmission assays, we found 5 (out of 105) pigs of the Chinese Wuzhishan minipig inbred line that did not transmit PERV to human cells, i.e., non-transmitting pigs. Whole-genome resequencing and full-length transcriptome sequencing of one non-transmitting pig showed that all of the pol genes were defective at both the genome and transcript levels. We speculate that the defective PERV pol genes in this pig might be attributable to the long-term inbreeding process. This discovery is promising for the development of a strain of highly homozygous and genetically stable pigs with defective PERV pol genes as a source animal species for xenotransplantation.