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Abstract This systematic review examines the landscape of extracellular vesicle (EV)‐related clinical trials to elucidate the field's trends in clinical applications and EV‐related methodologies, with an additional focus on the acknowledgement of EV subpopulations. By analysing data from public reporting repositories, we catalogued 471 EV‐related clinical trials to date, with indications for over 200 diseases. Diagnostics and companion diagnostics represented the bulk of EV‐related clinical trials with cancer being the most frequent application. EV‐related therapeutics trials mainly utilized mesenchymal stromal cell (MSC) EVs and were most frequently used for treatment of respiratory illnesses. Ultracentrifugation and RNA‐sequencing were the most common isolation and characterization techniques; however, methodology for each was not frequently reported in study records. Most of the reported characterization relied on bulk characterization of EV isolates, with only 11% utilizing EV subpopulations in their experimental design. While this may be connected to a lack of available techniques suitable for clinical implementation, it also highlights the opportunity for use of EV subpopulations to improve translational efforts. As academic research identifies more chemically distinct subpopulations and technologies for their enrichment, we forecast to more refined EV trials in the near future. This review emphasizes the need for meticulous methodological reporting and consideration of EV subpopulations to enhance the translational success of EV‐based interventions, pointing towards a paradigm shift in personalized medicine.

Abstract To explore the impact of the Mediterranean diet on cardiovascular risk factors, glycemic control and weight loss in patients with type 2 diabetes(T2D) by a meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Cochrance Library, EMBASE and four Chinese databases to identify RCTs that compared the Mediterranean diet with control diets in patients with T2D up to December 2021. The Risk of Bias of the included studies was assessed using the version 2 of the Cochrane risk-of-bias tools for randomized trials (ROB 2). Seven RCTs with 1371 patients met the eligibility criteria and entered into the meta-analysis. Compared to control diets, the beneficial effects of Mediterranean diet were not statistically significant in high-density lipoprotein (MD = 2.33; 95% CI: -0.27 to 4.92), low-density lipoprotein (MD = -2.34; 95% CI -5.67 to 0.99) and total cholesterol (MD = 2.60; 95% CI: -0.95 to 6.15). But Mediterranean diet led to reduce the level of diastolic blood pressure (MD = -1.20; 95% CI: -2.21 to -0.19) and systolic blood pressure (MD = -4.17; 95% CI: -7.12 to -1.22). Meanwhile, Mediterranean diet showed beneficial effects in glycemic control (HbA1[%]: MD = -0.39, 95% CI: -0.58 to -0.20; fasting plasma glucose: MD = -15.12, 95% CI: -24.69 to -5.55) and weight loss (BMI: MD = -0.71, 95% CI: -1.30 to -0.78; WC: MD = -1.69; 95% CI: -3.35 to -0.02) compared to the control diets. The meta-analysis presented evidence supporting the beneficial effects of the Mediterranean diet on blood pressure, glycemic control, and weight loss. However, the impact of the Mediterranean diet on the lipid profile was not found to be significant, warranting further verification. This Meta-analysis was registered on the INPLASY website (Registration number: INPLASY 202160096).

IntroductionRepresentations in working memory can affect distractor suppression in human visual search, and this process is modulated by a separate top-down cognitive control. An increasing body of research has demonstrated that patients with substance use disorder (SUD) have deficits in cognitive control over filtering interference by perceptual distractors. However, their ability to resist proactive interference from working memory has received comparatively less attention.MethodsHere, we investigate this issue by employing a working memory/visual search dual-task paradigm. An intervening gap-location search task was instructed to be performed while participants memorized a written color word, with congruent auditory information present during the memory encoding phase on half of the trials.ResultsResults showed that there was a reliable response time (RT) advantage when the meaning of the memory sample agreed with the color of one of the distractors under the visual alone condition. However, such a result was only found in the control group. More importantly, both groups exhibited comparable facilitation under the audiovisual condition, with the facilitation effect appearing later in the SUD group. Furthermore, the facilitation effect was superior in magnitude and time course under the audiovisual condition to the visual alone condition.DiscussionThese findings highlight how patients with SUD resist distractor interference at the memory level and extend our understanding of how working memory, selective attention, and audiovisual enhancement interact to optimize perceptual decisions in patients with SUD.

Rice kernel smut caused by the biotrophic basidiomycete fungus Tilletia horrida causes significant yield losses in hybrid rice-growing areas around the world. Cytochrome P450 (CYP) enzyme is a membrane-bound heme-containing monooxygenase. In fungi, CYPs play a role in cellular metabolism, adaptation, pathogenicity, decomposition, and biotransformation of hazardous chemicals. In this study, we identified 20 CYP genes based on complete sequence analysis and functional annotation from the T. horrida JY-521 genome. The subcellular localization, conserved motifs, and structures of these 20 CYP genes were further predicted. The ThCYP genes exhibit differences in gene structures and protein motifs. Subcellular localization showed that they were located in the plasma membrane, cytoplasm, nucleus, mitochondria, and extracellular space, indicating that they had multiple functions. Some cis-regulatory elements related to stress response and plant hormones were found in the promoter regions of these genes. Protein–protein interaction (PPI) analysis showed that several ThCYP proteins interact with multiple proteins involved in the ergosterol pathway. Moreover, the expression of 20 CYP genes had different responses to different infection time points and underwent dynamic changes during T. horrida JY-521 infection, indicating that these genes were involved in the interaction with rice and their potential role in the pathogenic mechanism. These results provided valuable resources for elucidating the structure of T. horrida CYP family proteins and laid an important foundation for further research of their roles in the pathogenesis.

Implantable vascular devices are widely used in clinical treatments for various vascular diseases. However, current approved clinical implantable vascular devices generally have high failure rates primarily due to their surface lacking inherent functional endothelium. Here, inspired by the pathological mechanisms of vascular device failure and physiological functions of native endothelium, we developed a new generation of bioactive parylene (poly(p-xylylene))-based conformal coating to address these challenges of the vascular devices. This coating used a polyethylene glycol (PEG) linker to introduce an endothelial progenitor cell (EPC) specific binding ligand LXW7 (cGRGDdvc) onto the vascular devices for preventing platelet adhesion and selectively capturing endogenous EPCs. Also, we confirmed the long-term stability and function of this coating in human serum. Using two vascular disease-related large animal models, a porcine carotid artery interposition model and a porcine carotid artery-jugular vein arteriovenous graft model, we demonstrated that this coating enabled rapid generation of self-renewable “living” endothelium on the blood contacting surface of the expanded polytetrafluoroethylene (ePTFE) grafts after implantation. We expect this easy-to-apply conformal coating will present a promising avenue to engineer surface properties of “off-the-shelf” implantable vascular devices for long-lasting performance in the clinical settings.

Biophysical factors play a fundamental role in human embryonic development. Traditional in vitro models of organogenesis focused on the biochemical environment and did not consider the effects of mechanical forces on developing tissue. While most human tissue has a Young’s modulus in the low kilopascal range, the standard cell culture substrate, plasma-treated polystyrene, has a Young’s modulus of 3 gigapascals, making it 10,000–100,000 times stiffer than native tissues. Modern in vitro approaches attempt to recapitulate the biophysical niche of native organs and have yielded more clinically relevant models of human tissues. Since Clevers’ conception of intestinal organoids in 2009, the field has expanded rapidly, generating stem-cell derived structures, which are transcriptionally similar to fetal tissues, for nearly every organ system in the human body. For this reason, we conjecture that organoids will make their first clinical impact in fetal regenerative medicine as the structures generated ex vivo will better match native fetal tissues. Moreover, autologously sourced transplanted tissues would be able to grow with the developing embryo in a dynamic, fetal environment. As organoid technologies evolve, the resultant tissues will approach the structure and function of adult human organs and may help bridge the gap between preclinical drug candidates and clinically approved therapeutics. In this review, we discuss roles of tissue stiffness, viscoelasticity, and shear forces in organ formation and disease development, suggesting that these physical parameters should be further integrated into organoid models to improve their physiological relevance and therapeutic applicability. It also points to the mechanotransductive Hippo-YAP/TAZ signaling pathway as a key player in the interplay between extracellular matrix stiffness, cellular mechanics, and biochemical pathways. We conclude by highlighting how frontiers in physics can be applied to biology, for example, how quantum entanglement may be applied to better predict spontaneous DNA mutations. In the future, contemporary physical theories may be leveraged to better understand seemingly stochastic events during organogenesis.

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine, but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA in utero, and can access and transfect major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, at 4 weeks after birth, we demonstrate that 50.99 ± 5.05%, 36.62 ± 3.42% and 23.7 ± 3.21% of myofiber in the diaphragm, heart and skeletal muscle, respectively, were transfected. Finally, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero. These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero, which provides a promising strategy for treating a wide variety of devastating diseases before birth.

Abstract Introduction Medical personnel should be in close proximity and high frequency of contact with patients, and be exposed to physical, biological and chemical risk factors for a long time. The incidence of various occupational exposures is high. however, there is still a lack of the medical staff Occupational Protection Core Competence Evaluation Index system with high reliability and validity. Aim Based on the theory of knowledge, attitude, and practice, the evaluation system of occupational protection ability of medical personnel was established, and the current situation of occupational protection ability of medical personnel at different levels was investigated, so as to take targeted training and intervention measures to improve the occupational protection ability of medical personnel and reduce the incidence of occupational exposure. Methods Based on the knowledge, attitude, and practice theory, the index system of occupational protection core competence of medical personnel was initially constructed by literature retrieval, expert consultation, group discussion, semi-structured interview and other qualitative and quantitative methods, and the reliability and validity of the index system was tested by Delphi expert consultation method. By convenient cluster sampling method, from March to September 2021, the current status of occupational protection core competence of medical personnel was investigated among medical staff from one Class III Grade A hospital and two medical schools in Jinan City, Shandong Province, China. Results The evaluation system for medical staff’s occupational protection ability included 3 first-level indexes, 11 second-level indexes, and 109 third-level indexes. A total of 684 valid questionnaires were collected from Grade III, Class A hospital medical staff and two medical school students in clinical practice in Shandong, China. Kruskal Walls test showed that there were significant differences in the overall distribution of occupational protection knowledge, attitude, and practice among registered nurses, nursing students, registered physicians, and physician students (H = 70.252, P

Restrictive dieters are those who expect to achieve body shape and weight control through dieting. However, they often have difficulty suppressing the desire to consume food when confronted with it. It has been shown that when high- and low-calorie foods are presented together, the attention of restrictive eaters is preferentially directed to high-calorie foods. However, whether attentional bias occurs when low-calorie foods are present alone and whether the allocation of attentional resources is consistent with that for high-calorie foods has yet to be explored. The present study focused on the effects of high-/low-calorie foods on attentional bias in restrictive dieters. Seventy-eight participants were recruited to participate in the experiment via the Dutch Eating Behavior Questionnaire (DEBQ) scale, which is administered in a rapid serial visual presentation (RSVP) task. The results revealed that failed restrictive dieters had the lowest percentage of correct answers at the lag2 level, indicating attentional bias. Failed restrictive dieters allocated more attentional resources to high-calorie foods than to low-calorie foods. Restrictive dieters showed no attentional bias when low-calorie foods were presented alone. The results suggest that low-calorie foods do not elicit an attentional bias in restrictive dieters and that the allocation of attentional resources is not consistent when compared to that for high-calorie foods.

Tidal flats are accumulations of fine-grained sediment formed under the action of tides and play a very important role in coastal protection. The northern part of Jiangsu coast, as a typical example of muddy coasts found all over the world, has experienced serious erosion since the Yellow River shifted northward, and the range of erosion has been gradually extending southward, now reaching the south of the Sheyang River estuary (SYRE). In order to address coastal erosion near the SYRE through protective measures, there is an urgent need for research on the spatial and temporal variation of coastal erosion processes and their control mechanisms in the SYRE and adjacent coastal areas. For this study, the tidal flats on the south side of the SYRE were selected as the study area, and the sediment dynamics in the upper and lower intertidal flat were observed in different seasons to investigate the erosion processes and their dynamic mechanisms. The results show that the tidal current and wave action in the observed intertidal flats are stronger in winter than in summer, and these intertidal flats erode under the combined action of waves and currents. During winter, the net transport of the near-bottom suspended sediment and bedload is primarily towards the southeast, while in summer, the direction tends toward the north and northeast. The net transport fluxes are larger in the lower part of the intertidal flat than in the upper part in summer and also larger in winter than in summer within the lower intertidal flat. Furthermore, the tidal flat erosion in the study area manifests as shoreline retreat and flat surface erosion. The average shoreline retreat rate increased from 23.3 m/a during 2014–2019 to 43.5 m/a during 2019–2021, and the average erosion depth of the lower and upper parts of the intertidal flat over a tidal cycle is, respectively, 1.98 cm and 0.24 cm in winter and 1.65 cm and 0.26 cm in summer. The ratio of the wave-induced bottom shear stress to the tidal current-induced bottom shear stress is 0.40~0.46 in the lower intertidal flat and increases to 0.66~0.67 in the upper intertidal flat, indicating that the intertidal flat erosion in the study area is primarily driven by tidal currents, with significant contributions from wave action, especially in the upper intertidal flat.

Extracellular vesicles (EVs) are cell-secreted nanovesicles that play an important role in long-range cell–cell communication. Although EVs pose a promising alternative to cell-based therapy, targeted in vivo delivery still falls short. Many studies have explored the surface modification of EVs to enhance their targeting capabilities. However, to our knowledge, there are no standardized practices to confirm the successful surface modification of EVs or calculate the degree of conjugation on EV surfaces (conjugation efficiency). These pieces of information are essential in the reproducibility of targeted EV therapeutics and the determination of optimized conjugation conditions for EVs to see significant therapeutic effects in vitro and in vivo. This review will discuss the vast array of techniques adopted, technologies developed, and efficiency definitions made by studies that have calculated EV/nanoparticle surface conjugation efficiency and how differences between studies may contribute to differently reported conjugation efficiencies.

This paper summarized the historical changes of mangrove in China, and the spatial distribution,species composition, changes of mangrove and the main influencing factors in each area. The main factors affecting mangrove ecosystem health in China mainly included: pollution, over culturing, ocean engineering, overfishing and biological invasion. Some suggestions on mangrove protection were proposed, including accelerating mangrove protection legislation, comprehensive improvement of surrounding environment, improving the system of ecological compensation, strengthening publicity and education, promoting the transformation of livelihood, and improving the effect of mangrove restoration in many ways.

Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration. However, current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration, thus leading to adverse tissue formation and decreased regenerative efficiency. Here, we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone regeneration. The biomaterial works by presenting two synthetic ligands, LLP2A and LXW7, explicitly targeting integrins α4β1 and αvβ3, respectively, expressed on the surfaces of the cells related to bone formation and vascularization, such as mesenchymal stem cells (MSCs), osteoblasts, endothelial progenitor cells (EPCs), and endothelial cells (ECs). In vitro, the LLP2A/LXW7 modified biomaterial improved the adhesion of MSCs, osteoblasts, EPCs, and ECs via integrin α4β1 and αvβ3, respectively. In an adult rat calvarial bone defect model, the LLP2A/LXW7 modified biomaterial enhanced bone formation and vascularization by synergistically regulating endogenous cells with osteogenic and angiogenic potentials, such as DLX5+ cells, osteocalcin+ cells, CD34+/CD45- cells and CD31+ cells. In a fetal sheep spinal bone defect model, the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse effects. This innovative biomaterial offers an off-the-shelf, easy-to-use, and biologically safe product suitable for vascularized bone regeneration in both fetal and adult disease environments.

Conventional synthetic vascular grafts are associated with significant failure rates due to their mismatched mechanical properties with the native vessel and poor regenerative potential. Though different tissue engineering approaches have been used to improve the biocompatibility of synthetic vascular grafts, it is still crucial to develop a new generation of synthetic grafts that can match the dynamics of native vessel and direct the host response to achieve robust vascular regeneration. The size of pores within implanted biomaterials has shown significant effects on macrophage polarization, which has been further confirmed as necessary for efficient vascular formation and remodeling. Here, we developed biodegradable, autoclavable synthetic vascular grafts from a new polyurethane elastomer and tailored the grafts' interconnected pore sizes to promote macrophage populations with a pro-regenerative phenotype and improve vascular regeneration and patency rate. The synthetic vascular grafts showed similar mechanical properties to native blood vessels, encouraged macrophage populations with varying M2 to M1 phenotypic expression, and maintained patency and vascular regeneration in a one-month rat carotid interposition model and in a four-month rat aortic interposition model. This innovative bioactive synthetic vascular graft holds promise to treat clinical vascular diseases.

The performance of marine environment parameter monitoring sensor is the guarantee of the quality of marine environment parameter data. This paper used the sensors of seawater temperature, conductivity, turbidity and chlorophyll as evaluation targets. The historical calibration data of the same instrument was used to evaluate the stability of the sensors. When the drift coefficient was near 1, the sensor was stability, and the drift coefficient was more or less than 1, the sensor data was drifted. The drift coefficient could be used to correct the historical data of each sensor in the calibration period. Before the correction, the error of each sensor was large and presents a one-way incremental change; the corrected error was reduced to the maximum error of the sensor and had a normal distribution. The sensor performance evaluation model based on historical calibration data could provide long-term sensor stability evaluation for users, which was beneficial to improve the performance and data accuracy of marine environmental monitoring sensors, expand the service capacity of measurement data.

Abstract Rice kernel smut (RKS), caused by the fungus Tilletia horrida, has become a major disease in rice-growing areas worldwide, especially since the widespread cultivation of high-yielding hybrid rice varieties. The disease causes a significant yield loss during the production of rice male sterile lines by producing masses of dark powdery teliospores. This review mainly summarizes the pathogenic differentiation, disease cycle, and infection process of the T. horrida, as well as the decoding of the T. horrida genome, functional genomics, and effector identification. We highlight the identification and characterization of virulence-related pathways and effectors of T. horrida, which could foster a better understanding of the rice–T. horrida interaction and help to elucidate its pathogenicity molecular mechanisms. The multiple effective disease control methods for RKS are also discussed, included chemical fungicides, the mining of resistant rice germplasms/genes, and the monitoring and early warning signs of this disease in field settings.

Abstract Peripheral nerve regeneration after injury is still a clinical problem. The application of autologous nerve grafting, the gold standard treatment, is greatly restricted. Acellular nerve allografts (ANAs) are considered promising alternatives, but they are difficult to achieve satisfactory therapeutic outcomes, which may be attributed to their compact inherent ultrastructure and substantial loss of extracellular matrix (ECM) components. Regarding these deficiencies, this study developed an optimized multichannel ANA by a modified decellularization method. These innovative ANAs were demonstrated to retain more ECM bioactive molecules and regenerative factors, with effective elimination of cellular antigens. The presence of microchannels with larger pore size allowed ANAs to gain higher porosity and better swelling performance, which improves their internal ultrastructure. Their mechanical properties were more similar to those of native nerves. Moreover, the optimized ANAs exhibited good biocompatibility and possessed significant advantages in supporting the proliferation and migration of Schwann cells in vitro. The in vivo results further confirmed their superior capacity to promote axon regrowth and myelination as well as restore innervation of target muscles, leading to better functional recovery than the conventional ANAs. Overall, this study demonstrates that the optimized multichannel ANAs have great potential for clinical application and offer new insight into the further improvement of ANAs.

Summary: Conventional approaches for screening anticancer drugs rely on chemical reactions, which are time consuming, labor intensive, and costly. Here, we present a protocol for label-free and high-throughput assessment of drug efficacy using a vision transformer and a Conv2D. We describe the steps for cell culture, drug treatment, data collection, and preprocessing. We then detail the building of deep learning models and their use to predict drug potency. This protocol can be adapted for screening chemicals that affect the density or morphological features of cells.For complete details on the use and execution of this protocol, please refer to Wang et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Ustilago crameri is a pathogenic basidiomycete fungus that causes foxtail millet kernel smut (FMKS), a devastating grain disease in most foxtail-millet-growing regions of the world. Here, we report an assembled high-quality genome sequence of U. crameri strain SCZ-6 isolated from the diseased grains of foxtail millet in Changzhi, Shanxi Province, China. The genome size is 19.55 Mb, consisting of 73 contigs (N50 = 840,209 bp) with a G + C content of 54.09%, and encoding 6576 predicted genes and 6486 genes supported by RNA-seq. Evolutionarily, U. crameri lies close to the barley smut U. hordei, and an obvious co-linearity was observed between these two smut fungi. We annotated the genome of U. crameri strain SCZ-6 using databases, identifying 1827 pathogen–host interaction (PHI)-associated genes, 1324 genes encoding fungal virulence factors, 259 CAZy-related genes, 80 genes encoding transporters, and 206 putative cytochrome P450 genes; their expression profiles at different inoculation time points were also detected. Additionally, 70 candidate pathogen effectors were identified according to their expression patterns and predicted functions. In summary, our results provide important insights into the pathogenic mechanisms of the pathogenesis-related genes of U. crameri and a robust foundation for further investigation.

The pressure-state-response (PSR) model was used to establish the evaluation index system of mangrove reserve protection effectiveness in this paper, taking Shankou Mangrove Reserve in Guangxi as an example. Based on the assessment result, some suggestions to improve the protection effectiveness of mangrove reserve were put forward. The results showed that the protection effect of Shankou Mangrove Reserve from 2008 to 2018 was good, and the ecosystem health status was good. At present, the main problems were as follows: there were still some aquaculture ponds in the reserve, which discharged aquaculture wastewater and domestic sewage of residents, resulting in serious eutrophication of seawater. In addition, the construction of professional personnel and community co-management needs to be improved in Shankou Mangrove Reserve.

Reacting to a moving object requires an ability to estimate when a moving object reaches its destination, also referred to as the time-to-contact (TTC) estimation. Although the TTC estimation of threatening visually moving objects is known to be underestimated, the effect of the affective content of auditory information on visual TTC estimation remains unclear. We manipulated the velocity and presentation time to investigate the TTC of a threat or non-threat target with the addition of auditory information. In the task, a visual or an audiovisual target moved from right to left and disappeared behind an occluder. Participants’ task was to estimate the TTC of the target, they needed to press a button when they thought that the target contacted a destination behind the occluder. Behaviorally, the additional auditory affective content facilitated TTC estimation; velocity was a more critical factor than presentation time in determining the audiovisual threat facilitation effect. Overall, the results indicate that exposure to auditory affective content can influence TTC estimation and that the effect of velocity on TTC estimation will provide more information than presentation time.

Abstract Natural and artificial cells are two common chassis in synthetic biology. Natural cells can perform complex tasks through synthetic genetic constructs, but their autonomous replication often causes safety concerns for biomedical applications. In contrast, artificial cells based on nonreplicating materials, albeit possessing reduced biochemical complexity, provide more defined and controllable functions. Here, for the first time, the authors create hybrid material‐cell entities termed Cyborg Cells. To create Cyborg Cells, a synthetic polymer network is assembled inside each bacterium, rendering them incapable of dividing. Cyborg Cells preserve essential functions, including cellular metabolism, motility, protein synthesis, and compatibility with genetic circuits. Cyborg Cells also acquire new abilities to resist stressors that otherwise kill natural cells. Finally, the authors demonstrate the therapeutic potential by showing invasion into cancer cells. This work establishes a new paradigm in cellular bioengineering by exploiting a combination of intracellular man‐made polymers and their interaction with the protein networks of living cells.

The lack of vascularization associated with deep burns delays the construction of wound beds, increases the risks of infection, and leads to the formation of hypertrophic scars or disfigurement. To address this challenge, we have fabricated a multi-functional pro-angiogenic molecule by grafting integrin αvβ3 ligand LXW7 and collagen-binding peptide (SILY) to a dermatan sulfate (DS) glycosaminoglycan backbone, named LXW7-DS-SILY (LDS), and further employed this to functionalize collagen-based Integra scaffolds. Using a large deep burn wound model in C57/BLK6 mice (8–10 weeks old, 26–32g, n = 39), we demonstrated that LDS-modified collagen-based Integra scaffolds loaded with endothelial cells (ECs) accelerate wound healing rate, re-epithelialization, vascularization, and collagen deposition. Specifically, a 2 cm × 3 cm full-thickness skin burn wound was created 48 h after the burn, and then wounds were treated with four groups of different dressing scaffolds, including Integra + ECs, Integra + LDS, and Integra + LDS + ECs with Integra-only as the control. Digital photos were taken for wound healing measurement on post-treatment days 1, 7, 14, 21, 28, and 35. Post-treatment photos revealed that treatment with the Intgera + LDS + ECs scaffold exhibited a higher wound healing rate in the proliferation phase. Histology results showed significantly increased re-epithelialization, increased collagen deposition, increased thin and mixed collagen fiber content, increased angiogenesis, and shorter wound length within the Integra + LDS + ECs group at Day 35. On Day 14, the Integra + LDS + ECs group showed the same trend. The relative proportions of collagen changed from Day 14 to Day 35 in the Integra + LDS + ECs and Integra + ECs groups demonstrated decreased thick collagen fiber deposition and greater thin and mixed collagen fiber deposition. LDS-modified Integra scaffolds represent a promising novel treatment to accelerate deep burn wound healing, thereby potentially reducing the morbidity associated with open burn wounds. These scaffolds can also potentially reduce the need for autografting and morbidity in patients with already limited areas of harvestable skin.

Abstract Background The sustainable development of rice production is facing severe threats by a variety of pathogens, such as necrotrophic Rhizoctonia solani and hemibiotrophic Xanthomonas oryzae pv. oryzae (Xoo). Mining and applying resistance genes to increase the durable resistance of rice is an effective method that can be used to control these diseases. Results In this research, we isolated and characterized CYP716A16, which is a positive regulator of rice to R. solani AG1-IA and Xoo, and belongs to the cytochrome P450 (CYP450) protein 716A subfamily. Overexpression (OE) of CYP716A16 resulted in enhanced resistance to R. solani AG1-IA and Xoo, while RNA interference (RNAi) of CYP716A16 resulted in increased susceptibility compared with wild-type (WT) plants. Additionally, jasmonic acid (JA)-dependent defense responses and reactive oxygen species (ROS) were activated in the CYP716A16-OE lines after R. solani AG1-IA inoculation. The comparative transcriptomic and metabolomics analysis of CYP716A16-OE and the WT lines showed that OE of CYP716A16 activated the biosynthesis of flavonoids and increased the amounts of narcissoside, methylophiopogonanone A, oroxin A, and amentoflavone in plants. Conclusion Based on these results, we suggest that JA-dependent response, ROS level, multiple resistance-related proteins, and flavonoid contents play an important role in CYP716A16-regulated R. solani AG1-IA and Xoo resistance. Our results broaden our knowledge regarding the function of a P450 protein 716A subfamily in disease resistance and provide new insight into the molecular mechanism of rice immune response.

Diabetic ischemic wound treatment remains a critical clinical challenge. Neovascularization plays a significant role in wound healing during all stages of the tissue repair process. Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds, particularly diabetic wounds in highly ischemic conditions. We previously identified a cyclic peptide LXW7 that specifically binds to integrin αvβ3 on endothelial progenitor cells (EPCs) and endothelial cells (ECs), activates vascular endothelial growth factor (VEGF) receptors, and promotes EC growth and maturation. In this study, we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides (SILY) to a dermatan sulfate (DS) glycosaminoglycan backbone, named LXW7-DS-SILY, and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix (ECM) scaffolds. We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment. When applied in an established Zucker Diabetic Fatty (ZDF) rat ischemic skin flap model, LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing, enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment. Altogether, this study provides a promising novel treatment to accelerate diabetic ischemic wound healing, thereby reducing limb amputation and mortality of diabetic patients.

Abstract Neuropsychological studies have demonstrated that the preferential processing of near-space and egocentric representation is associated with the self-prioritization effect (SPE). However, relatively little is known concerning whether the SPE is superior to the representation of egocentric frames or near-space processing in the interaction between spatial reference frames and spatial domains. The present study adopted the variant of the shape-label matching task (i.e., color-label) to establish an SPE, combined with a spatial reference frame judgment task, to examine how the SPE leads to preferential processing of near-space or egocentric representations. Surface-based morphometry analysis was also adopted to extract the cortical thickness of the ventral medial prefrontal cortex (vmPFC) to examine whether it could predict differences in the SPE at the behavioral level. The results showed a significant SPE, manifested as the response of self-associated color being faster than that of stranger-associated color. Additionally, the SPE showed a preference for near-space processing, followed by egocentric representation. More importantly, the thickness of the vmPFC could predict the difference in the SPE on reference frames, particularly in the left frontal pole cortex and bilateral rostral anterior cingulate cortex. These findings indicated that the SPE showed a prior entry effect for information at the spatial level relative to the reference frame level, providing evidence to support the structural significance of the self-processing region.

Acquired radioresistance is a challenge for the cure of glioblastoma. Here, the authors show that radioresistant glioblastoma boosts mitochondrial fatty acid oxidation that fuels cell proliferation and induces immunosuppression via CD47 mediated anti-phagocytosis. Inhibition of FAO by etomoxir combined with anti-CD47 antibodies sensitizes glioblastoma to radiotherapy.

Originally approved by the U.S. Food and Drug Administration (FDA) for its antihistamine properties, clemastine can also promote white matter integrity and has shown promise in the treatment of demyelinating diseases such as multiple sclerosis. Here, we conducted an in-depth analysis of the feasibility, safety, and neuroprotective efficacy of clemastine administration in near-term lambs (n = 25, 141–143 days) following a global ischemic insult induced via an umbilical cord occlusion (UCO) model. Lambs were randomly assigned to receive clemastine or placebo postnatally, and outcomes were assessed over a six-day period. Clemastine administration was well tolerated. While treated lambs demonstrated improvements in inflammatory scores, their neurodevelopmental outcomes were unchanged.

Summary: During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection. Herein, we demonstrate that radiosensitivity is increased in mice with the deficient Period 2 gene (Per2def) due to impaired DNA repair and mitochondrial function in progenitor bone marrow hematopoietic stem cells and monocytes. Per2 induction and radioprotection are also identified in LDR-treated Per2wt mouse cells and in human skin (HK18) and breast (MCF-10A) epithelial cells. LDR-boosted PER2 interacts with pGSK3β(S9) which activates β-catenin and the LEF/TCF mediated gene transcription including Per2 and genes involved in DNA repair and mitochondrial functions. This study demonstrates that PER2 plays an active role in LDR adaptive radioprotection via PER2/pGSK3β/β-catenin/Per2 loop, a potential target for protecting normal cells from radiation injury.

Myocardin is known as an important transcriptional regulator in smooth and cardiac muscle development as well as a tumor suppressor. However, the pathological function of myocardin in NSCLC metastasis is poorly understood. Here, we have described novel roles for myocardin in the metastatic cascade using in vitro and in vivo models. We demonstrate that myocardin deficiency is sufficient to trigger epithelial–mesenchymal transition (EMT) process but reduces metastatic potential of NSCLC in vivo. Myocardin deficiency reduces lung cancer metastasis because of persistent EMT and decreasing colonization capacity. Restoring myocardin expression in colonization stage promotes the metastasis of lung cancer cells. An epigenetically negative feedback loop formed by myocardin and PRMT5/MEP50 complex prevents EMT. We also uncover the unknown mechanism of myocardin suppression in lung cancer tissues that PRMT5/MEP50 complex negatively regulates myocardin expression. It helps to reconcile conflicting results that have challenged the significance of EMT and cancer metastasis and explain the phenotype of myocardin suppression in lung cancer cells.

Sedimentary organic matter (OM) in coastal systems is inherently diverse, often with multiple particulate sources and transport histories. The Taiwan Strait (TS) is a typical shallow conduit region, linking the East and South China Seas. Strong ocean currents, coastal upwellings, distal large rivers, and proximal small mountainous rivers all influence the distribution of OM in the TS. We investigated the covarying patterns in the distribution of gain size classes of sand, silt, and clay; terrestrial-sourced biomarkers (n-C27+29+31 alkanes, n-C26+28+30 fatty acids (FAs), and n-C28+30+32 alkanols); marine-sourced biomarkers (phytoplankton-derived alkenones, brassicasterol, dinosterol, and zooplankton-derived cholesterol) in sea floor sediment; indicator satellite-derived primary production (Chl-a); and water-mass indicator (sea surface temperature, SST). We used an empirical orthogonal/eigen function (EOF) analysis to distinguish the influence of four hypothetical sources that entered the TS through the north, south, west, and east boundaries. Results show that input sources from the south-bound ZMCC (Zhejiang-Fujian Coastal Current) and north-bound SCSWC (South China Sea Warm Current) had the dominant influence on the OM distributions buried in the TS. Input sources via river plumes on lateral boundaries and upwellings in the TS were the secondary factors that affected the sedimentary OM distribution. Within this source-to-sink system of multiple sources and transport processes, silt and clay were the major carriers of the OM signals. Terrestrial biomarkers and primary production (Chl-a) were associated with the two major current systems and river plumes along the edge of TS. Marine biomarkers were associated with upwellings in the interior of the TS. Our finding points out that the physical systems of ocean currents, river plumes, and upwelling not only determine the distributions of biomarkers in the TS but also determine the diversity of OM in the TS.

With the booming development of new technologies such as cloud computing, big data and the continuous upgrading of communication infrastructure, the major domestic ISPs have proposed the development strategy of building a centralized control and flexible cloud network infrastructure under the trend of intelligent-traction network transformation.As a path calculation protocol widely used in the existing SDN architecture, PCEP protocol was often used to solve the problem of cross-layer and cross-domain path computing under complex network environment.The application of PCEP protocol in cloud-network convergence scenario was discussed and an end-to-end traffic guarantee scheme was introduced based on PCEP protocol which could ensure the connection-oriented network communication and make end-to-end service guarantee in native IP environment.It helps to improve the operators' ability of real-time perception, agile response and intelligent analysis of the network and meets the operation and maintenance management requirements such as global scheduling of communication resources, comprehensive opening of capabilities and flexible architecture.

Abstract Background Paraneoplastic syndrome is a distant effect caused by malignant tumors, which is related to the production of cellular immune response. The nervous system is the most common involved system of paraneoplastic syndrome. It is easy to be misdiagnosed. Lung cancer is the most common cancer relating to paraneoplastic neurological syndrome (PNS). Method This study retrospectively analyzed clinical data of patients with the combination of PNS and lung cancer between January 2005 and March 2021 at Qilu Hospital of Shandong University, China. Results A total of 111 patients were diagnosed with lung cancer complicated with PNS. A total of 95 (85.6%) cases had neurological symptoms as the first symptom. Sixty‐three cases had the pathological results. A total of 43 (68.3%) of small cell lung cancer (SCLC) were diagnosed. PNS patients diagnosed with SCLC included peripheral neuropathy (15 cases, 34.9%). PNS patients diagnosed with non‐small cell lung cancer (NSCLC) included peripheral neuropathy (6 cases, 30%) and limbic encephalitis (6 cases, 30%). Anti‐Hu is popular in patients with SCLC (12 cases, 42.9%) and NSCLC (6 cases, 40%). Conclusions Most patients with PNS had neurological symptoms as the first symptom. It was more common in males. It had a higher incidence in SCLC. Peripheral neuropathy was the most common PNS associated with SCLC, followed by Lambert‐Eaton syndrome. Peripheral neuropathy and limbic encephalitis were the most common PNS associated with NSCLC. Anti‐Hu is the most common antibodies both in SCLC and NSCLC. Tumor markers do not have significant difference between different pathological types.

Abstract Background Tetraspanin expression of extracellular vesicles (EVs) is often used as a surrogate for their detection and classification, a practice that typically assumes their consistent expression across EV sources. Results Here we demonstrate that there are distinct patterns in colocalization of tetraspanin expression of EVs enriched from a variety of in vitro and in vivo sources. We report an optimized method for the use of single particle antibody-capture and fluorescence detection to identify subpopulations according to tetraspanin expression and compare our findings with nanoscale flow cytometry. We found that tetraspanin profile is consistent from a given EV source regardless of isolation method, but that tetraspanin profiles are distinct across various sources. Tetraspanin profiles measured by flow cytometry do not totally agree, suggesting that limitations in subpopulation detection significantly impact apparent protein expression. We further analyzed tetraspanin expression of single EVs captured non-specifically, revealing that tetraspanin capture can bias the apparent multiplexed tetraspanin profile. Finally, we demonstrate that this bias can have significant impact on diagnostic sensitivity for tumor-associated EV surface markers. Conclusion Our findings may reveal key insights into protein expression heterogeneity of EVs that better inform EV capture and detection platforms for diagnostic or other downstream use. Graphical abstract

Abstract Background Rice (Oryza sativa) bacterial leaf blight (BLB), caused by the hemibiotrophic Xanthomonas oryzae pv. oryzae (Xoo), is one of the most devastating diseases affecting the production of rice worldwide. The development and use of resistant rice varieties or genes is currently the most effective strategy to control BLB. Results Here, we used 259 rice accessions, which are genotyped with 2 888 332 high-confidence single nucleotide polymorphisms (SNPs). Combining resistance variation data of 259 rice lines for two Xoo races observed in 2 years, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) conferring plant resistance against BLB. The expression levels of genes, which contains in GWAS results were also identified between the resistant and susceptible rice lines by transcriptome analysis at four time points after pathogen inoculation. From that 109 candidate resistance genes showing significant differential expression between resistant and susceptible rice lines were uncovered. Furthermore, the haplotype block structure analysis predicted 58 candidate genes for BLB resistance based on Chr. 7_707158 with a minimum P-value (–log 10 P = 9.72). Among them, two NLR protein-encoding genes, LOC_Os07g02560 and LOC_Os07g02570, exhibited significantly high expression in the resistant line, but had low expression in the susceptible line of rice. Conclusions Together, our results reveal novel BLB resistance gene resources, and provide important genetic basis for BLB resistance breeding of rice crops.

Information from multiple sensory modalities interacts. Using functional magnetic resonance imaging (fMRI), we aimed to identify the neural structures correlated with how cooccurring sound modulates the visual motor response execution. The reaction time (RT) to audiovisual stimuli was significantly faster than the RT to visual stimuli. Signal detection analyses showed no significant difference in the perceptual sensitivity (d’) between audiovisual and visual stimuli, while the response criteria (β or c) of the audiovisual stimuli was decreased compared to the visual stimuli. The functional connectivity between the left inferior parietal lobule (IPL) and bilateral superior temporal gyrus (STG) was enhanced in Go processing compared with No-go processing of audiovisual stimuli. Furthermore, the left precentral gyrus (PreCG) showed enhanced functional connectivity with the bilateral STG and other areas of the ventral stream in Go processing compared with No-go processing of audiovisual stimuli. These results revealed that the neuronal network correlated with modulations of the motor response execution after the presentation of both visual stimuli along with cooccurring sound in a multisensory Go/Nogo task, including the left IPL, left PreCG, bilateral STG and some areas of the ventral stream. The role of the interaction between the IPL and STG in transforming audiovisual information into motor behavior is discussed. The current study provides a new perspective for exploring potential brain mechanisms underlying how humans execute appropriate behaviors on the basis of multisensory information.

Objectives: Previous studies have widely demonstrated that inhibition of return (IOR) with audiovisual targets decreases due to audiovisual integration (AVI). It is currently unclear, however, whether the impaired AVI in children with ADHD has effects on IOR. The present study used the cue-target paradigm to explore differences between the IOR of audiovisual targets and the IOR of visual targets in ADHD and typically developing (TD) children. Method: A total of 81 native Chinese speakers aged 6 to 13 years were recruited, including 38 children with ADHD and 43 age- and sex-matched TD children. Results: The results showed that there was a smaller magnitude of IOR with audiovisual targets as compared with visual targets in the two groups. Importantly, the reduction of IOR in audiovisual conditions was significantly smaller in children with ADHD than in children with TD. Race model analyses further confirmed that differences in IOR between ADHD and TD are due to deficits of audiovisual integration in ADHD. Conclusion: The results indicated that children with ADHD have impaired audiovisual integration, which has a minimal impact on IOR.

Abstract Neural crest stem cells (NCSCs) are a transient population of cells that arise during early vertebrate development and harbor stem cell properties, such as self‐renewal and multipotency. These cells form at the interface of non‐neuronal ectoderm and neural tube and undergo extensive migration whereupon they contribute to a diverse array of cell and tissue derivatives, ranging from craniofacial tissues to cells of the peripheral nervous system. Neural crest‐like stem cells (NCLSCs) can be derived from pluripotent stem cells, placental tissues, adult tissues, and somatic cell reprogramming. NCLSCs have a differentiation capability similar to NCSCs, and possess great potential for regenerative medicine applications. In this review, we present recent developments on the various approaches to derive NCLSCs and the therapeutic application of these cells for tissue regeneration.

Abstract Inhibition of return (IOR) refers to the slower response to targets appearing on the same side as the cue (valid locations) than to targets appearing on the opposite side as the cue (invalid locations). Previous behaviour studies have found that the visual IOR is larger than the audiovisual IOR when focusing on both visual and auditory modalities. Utilising the high temporal resolution of the event-related potential (ERP) technique we explored the possible neural correlates with the behaviour IOR difference between visual and audiovisual targets. The behavioural results revealed that the visual IOR was larger than the audiovisual IOR. The ERP results showed that the visual IOR effect was generated from the P1 and N2 components, while the audiovisual IOR effect was derived only from the P3 component. Multisensory integration (MSI) of audiovisual targets occurred on the P1, N1 and P3 components, which may offset the reduced perceptual processing due to audiovisual IOR. The results of early and late differences in the neural processing of the visual IOR and audiovisual IOR imply that the two target types may have different inhibitory orientation mechanisms.

Although evidence has shown that working memory (WM) can be differentially affected by the multisensory congruency of different visual and auditory stimuli, it remains unclear whether different multisensory congruency about concrete and abstract words could impact further WM retrieval. By manipulating the attention focus toward different matching conditions of visual and auditory word characteristics in a 2-back paradigm, the present study revealed that for the characteristically incongruent condition under the auditory retrieval condition, the response to abstract words was faster than that to concrete words, indicating that auditory abstract words are not affected by visual representation, while auditory concrete words are. Alternatively, for concrete words under the visual retrieval condition, WM retrieval was faster in the characteristically incongruent condition than in the characteristically congruent condition, indicating that visual representation formed by auditory concrete words may interfere with WM retrieval of visual concrete words. The present findings demonstrated that concrete words in multisensory conditions may be too aggressively encoded with other visual representations, which would inadvertently slow WM retrieval. However, abstract words seem to suppress interference better, showing better WM performance than concrete words in the multisensory condition.

As one of the main interfaces of the Earth system, estuaries show the strongest land–sea interaction in the carbon cycle, which links terrestrial ecosystems to the marginal sea. Furthermore, estuaries are considered as one of the most active intermediate reservoirs for both terrestrial and marine matter due to complex hydrodynamic processes regulated by the river runoff, wave and tide. Processing of organic matter (OM) in tidal estuaries modifies its transfer and transformation from the river to the sea, so studies of on the source and distributions of estuarine OM can help us understand the behavior of production, exchange, transport and burial of diverse OM within this transition zone before entering the marginal sea. In this paper, we took the Minjiang River Estuary (MRE) as a typical system in which there is strong influence of the tide. The source, composition and spatial distribution of OM in surface sediments of MRE were deciphered based on multiple organic geochemical properties for source-specific biomarkers (n-alkanes, n-alkanols, sterols) and bulk OM. Results show that sedimentary organic components were negatively correlated with sediment grain size, which indicates fine particles such as silt and clay are the major carriers of the OM signals in tidal estuaries. Source-specific biomarker proxies indicate that in terms of source diversity the sedimentary OM in the MRE shows mixed signals of terrestrial and marine sources, and the proportion of terrestrial OM decreases with the increase in distance from the land. The fractional contributions of OM from the riverine (i.e., terrestrial), marine and deltaic sources were quantitatively estimated using a Monte Carlo (MC) three-end-member mixing model based on C/N and δ13C values, and the average contributions of the three sources are 40 ± 10%, 48 ± 10% and 12 ± 4%, respectively, with little contribution from deltaic sources. The dispersion of sedimentary OM from different sources in the MRE is primarily controlled by the depositional environment determined by dynamic conditions and tidal processes play a significant role in the redistribution of sedimentary OM dispersion patterns. Compared with other large estuaries in southeast China, the OM accumulation contribution in the tide dominated small and medium-sized estuaries such as the MRE which is largely dependent on riverine and marine deliveries. The MRE has a high potential for both terrestrial and marine organic carbon (OC) burial, with an accumulation rate of 3.39 ± 1.83 mg cm−2 yr−1 for terrestrial OC, and an accumulation rate of 3.18 ± 0.68 mg cm−2 yr−1 for marine OC in muddy sediment, making it an important contributor to the sedimentary carbon sink of the marginal sea.

Coastal wetlands are natural complexes situated between terrestrial and marine ecosystems and are one of the most productive ecosystems in terms of global biomass production. However, under the influence of intensive human activity, global coastal wetlands have undergone rapid degradation. In this study, RS technology, landscape ecology, and object-oriented methods were used to interpret remote sensing images from different periods and analyze the dynamic changes in landscape patterns and their driving mechanisms in coastal wetlands in the Luoyangjiang River estuary from 1983 to 2021 by considering changes in the landscape pattern index. The results show that the patch areas of all the types of wetland landscapes in the Luoyangjiang River estuary changed, and the patch areas of mangroves and Spartina alterniflora increased. The patch density of the coastal wetlands increased significantly, the index of mangrove aggregation increased, and the index of separation decreased. From the perspective of the overall characteristic value of the landscape pattern, the landscape diversity index and the evenness index of the study area gradually increased, and the difference in the proportion of different types of landscape was reduced. Additionally, the patch number and patch diversity significantly increased, the maximum patch index and the spread index decreased, and the landscape separation index significantly increased. Rapid urbanization and the implementation of many ecological restoration projects were shown to be the main factors driving changes in the landscape indices of coastal wetlands in the Luoyangjiang River estuary. In the study period, rapid urbanization significantly reduced the area of coastal wetlands, and the implementation of ecological restoration projects increased the fragmentation, heterogeneity, and dispersion of wetland landscapes in the study area and decreased the aggregation of wetland landscapes. Moreover, the distribution of all the types of landscapes gradually became more uniform.

The data provided in this article are partial fragments of the Cytochrome c oxidase subunit 1 mitochondrial gene (CO1) sequences of 175 tissues sampled from sharks and batoids collected from Malaysian waters, from June 2015 to June 2022. The barcoding was done randomly for six specimens from each species, so as to authenticate the code. We generated barcodes for 67 different species in 20 families and 11 orders. DNA was extracted from the tissue samples following the Chelex protocols and amplified by polymerase chain reaction (PCR) using the barcoding universal primers FishF2 and FishR2. A total of 654 base pairs (bp) of barcode CO1 gene from 175 samples were sequenced and analysed. The genetic sequences were blasted into the NCBI GenBank and Barcode of Life Data System (BOLD). A review of the blast search confirmed that there were 68 valid species of sharks and batoids that occurred in Malaysian waters. We provided the data of the COI gene mid-point rooting phylogenetic relation trees and analysed the genetic distances among infra-class and order, intra-species, inter-specific, inter-genus, inter-familiar, and inter-order. We confirmed the addition of Squalus edmundsi, Carcharhinus amboinensis, Alopias superciliosus, and Myliobatis hamlyni as new records for Malaysia. The establishment of a comprehensive CO1 database for sharks and batoids will help facilitate the rapid monitoring and assessment of elasmobranch fisheries using environmental DNA methods.

The emergence of tumour adaptive radioresistance can limit the success of radiation therapy and immunotherapy in breast cancer. In this study, the authors demonstrate that CD47 and HER2 are coordinating in tumor response to radiation and that co-blockage of both receptors can eliminate radiorestistant breast cancer cells.

Abstract Background Canine inflammatory brain disease (IBD) is a severe inflammatory disorder characterized by infiltration of activated immune cell subsets into the brain and spinal cord. Multipotent mesenchymal stromal cells (MSCs) are a promising therapy for IBD, based on their potent pro-angiogenic, neuroprotective, and immunomodulatory properties. The aims of this study were to compare the immunomodulatory attributes of canine adipose-derived MSCs (ASCs) and placenta-derived MSCs (PMSCs) in vitro. These data will serve as potency information to help inform the optimal MSC cell source to treat naturally occurring canine IBD. Methods Indoleamine 2,3 dioxygenase (IDO) activity and prostaglandin E2 (PGE2) concentration at baseline and after stimulation with interferon gamma (IFNγ) and/or tumor necrosis factor alpha (TNFα) were measured from canine ASC and PMSC cultures. Leukocyte suppression assays (LSAs) were performed to compare the ability of ASCs and PMSCs to inhibit activated peripheral blood mononuclear cell (PBMC) proliferation. IDO activity and PGE2; interleukin (IL)-2, IL-6, and IL-8; TNFα; and vascular endothelial growth factor (VEGF) concentrations were also measured from co-culture supernatants. Cell cycle analysis was performed to determine how ASCs and PMSCs altered lymphocyte proliferation. Results Activated canine MSCs from both tissue sources secreted high concentrations of IDO and PGE2, after direct stimulation with IFNγ and TNFα, or indirect stimulation by activated PBMCs. Both ASCs and PMSCs inhibited activated PBMC proliferation in LSA assays; however, PMSCs inhibited PBMC proliferation significantly more than ASCs. Blocking PGE2 and IDO in LSA assays determined that PGE2 is important only for ASC inhibition of PBMC proliferation. Activated ASCs increased IL-6 and VEGF secretion and decreased TNFα secretion, while activated PMSCs increased IL-6, IL-8, and VEGF secretion. ASCs inhibited lymphocyte proliferation via cell cycle arrest in the G0/G1 and PMSCs inhibited lymphocyte proliferation via induction of lymphocyte apoptosis. Conclusion Our results demonstrate that ASCs and PMSCs have substantial in vitro potential as a cell-based therapy for IBD; however, PMSCs more potently inhibited lymphocyte proliferation by inducing apoptosis of activated lymphocytes. These data suggest that the mechanism by which ASCs and PMSCs downregulate PBMC proliferation differs. Additional studies may elucidate additional mechanisms by which canine MSCs modulate neuroinflammatory responses.

Abstract Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non‐diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient‐specific induced pluripotent stem cells (HA‐iPSCs) could provide a renewable supply of ECs. The HA‐iPSC‐derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA‐iPSC‐derived ECs were retained in the animals for at least 10‐16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA‐iPSC‐derived ECs significantly reduced blood loss in a tail‐clip bleeding test and produced therapeutic plasma levels (11.2%‐369.2%) of FVIII. Thus, our studies provide proof‐of‐concept that HA‐iPSC‐derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns.

In the central nervous system, the maturation of glial cells is temporally and functionally coupled with that of the vascular network during postnatal development. Here the authors show that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling, while astroglial HIFα participates through Wnt-dependent signaling.