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Reclamation space, as an important part connecting land and sea, is a key link in land-sea coordination. Taking Shenzhen as an example, by combing the Landsat remote sensing image data from 1980 to 2020, analyzing the scale of reclamation and the change of coastline and interpreting the background, it is found that the reclamation history in Shenzhen has gone through four stages: independent construction by harbor enterprises under pilot development (1980—1986), expansion of local industrial infrastructure in the separation of government and enterprise (1986—1996), strengthening of the dual role of the government under resource shortage (1996—2010), and consideration of multiple benefits in optimization of stock space (2010—2020). The total reclamation area reaches 91.68 km2, the retention rate of natural coastline has decreased by 49.92%, and the continuous years of reclamation have had a negative impact on the ecological security of the coastal zone. On this basis, this paper points out that the government, as the benefit-oriented policy subject, has had an important impact on its own, corporate and public behavior on reclamation. Finally, based on the experience gained from Shenzhen, the spatial development of other coastal cities should focus on the ecological restoration and benefit compensation of historical reclamation projects and on the trade-off between economic and ecological benefits of new reclamation projects.

Abstract To rescue ischemic myocardium from progressing to myocardial infarction, timely identification of the infarct size and reperfusion is crucial. However, fast and accurate identification, as well as the targeted protection of injured cardiomyocytes following ischemia/reperfusion (I/R) injury, remain significantly challenging. Here, a near infrared heptamethine dye IR‐780 is shown that has the potential to quickly monitor the area at risk following I/R injury by selectively entering the cardiomyocytes of the at‐risk heart tissues. Preconditioning with IR‐780 or timely IR‐780 administration before reperfusion significantly protects the heart from ischemia and oxidative stress‐induced cell death, myocardial remodeling, and heart failure in both rat and pig models. Furthermore, IR‐780 can directly bind to F0F1‐ATP synthase of cardiomyocytes, rapidly decrease the mitochondrial membrane potential, and subsequently slow down the mitochondrial energy metabolism, which induces the mitochondria into a “quiescent state” and results in mitochondrial permeability transition pore inhibition by preventing mitochondrial calcium overload. Collectively, the findings show the feasibility of IR‐780‐based imaging and protection strategy for I/R injury in a preclinical context and indicate that moderate mitochondrial function depression is a mode of action that can be targeted in the development of cardioprotective reagents.

The electrocatalytic oxidation of urea combined with wastewater splitting is considered a promising approach for sustainable hydrogen production, characterized by minimal energy consumption. However, its evolution is greatly hindered by the shortage of efficient and easily accessible electrocatalytic materials. Here, a facile electrochemical activation strategy was conceived and proposed to construct a Cu-doped NiOOH nanolayer encapsulated on Cu2O nanodendrites on Cu mesh substrate (Cu-NiOOH/Cu2O/CM) from the electrodeposited Ni/Cu2O/CM heterostructured precatalyst. It was verified that the incorporation of Cu not only facilitates the rapid formation of Ni(III) species but also contributes to the formation of Cu-Ni(III) bifunctional electrocatalytic active sites. Benefiting from the accessible Cu-Ni(III) dual active sites, high active surface area, good hydrophilic and aerophobic surface properties and superior electrical conductivity of the Cu mesh substrate, the as-prepared Cu-NiOOH/Cu2O/CM exhibits enhanced bifunctional electrocatalytic abilities for electrocatalytic urea oxidation reaction (UOR) and hydrogen evolution reaction (HER). Particularly, for the Cu-NiOOH/Cu2O/CM||Cu-NiOOH/Cu2O/CM configuration toward the UOR||HER coupled system, a significantly reduced cell voltage of 1.43 V vs. RHE @ 10 mA·cm−2 was obtained. The observed cell voltage for the conventional overall water splitting is approximately 190 mV higher than that observed for overall urea splitting. This study proposes a viable approach to achieve and optimize the bifunctional UOR/HER performance of NiOOH active species, which holds significant importance for efficient and stable hydrogen generation from urea-contaminated substandard water.

Abstract Background Sepsis poses a serious threat to human life and health, with limited options for current clinical treatments. Acupuncture plays an active role in treating sepsis. However, previous studies have focused on the neuromodulatory effect of acupuncture, neglecting its network modulatory effect. Exosomes, as a new way of intercellular communication, may play an important role in transmitting acupuncture information. This paper explores the possibility of electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs as a potential treatment for sepsis. Methods The sepsis mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS) (12 mg/kg, 24 mg/kg), and EA (continuous wave, 10 Hz, intensity 5) or intraperitoneal injection of Acupuncture Exosomes (Acu-exo) were performed before the model establishment. The therapeutic effect was evaluated by survival rate, ELISA, H&E staining and lung wet/dry weight ration (W/D). In vivo imaging of small animals was used to observe the accumulation of Acu-exo in various organs of sepsis mice. LPS was used to induce macrophages in cell experiments, and the effect of Acu-exo on macrophage inflammatory cytokines was observed. In addition, The miRNA sequencing method was further used to detect the serum exosomes of normal and EA-treated mice, and combined with network biology analysis methods to screen possible key targets. Results EA and Acu-exo reduced the W/D and lung tissue damage in sepsis mice, down-regulated the expression of serum inflammatory cytokines TNF-α and IL-6, and increased the survival rate of sepsis mice. In vivo imaging of small animals found that Acu-exo were accumulated in the lungs of sepsis mice. Cell experiments proved that Acu-exo down-regulated the expression of inflammatory cytokines TNF-α, IL-6 and IL-1β to alleviate the inflammatory response induced by LPS in macrophages. MiRNA sequencing revealed 53 differentially expressed miRNAs, and network biology analysis revealed the key targets of Acu-exo in sepsis treatment. Conclusion Electroacupuncture-driven endogenous circulating serum exosomes and their carried miRNAs may be a potential treatment for sepsis.

Abstract The current view of hematopoiesis considers leukocytes on a continuum with distinct developmental origins, and which exert non-overlapping functions. However, there is less known about the function and phenotype of ontogenetically distinct neutrophil populations. In this work, using a photoconvertible transgenic zebrafish line; Tg(mpx:Dendra2), we selectively label rostral blood island-derived and caudal hematopoietic tissue-derived neutrophils in vivo during steady state or upon injury. By comparing the migratory properties and single-cell expression profiles of both neutrophil populations at steady state we show that rostral neutrophils show higher csf3b expression and migration capacity than caudal neutrophils. Upon injury, both populations share a core transcriptional profile as well as subset-specific transcriptional signatures. Accordingly, both rostral and caudal neutrophils are recruited to the wound independently of their distance to the injury. While rostral neutrophils respond uniformly, caudal neutrophils respond heterogeneously. Collectively, our results reveal that co-existing neutrophils populations with ontogenically distinct origin display functional differences.

Coronary artery disease (CAD) is caused by atherosclerotic lesions in the coronary vessels. Endoplasmic reticulum stress (ERS) acts in cardiovascular disease, and its role in CAD is not clear. A total of 13 differentially expressed ERS-related genes (DEERSRGs) in CAD were identified. Functional enrichment analysis demonstrated the DEERSRGs were mainly enriched in endoplasmic reticulum (ER)-related pathways. Then, eight genes (RCN2, HRC, DERL2, RNF183, CRH, TMED2, PPP1R15A, and IL1A) were authenticated as ERS-related biomarkers in CAD by least absolute shrinkage and selection operator (LASSO). The receiver operating characteristic (ROC) analysis showed that the LASSO logistic model constructed based on biomarkers had a better diagnostic effect, which was confirmed by the ANN and GSE23561 datasets. Also, ROC results showed that seven of the eight biomarkers had better diagnostic effects. The nomogram model had good predictive power, and biomarkers were mostly enriched in pathways associated with CAD. The biomarkers were significantly associated with 10 immune cells, and RCN2, DERL2, TMED2, and RNF183 were negatively correlated with most chemokines. Eight biomarkers had significant correlations with both immunoinhibitors and immunostimulators. In addition, eight biomarkers were significantly different in both CAD and control samples, CRH and HRC were upregulated in CAD. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed that RCN2, HRC, DERL2, CRH, and IL1A were consistent with the bioinformatics analysis. RCN2, HRC, DERL2, RNF183, CRH, TMED2, PPP1R15A, and IL1A were identified as biomarkers of CAD. Functional enrichment analysis and immunoassays for biomarkers provide new ideas for the treatment of CAD.

Sepsis is a condition that greatly impacts the brain, leading to neurological dysfunction and heightened mortality rates, making it one of the primary organs affected. Injury to the central nervous system can be attributed to dysfunction of various organs throughout the entire body and imbalances within the peripheral immune system. Furthermore, central nervous system injury can create a vicious circle with infection-induced peripheral immune disorders. We collate the pathogenesis of septic encephalopathy, which involves microglial activation, programmed cell death, mitochondrial dysfunction, endoplasmic reticulum stress, neurotransmitter imbalance, and blood–brain barrier disruption. We also spotlight the effects of intestinal flora and its metabolites, enterocyte-derived exosomes, cholinergic anti-inflammatory pathway, peripheral T cells and their cytokines on septic encephalopathy.

Abstract Cognitive impairment is a prevalent neurological disorder that burdens families and the healthcare system. Current conventional therapies for cognitive impairment, such as cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists, are unable to completely stop or reverse the progression of the disease. Also, these medicines may cause serious problems with the digestive system, cardiovascular system, and sleep. Clinically, stimulation of acupoints has the potential to ameliorate the common symptoms of a variety of cognitive disorders, such as memory deficit, language dysfunction, executive dysfunction, reduced ability to live independently, etc. There are common acupoint stimulation mechanisms for treating various types of cognitive impairment, but few systematic analyses of the underlying mechanisms in this domain have been performed. This study comprehensively reviewed the basic research from the last 20 years and found that acupoint stimulation can effectively improve the spatial learning and memory of animals. The common mechanism may be that acupoint stimulation protects hippocampal neurons by preventing apoptosis and scavenging toxic proteins. Additionally, acupoint stimulation has antioxidant and anti-inflammatory effects, promoting neural regeneration, regulating synaptic plasticity, and normalizing neural circuits by restoring brain functional activity and connectivity. Acupoint stimulation also inhibits the production of amyloid β-peptide and the phosphorylation of Tau protein, suggesting that it may protect neurons by promoting correct protein folding and regulating the degradation of toxic proteins via the autophagy-lysosomal pathway. However, the benefits of acupoint stimulation still need to be further explored in more high-quality studies in the future.

An integrated scRNA-seq and scATAC-seq analysis of retina from the goldfish, Carassius auratus, reveals global biases in expression patterns between the two (L and S) subgenomes that resulted from ancestral whole-genome duplication.

Male pregnancy in syngnathids (seahorses, pipefishes, and sea dragons) is an evolutionary innovation in the animal kingdom. Paternal immune resistance to the fetus is a critical challenge, particularly in seahorses with fully enclosed brood pouches and sophisticated placentas. In this study, comparative genomic analysis revealed that all syngnathid species lost three vertebrate-conserved Toll-like receptors (TLR1, TLR2, and TLR9), of which all play essential roles in immune protection and immune tolerance in the uterus and placenta. Quantitative real-time PCR (qRT-PCR) analysis showed that the TLR paralog genes including TLR18, TLR25, and TLR21 were highly expressed in the placenta inside the seahorse brood pouch and changed dynamically during the breeding cycle, suggesting the potentially important role of the TLRs during male pregnancy. Furthermore, the immune challenge test in vitro showed a remarkable expression response from all three TLR genes to specific pathogenic antigens, confirming their immune function in seahorse brood pouches. Notably, the altered antigen recognition spectrum of these genes appeared to functionally compensate in part for the lost TLRs, in contrast to that observed in other species. Therefore, we suggest that gene loss and co-option of TLRs may be a typical evolutionary strategy for facilitating paternal immunological adaptation during male pregnancy.

Summary: Background: Macrophages at infection sites are considered as the promising therapeutic targets to prevent sepsis development. The Nrf2/Keap1 system acts as a critical modulator of the antibacterial activity of macrophages. Recently, Keap1–Nrf2 protein–protein interaction (PPI) inhibitors have emerged as safer and stronger Nrf2 activators; however, their therapeutic potential in sepsis remains unclear. Herein, we report a unique heptamethine dye, IR-61, as a Keap1–Nrf2 PPI inhibitor that preferentially accumulates in macrophages at infection sites. Methods: A mouse model of acute lung bacterial infection was used to investigate the biodistribution of IR-61. SPR study and CESTA were used to detect the Keap1 binding behaviour of IR-61 in vitro and in cells. Established models of sepsis in mice were used to determine the therapeutic effect of IR-61. The relationship between Nrf2 levels and sepsis outcomes was preliminarily investigated using monocytes from human patients. Findings: Our data showed that IR-61 preferentially accumulated in macrophages at infection sites, enhanced bacterial clearance, and improved outcomes in mice with sepsis. Mechanistic studies indicated that IR-61 potentiated the antibacterial function of macrophages by activating Nrf2 via direct inhibition of the Keap1–Nrf2 interaction. Moreover, we observed that IR-61 enhanced the phagocytic ability of human macrophages, and the expression levels of Nrf2 in monocytes might be associated with the outcomes of sepsis patients. Interpretations: Our study demonstrates that the specific activation of Nrf2 in macrophages at infection sites is valuable for sepsis management. IR-61 may prove to be a Keap1-Nrf2 PPI inhibitor for the precise treatment of sepsis. Funding: This work was supported by the National Natural Science Foundation of China (Major program 82192884), the Intramural Research Project (Grants: 2018-JCJQ-ZQ-001 and 20QNPY018), and the Chongqing National Science Foundation (CSTB2022NSCQ-MSX1222).

Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.

Background Acute exacerbation is an important cause for the significant decline of lung function in patients with chronic airway disease, which seriously affects the health and quality of life of patients, and significantly increases the medical and economic burden of the disease. Early identification of different inflammatory phenotypes in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and asthma-COPD overlap (ACO) and timely and precise treatment are important in reducing the occurrence of exacerbations, controlling disease progression, and improving quality of life. Objective To compare the clinical characteristics of AECOPD with different inflammatory phenotypes and ACO patients and their response to glucocorticoid therapy, and to provide a reference for further guiding the application of glucocorticoids. Methods The basic clinical data of AECOPD and ACO patients hospitalized in respiratory and critical care Medicine Department of the Second Hospital of Hebei Medical University from January 2018 to December 2020 were collected. The basic clinical data were collected, and the peripheral blood eosinophils (EOS) percentage (2%) was used as the critical value, EOS%≥2% was defined as EOS group, EOS%

Neurogenic pain rises because of nervous system damage or dysfunction and is the most difficult to treat among other pathological pains. Acupuncture has been reported as a great treatment option for neurogenic pain owing to its unlimited advantages. However, previous studies on the analgesic effects of acupuncture for NP were scattered and did not form a whole. In this study, we first comprehensively review the relevant basic articles on acupuncture for NP published in the last 5 years and summarize the analgesic mechanisms of acupuncture in terms of nerve signaling, neuro-immune crosstalk, and metabolic and oxidative stress regulation. Acupuncture inhibits the upstream excitatory system and suppresses neuronal transmission efficiency by downregulating glutamate, NMDA receptors, P2XR, SP, CGRP, and other neurotransmitters and receptors in the spinal cord, as well as plasma channels such as TRPV1, HCN. It can also activate the downstream pain inhibitory pathway by upregulating opioid peptide (β-endorphin), MOR receptors, GABA and GABA receptors, bi-directional regulating 5-hydroxytryptamine (5-HT) and its receptors (upregulate 5-HT 1A and downregulate 5-HT7R) and stimulating hypothalamic appetite-modifying neurons. Moreover, neuroinflammation in pain can be inhibited by acupuncture through inhibiting JAK2/STAT3, PI3K/mTOR pathways, down regulating chemokine receptor CX3CR1 on microglia and up regulating adenosine receptor A1Rs on astrocytes, inhibiting the activation of glia and reducing TNF-α and other inflammatory substances. Acupuncture also inhibits neuronal glucose metabolism by downregulating mPFC's GLUT-3 and promotes metabolic alterations of the brain, thus exerting an analgesic effect. In conclusion, the regulation of nerve signal transduction and neuroimmune crosstalk at the peripheral and central levels mediates the analgesic effects of acupuncture for neuropathic pain in an integrated manner. These findings provide a reliable basis for better clinical application of acupuncture in the management of neuropathic pain.

Abstract Cutaneous wound healing requires intricate synchronization of several key processes. Among them, local nerve regeneration is known to be vitally important for proper repair. However, the underlying mechanisms of local nerve regeneration are still unclear. Fibroblasts are one of the key cell types within the skin whose role in local nerve regeneration has not been extensively studied. In our study, we found skin fibroblasts were in tight contact with regenerated nerves during wound healing, while rare interactions were shown under normal circumstances. Moreover, skin fibroblasts surrounding the nerves were shown to be activated and reprogrammed to exhibit neural cell‐like properties by upregulated expressing inhibitor of DNA binding 1 (ID1) and ID3. Furthermore, we identified the regulation of integrin α6 (Itga6) by ID1/ID3 in fibroblasts as the mechanism for axon guidance. Accordingly, transplantation of the ID1/ID3‐overexpressing fibroblasts or topical injection of ID1/ID3 lentivirus significantly promoted local nerve regeneration and wound healing following skin excision or sciatic nerve injury. Therefore, we demonstrated a new role for skin fibroblasts in nerve regeneration following local injury by directly contacting and guiding axon regrowth, which might hold therapeutic potential in peripheral nerve disorders and peripheral neuropathies in relatively chronic refractory wounds.

ObjectiveTo evaluate the efficacy and safety of acupuncture in treating symptoms for Cancer-related Insomnia(CRI) patients.MethodsSeven databases were searched from the time of database establishment to 31 March 2022. Randomized Controlled Trials (RCTs) on acupuncture intervention for CRI were collected. Literature screening and data extraction were performed independently by two researchers. Meta-analysis was performed using RevMan 5.4 software.ResultsA total of 13 articles with 1,109 participants were included. Five hundred and seventeen in the treatment group and 592 in the control group. Ten of the RCTs used the PSQI rating scale and four randomized controlled trials used the ISI rating scale, and the PSQI and ISI were analyzed together as continuous data. The results of the meta-analysis were: MD = −1.83, 95%CI = [−2.71, −0.94], P < 0.0001, indicating a significant improvement in PSQI scores in patients with CRI by acupuncture intervention; MD = 0.79, 95%CI = [−0.46, 2.03], P = 0.22. Acupuncture was not statistically significant on ISI scores for patients with CRI compared to controls, which does not yet indicate that acupuncture is effective for symptoms in patients with CRI. The results of the meta-analysis of the other 4 items using sleep disorder logs as efficacy analysis data were as follow, relative risk RR = 0.47, 95%CI = [0.33, 0.66], P < 0.0001. The difference was statistically significant, indicating that acupuncture can improve the symptoms of CRI patients compared to control group.ConclusionAcupuncture can improve the symptoms of patients with CRI to some extent, but due to the relatively small number and low quality of the included literature in this study, more high-quality clinical trials are needed as supplement the evidences in future.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/.

Diffusing fluid from methane seepage in cold seep field creates zones with physicochemical gradients and divergent ecosystems like the mussel beds and clam beds. Three species of brittle stars (Ophiuroidea) were discovered in the Haima cold seep fields, of which Ophiophthalmus serratus and Histampica haimaensis were found on top of or within mussel beds and clam beds, whereas Amphiura sp. was only collected from muds in the clam bed assemblage. Here, we evaluated the genetic signatures of micro-environmental adaptation of brittle stars to cold seep through the comparison of mitogenomes. This study provided two complete mitogenome sequences of O. serratus and Amphiura sp. and compared with those of H. haimaensis and other non-seep species. We found that the split events of the seep and non-seep species were as ancient as the Cretaceous period (∼148–98 Mya). O. serratus and H. haimaensis display rapid residue mutation and mitogenome rearrangements compared to their shallow or deep-sea relatives, in contrast, Amphiura sp. only show medium, regardless of nucleotide mutation rate or mitogenome rearrangement, which may correlate with their adaptation to one or two micro-ecosystems. Furthermore, we identified 10 positively selected residues in ND4 in the Amphiura sp. lineage, suggesting important roles of the dehydrogenase complex in Amphiura sp. adaptive to the cold seep environment. Our results shed light on the different evolutionary strategies during colonization in different micro-environments.

Background: Complex surgical plans and consideration of risks and benefits often cause decisional conflicts for decision-makers in aortic dissection (AD) surgery, resulting in decision delay. Shared decision-making (SDM) improves decision readiness and reduces decisional conflicts. The purpose of this study was to investigate the impact of SDM on decision quality in AD. Methods: One hundred and sixty AD decision-makers were divided into two groups: control (n = 80) and intervention (n = 80). The surgical plan for the intervention group was determined using patient decision aids. The primary outcome was decisional conflict. Secondary outcomes included decision preparation, decision satisfaction, surgical method, postoperative complications, actual participation role, and duration of consultation. The data were analyzed with SPSS 26.0 (IBM Corp., Chicago, IL, USA). p < 0.05 was considered statistically significant. Results: The decisional conflict score was significantly lower in the intervention group than in the control group (p < 0.001). The decision preparation and decision satisfaction scores in the intervention group were significantly higher than those in the control group (p < 0.001). There were more SDM decision-makers in the intervention group (16 [20%] vs. 42 [52.50%]). There was no statistical significance in the choice of surgical, postoperative complications, duration of consultation, and hospital and post-operative intensive care unit stay time (p = 0.267, p = 0.130, p = 0.070, p = 0.397, p = 0.421, respectively). Income, education level, and residence were the influencing factors of decision-making conflict. Conclusions: SDM can reduce decisional conflict, improve decision preparation and satisfaction, and help decision-makers actively participate in the medical management of patients with AD without affecting the medical outcome.

Abstract Acupuncture is used in the treatment of a variety of inflammatory conditions and diseases. However, the mechanisms of its anti-inflammatory action are complex and have not been systematically investigated. Macrophages are key components of the innate immune system, thus, balancing the M1/M2 macrophage ratio and modulating cytokine levels in the inflammatory environment may be desirable therapeutic goals. Evidence has shown that acupuncture has anti-inflammatory actions that affect multiple body systems, including the immune, locomotory, endocrine, nervous, digestive, and respiratory systems, by downregulating pro-inflammatory M1 and upregulating anti-inflammatory M2 macrophages, as well as by modulating associated cytokine secretion. Macrophage polarization is controlled by the interlocking pathways of extrinsic factors, the local tissue microenvironment, and the neural-endocrine-immune systems. It has been suggested that polarization of T lymphocytes and cytokine secretions resulting in modulation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, may be upstream mechanisms of acupuncture-induced macrophage polarization. We further propose that macrophage polarization could be the principal pathway involved in acupuncture immune regulation and provide the scientific basis for the clinical application of acupuncture in inflammatory conditions.

Adeno-associated viral (AAV) vectors have emerged as the preferred platform for in vivo gene transfer because of their combined efficacy and safety. However, insertional mutagenesis with the subsequent development of hepatocellular carcinomas (HCCs) has been recurrently noted in newborn mice treated with high doses of AAV, and more recently, the association of wild-type AAV integrations in a subset of human HCCs has been documented. Here, we address, in a comprehensive, prospective study, the long-term risk of tumorigenicity in young adult mice following delivery of single-stranded AAVs targeting liver. HCC incidence in mice treated with therapeutic and reporter AAVs was low, in contrast to what has been previously documented in mice treated as newborns with higher doses of AAV. Specifically, HCCs developed in 6 out 76 of AAV-treated mice, and a pathogenic integration of AAV was found in only one tumor. Also, no evidence of liver tumorigenesis was found in juvenile AAV-treated mucopolysaccharidosis type VI (MPS VI) cats followed as long as 8 years after vector administration. Together, our results support the low risk of tumorigenesis associated with AAV-mediated gene transfer targeting juvenile/young adult livers, although constant monitoring of subjects enrolled in AAV clinical trial is advisable.

Drought and nutrient deficiency pose great challenges to the successful establishment of native plants on the Qinghai-Tibet Plateau. The dominant factors and strategies that affect the adaptation of alpine herbs to dry and nutrient-deficient environments remain unclear. Three water gradients were established using two-factor controlled experiments: low water (WL), medium water (WM), and high water (WH). The field water-holding capacities were 35%, 55%, and 75%, respectively. Nitrogen fertilizer (N) was applied at four levels: control (CK), low (FL), medium (FM), and high (FH) at 0, 110, 330, and 540 mg/kg, respectively. The results revealed that N was the main limiting factor, rather than phosphorous (P), in Festuca coelestis under drought stress. Under water shortage conditions, F. coelestis accumulated more proline and non-structural carbohydrates, especially in the aboveground parts of the leaves and stems; however, the root diameter and aboveground nitrogen use efficiency were reduced. Appropriate N addition could mitigate the adverse effects by increasing the release of N, P, and enzyme activity in the bulk soil and rhizosphere to balance their ratio, and was mainly transferred to the aboveground parts, which optimized the supply uptake relationship. The effects of water and fertilizer on the physiological adaptability and nutrient utilization of F. coelestis were verified using structural equation modeling. Based on their different sensitivities to water and nitrogen, the WHFM treatment was more suitable for F. coelestis establishment. Our results demonstrated that the disproportionate nutrient supply ability and preferential supply aboveground compared to below ground were the main factors influencing F. coelestis seedling establishment under drought conditions. This study provides evidence for a better understanding of herbaceous plants living in high mountain regions and offers important information for reducing the risk of ecological restoration failure in similar alpine regions.

This study aims to explore a preparation method based on a combination of melting and ultrasound to produce a Ga2O3/ZnO (GZ) spherical composite with a snake raspberry structure for the degradation of methyl orange at room temperature in dark. The catalyst exists in the form of a (GZ) composite and an anhydrous ethanol mixture after the ultrasonic treatment of premelted GaZn liquid metal alloy in anhydrous ethanol. The degradation activity of the catalyst was evaluated according to the amount of catalyst, alloy extraction temperature, acid–base environment, and inorganic salt ions. A transmission electron microscope (TEM) was used to confirm that the material was Ga2O3 coated with ZnO, with a structure similar to that of snakeberry. The electron paramagnetic resonance (EPR) and a series of free radical inhibition experiments demonstrated that ·O2− is produced during the ultrasonic preparation of the catalyst and plays an important role in the degradation process after adding MO. The removal rate of MO reached 99.75% at 3 min. Three possible degradation pathways were proposed based on the intermediates produced during the degradation process, which were identified by liquid chromatography–mass spectrometry (LC–MS). The results of this study may provide a new choice for the degradation of organic pollutants.

Adipose tissue macrophages are central to controlling inflammation in the context of obesity. Here the authors present a new infrared dye (IR-61) that accumulates in the mitochondria of these cells resulting in anti-inflammatory effects that counter obesity-associated pathology in mice.

Abstract Goldfish is an ornamental fish with diverse phenotypes. However, the limited genomic resources of goldfish hamper our understanding of the genetic basis for its phenotypic diversity. To provide enriched genomic resources and infer possible mechanisms underlying skin pigmentation, we performed a large-scale transcriptomic sequencing on 13 adult goldfish tissues, larvae at one- and three-days post hatch, and skin tissues with four different color pigmentation. A total of 25.52 Gb and 149.80 Gb clean data were obtained using the PacBio and Illumina platforms, respectively. Onto the goldfish reference genome, we mapped 137,674 non-redundant transcripts, of which 5.54% was known isoforms and 78.53% was novel isoforms of the reference genes, and the remaining 21,926 isoforms are novel isoforms of additional new genes. Both skin-specific and color-specific transcriptomic analyses showed that several significantly enriched genes were known to be involved in melanogenesis, tyrosine metabolism, PPAR signaling pathway, folate biosynthesis metabolism and so on. Thirteen differentially expressed genes across different color skins were associated with melanogenesis and pteridine synthesis including mitf, ednrb, mc1r, tyr, mlph and gch1, and xanthophore differentiation such as pax7, slc2a11 and slc2a15. These transcriptomic data revealed pathways involved in goldfish pigmentation and improved the gene annotation of the reference genome.

Viviparity has originated independently more than 150 times in vertebrates, while the male pregnancy only emerged in Syngnathidae fishes, such as seahorses. The typical male pregnancy seahorses have closed sophisticated brood pouch that act as both uterus and placenta, representing an excellent model system for studying the evolutionary process of paternal immune protection. Phylogenetic analysis indicated that the hampII gene family has multiple tandem duplicated genes and shows independent lineage-specific expansion in seahorses, and they had the highest ratio of nonsynonymous substitutions to synonymous substitutions (dN/dS) in the seahorse phylogenetic branch. The expression levels of hampIIs in the brood pouch placenta were significantly higher during pregnancy than non-pregnancy. Both LPS stimulation test in vivo and cytotoxicity test in vitro proved the immunological protection function of hampIIs against pathogen infection in seahorse. Besides, seahorse hampII peptides exhibit weaker antibacterial function, but stronger agglutination and free endotoxin inhibition. We assumed that the modified immunological function seemed to be a trade-off between the resistance to microbial attack and offspring protection. In brief, this study suggests that the rapid co-option of hampIIs contributes to the evolutionary adaption to paternal immune care during male pregnancy.

PurposeThe purpose of the current study was to compare the effects of local anesthesia (LA) and general anesthesia (GA) on the surgical process and postoperative recovery of patients with unilateral chronic subdural hematoma (CSDH).Patients and MethodsA retrospective cohort study was conducted on patients with unilateral CSDH who underwent burr hole surgery between the years 2013 and 2018. Patients who received local anesthesia were allocated to the LA group, and the patients who received general anesthesia were allocated to the GA group. The clinical data, postoperative complication, length of stay, and hospitalization cost of these two groups were compared and analyzed.ResultsData from 105 patients was collected for this study. Fifty one patients were assigned to the LA group and 54 to GA group. The duration of anesthesia and operation of the LA group was 37.71 (10.55) min; while for the GA group the duration was 56.04 (8.37) min (p < 0.001). The time from operation to discharge in GA group was greatly longer than that in LA group [(8.51 (1.49) days vs. 10.46 (2.34) days, respectively; p < 0.001]. Hospitalization cost for LA group was 2,721.54 (504.66) USD, which was significantly lesser than that for GA patients [3,314.82 (493.52) USD; p < 0.001]. The total number of complications in LA patients was less than that in GA patients [6 vs. 29 cases, respectively; p < 0.001]. The number of patients with residual hematoma in the LA group was

Wheat yield is not only affected by three components of yield, but also affected by plant height (PH). Identification and utilization of the quantitative trait loci (QTL) controlling these four traits is vitally important for breeding high-yielding wheat varieties. In this work, we conducted a QTL analysis using the recombinant inbred lines (RILs) derived from a cross between two winter wheat varieties of China, “Nongda981” (ND981) and “Nongda3097” (ND3097), exhibiting significant differences in spike number per unit area (SN), grain number per spike (GNS), thousand grain weight (TGW), and PH. A total of 11 environmentally stable QTL for these four traits were detected. Among them, four major and stable QTLs (QSn.cau-4B-1.1, QGns.cau-4B-1, QTgw.cau-4B-1.1, and QPh.cau-4B-1.2) explaining the highest phenotypic variance for SN, GNS, TGW, and PH, respectively, were mapped on the same genomic region of chromosome 4B and were considered a QTL cluster. The QTL cluster spanned a genetic distance of about 12.3 cM, corresponding to a physical distance of about 8.7 Mb. Then, the residual heterozygous line (RHL) was used for fine mapping of the QTL cluster. Finally, QSn.cau-4B-1.1, QGns.cau-4B-1, and QPh.cau-4B-1.2 were colocated to the physical interval of about 1.4 Mb containing 31 annotated high confidence genes. QTgw.cau-4B-1.1 was divided into two linked QTL with opposite effects. The elite NILs of the QTL cluster increased SN and PH by 55.71–74.82% and 14.73–23.54%, respectively, and increased GNS and TGW by 29.72–37.26% and 5.81–11.24% in two environments. Collectively, the QTL cluster for SN, GNS, TGW, and PH provides a theoretical basis for improving wheat yield, and the fine-mapping result will be beneficial for marker-assisted selection and candidate genes cloning.

Few fishes have evolved elevated body temperatures compared with ambient temperatures, and only in opah (Lampris spp) is the entire body affected. To understand the molecular basis of endothermy, we analyzed the opah genome and identified 23 genes with convergent amino acid substitutions across fish, birds, and mammals, including slc8b1, which encodes the mitochondrial Na+/Ca2+ exchanger and is essential for heart function and metabolic heat production. Among endothermic fishes, 44 convergent genes with suggestive metabolic functions were identified, such as glrx3, encoding a crucial protein for hemoglobin maturation. Numerous genes involved in the production and retention of metabolic heat were also found to be under positive selection. Analyses of opah's unique inner-heat-producing pectoral muscle layer (PMI), an evolutionary key innovation, revealed that many proteins were co-opted from dorsal swimming muscles for thermogenesis and oxidative phosphorylation. Thus, the opah genome provides valuable resources and opportunities to uncover the genetic basis of thermal adaptations in fish. Public summary: • Endothermy has evolved multiple times in fishes (teleosts and chondrichthyans) • Opah genome explaining genetic changes in heat production and the sensory and immune system • Convergent evolution of genes in endothermic vertebrate lineages was investigated • Analyses of the pectoral muscle of opah revealed numerous highly expressed genes for thermogenesis

Rice (Oryza sativa L.) is one of the most significant food crops worldwide. Flooding can significantly impact the survival and emergence of rice seedlings in the direct planting form of rice, leading to a loss of production. This work investigated the critical phase of rice seed germination to the seedling establishment under submergence stress. It also explored the underlying physiological and molecular processes of shoot and root submergence tolerance. Physiological and transcriptomic analysis of flood-tolerant varieties (LS273) and non-flood-tolerant varieties (ZZ39) were performed. Under submergence stress, LS273 showed longer roots, taller shoots than ZZ39, and lower levels of malondialdehyde and GSSG, but a greater level of GSH/GSSG. In response to stress induced by submersion, LS273 produces more auxin than ZZ39. Within shoots, 4285 DEGs specific to LS273 and 4389 DEGs specifics to ZZ39 were found using the RNA-seq technique. There were 3983 specific DEGs in LS273 and 3292 specific DEGs in ZZ39 in the roots. Antioxidants and plant growth hormones were primarily mentioned in the annotations for these DEGs. Overall, our research provides a thorough foundation for investigating the molecular network underlying shoots’ and roots’ resistance to submergence stress in rice seedlings, leading us to hypothesize that the resistance of flood-tolerant rice may be attributed to high levels of oxidation resistance and auxin accumulation.

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver. Keywords: glycogen storage disorder type Ia, von Gierke disease, glucose-6-phosphatase, hepatocellular carcinoma, genome editing

Sodium dodecyl sulfate-sedimentation volume is an important index to evaluate the gluten strength of common wheat and is closely related to baking quality. In this study, a total of 15 quantitative trait locus (QTL) for sodium dodecyl sulfate (SDS)-sedimentation volume (SSV) were identified by using a high-density genetic map including 2,474 single-nucleotide polymorphism (SNP) markers, which was constructed with a doubled haploid (DH) population derived from the cross between Non-gda3753 (ND3753) and Liangxing99 (LX99). Importantly, four environmentally stable QTLs were detected on chromosomes 1A, 2D, and 5D, respectively. Among them, the one with the largest effect was identified on chromosome 1A (designated as QSsv.cau-1A.1) explaining up to 39.67% of the phenotypic variance. Subsequently, QSsv.cau-1A.1 was dissected into two QTLs named as QSsv.cau-1A.1.1 and QSsv.cau-1A.1.2 by saturating the genetic linkage map of the chromosome 1A. Interestedly, favorable alleles of these two loci were from different parents. Due to the favorable allele of QSsv.cau-1A.1.1 was from the high-value parents ND3753 and revealed higher genetic effect, which explained 25.07% of the phenotypic variation, mapping of this locus was conducted by using BC3F1 and BC3F2 populations. By comparing the CS reference sequence, the physical interval of QSsv.cau-1A.1.1 was delimited into 14.9 Mb, with 89 putative high-confidence annotated genes. SSVs of different recombinants between QSsv.cau-1A.1.1 and QSsv.cau-1A.1 detected from DH and BC3F2 populations showed that these two loci had an obvious additive effect, of which the combination of two favorable loci had the high SSV, whereas recombinants with unfavorable loci had the lowest. These results provide further insight into the genetic basis of SSV and QSsv.cau-1A.1.1 will be an ideal target for positional cloning and wheat breeding programs.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.

The domestication process exerts different phenotypic plasticity between slow- and fast-growing breeds of chicken. Feed restriction has a critical role in production performance, physiological plasticity, and stress response. Our study aimed to explore how feed restriction programed the organ index, dopamine, and hippocampal transcriptome profile between slow- and fast-growing chickens, which were fed either ad libitum (SA and FA), or feed restricted to 70% of ad libitum (SR and FR), for 30 days. Results showed that feed restriction influenced the brain organ index (P < 0.05), but not the organ index of the heart, liver, and spleen. The slow-growing breed tested had a higher brain organ index than the fast-growing breed (P < 0.05). Under feed restriction conditions, both the slow- and fast-growing breeds had significantly elevated dopamine concentrations (P < 0.05) compared to those fed ad libitum. In the GO term, upregulated genes in the FA group were enriched in the mitochondria, respiratory chain, and energy metabolism compared to the SA group (P < 0.05). Membranes and ribosomes were enriched in the cellular component between the SR and FR groups (P < 0.05). In the KEGG functional pathways, upregulated DEGs in the FR group were enriched in the cardiovascular disease category and neurodegenerative disease category compared to the FA group (P < 0.05). Downregulated DEGs in the FA group were enriched in the oxidative phosphorylation and neurodegenerative disease categories (Parkinson's disease and Huntington's disease) compared with the SA group (P < 0.05). Upregulated DEGs in the FR group were enriched in the cardiovascular disease category, neurodegenerative disease category, and energy metabolism than the SR group (P < 0.05). In conclusion, feed restriction had profound effects on the brain organ index and plasma dopamine in the slow- and fast-growing chickens. Feed restriction may result in issues relating to cardiovascular and neurodegenerative diseases in the fast-growing breed tested, but not in the slow-growing breed.

Migratory birds spend several months in their breeding grounds in sympatry with local resident birds and relatively shorter periods of time at stopover sites. During migration, parasites may be transmitted between migratory and resident birds. However, to what extent they share these parasites remains unclear. In this study, we compared the assemblages of haemosporidian parasites in migratory, resident, and passing birds, as well as the correlations between parasite assemblages and host phylogeny. Compared with passing birds, migratory birds were more likely to share parasites with resident birds. Shared lineages showed significantly higher prevalence rates than other lineages, indicating that common parasites are more likely to spill over from the current host to other birds. For shared lineages, the prevalence was significantly higher in resident birds than in migratory birds, suggesting that migratory birds pick up parasites at their breeding ground. Among the shared lineages, almost two-thirds presented no phylogenetic signal in their prevalence, indicating that parasite transmission among host species is weakly or not correlated with host phylogeny. Moreover, similarities between parasite assemblages are not correlated with either migration status or the phylogeny of hosts. Our results show that the prevalence, rather than host phylogeny, plays a central role in parasite transmission between migratory and resident birds in breeding grounds.

Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.

As nickel-based alloys are more and more widely used in engineering fields for bearing cyclic loadings, it is necessary to study their very-high-cycle fatigue (VHCF) properties. In this paper, the fatigue properties of nickel-based alloy 625 were investigated using an ultrasonic fatigue test apparatus. The fracture microscopy shows that around the crack initiation site there are two characteristic zones, a rough area (RA) and a fine granular area (FGA). Inclusions caused the interior fatigue crack initiation, and the coalescence of neighboring micro cracks was strongly influenced by the local microstructure, resulting in the RA morphology. Subsequently, the contact and compressing of the crack surfaces contributed to the formation of the FGA. Finally, the stress intensity factors of the RA and FGA were quantitatively evaluated for further discussion of the crack initiation and propagation processes.

The excessive consumption of fossil energy caused an energy crisis and a series of environmental issues. Therefore, it is necessary to develop sustainable and clean energy sources. Electrocatalysts play an important role in the development of various new energy devices; in particular, high-efficiency and low-cost catalysts are essential for the large-scale application of these new devices. Among the many electrocatalysts, metal chalcogenides (sulfides, selenides, and tellurides) as emerging materials own abundant active sites and good electrical conductivity and are widely studied for their excellent electrocatalytic performances. This Perspective reviews the recent applications of metal chalcogenide materials in electrocatalysis, including hydrogen evolution reaction, oxygen evolution reaction, and electrolyzing water and specifically summarizes different optimization strategies and catalytic reaction mechanisms. The several regulation strategies include heteroatom doping, phase engineering, heterostructures, and hybrid materials, which are capable of improving conductivity, increasing active site exposure, and reducing the energy barrier of catalytic reactions to enhanced electrocatalytic performances. In Sec. IV, the existing problems and future challenges are proposed for the improvement of catalytic performance of metal chalcogenide materials, which provide an insight into and valuable guidelines for the future development of high-efficiency and low-cost electrocatalysts for new energy devices.

Calcification of various tissues is a significant health issue associated with aging, cancer and autoimmune diseases. There are both environmental and genetic factors behind this phenomenon and understanding them is essential for the development of efficient therapeutic approaches. Pseudoxanthoma elasticum (PXE) is a rare genetic disease, a prototype for calcification disorders, resulting from the dysfunction of ABCC6, a transport protein found in the membranes of cells. It is identified by excess calcification in a variety of tissues (e.g., eyes, skin, arteries) and currently it has no cure, known treatments target the symptoms only. Preclinical studies of PXE have been successful in mice, proving the usefulness of animal models for the study of the disease. Here, we present a new zebrafish (Danio rerio) model for PXE. By resolving some ambiguous assemblies in the zebrafish genome, we show that there are two functional and one non-functional paralogs for ABCC6 in zebrafish (abcc6a, abcc6b.1, and abcc6b.2, respectively). We created single and double mutants for the functional paralogs and characterized their calcification defects with a combination of techniques. Zebrafish deficient in abcc6a show defects in their vertebral calcification and also display ectopic calcification foci in their soft tissues. Our results also suggest that the impairment of abcc6b.1 does not affect this biological process.

The gaze cueing effect is characterized by faster attentional orienting to a gazed-at than a non-gazed-at target. This effect is often enhanced when the gazing face bears an emotional expression, though this finding is modulated by a number of factors. Here, we tested whether the type of task performed might be one such modulating factor. Target localization and target discrimination tasks are the two most commonly used gaze cueing tasks, and they arguably differ in cognitive resources, which could impact how emotional expression and gaze cues are integrated to orient attention. In a within-subjects design, participants performed both target localization and discrimination gaze cueing tasks with neutral, happy, and fearful faces. The gaze cueing effect for neutral faces was greatly reduced in the discrimination task relative to the localization task, and the emotional enhancement of the gaze cueing effect was only present in the localization task and only when this task was performed first. These results suggest that cognitive resources are needed for gaze cueing and for the integration of emotional expressions and gaze cues. We propose that a shift toward local processing may be the mechanism by which the discrimination task interferes with the emotional modulation of gaze cueing. The results support the idea that gaze cueing can be greatly modulated by top-down influences and cognitive resources and thus taps into endogenous attention. Results are discussed within the context of the recently proposed EyeTune model of social attention.

Summary: Seahorses epitomize the exuberance of evolution. They have the unique characteristic of male pregnancy, which includes the carrying of many embryos in a brood pouch that incubates and nourishes the embryos, similar to the mammalian placenta. However, the regulatory networks underlying brood pouch formation and pregnancy remain largely unknown. In this study, comparative transcriptomic and metabolomic profiling on the lined seahorse Hippocampus erectus, with unformed, newly formed, and pregnant brood pouches identified a total of 141 and 2,533 differentially expressed genes together with 73 and 121 significantly differential metabolites related to brood pouch formation and pregnancy, respectively. Specifically, integrative omics analysis revealed that retinoic acid (RA) synthesis and signaling pathway played essential roles in the formation of the brood pouch and pregnancy. RA might function upstream of testosterone and progesterone, thereby directly influencing brood pouch formation by regulating the expression of fshr and cyp7a1. Our results also revealed that RA regulates antioxidant defenses, particularly during male pregnancy. Alternatively, pregnancy caused a consistent decrease in RA, canthaxanthin, astaxanthin, and glutathione synthetase, and an increase in susceptibility to oxidative stress, which may balance brood pouch development and reproduction in seahorses and pave the way to successful gestation.

Spinal cord injury (SCI) is a structural event with devastating consequences worldwide. Due to the limited intrinsic regenerative capacity of the spinal cord in adults, the neural restoration after SCI is difficult. Acupuncture is effective for SCI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve neural protection by the inhibition of inflammation, oxidation, and apoptosis. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating multiple cellular signal transduction pathways, such as the Wnt, Notch, and Rho/Rho kinase (ROCK) pathways. Several studies have demonstrated that the efficacy of combining acupuncture with mesenchymal stem cells (MSCs) transplantation is superior to either procedure alone. The advantage of the combined treatment is dependent on the ability of acupuncture to enhance the survival of MSCs, promote their differentiation into neurons, and facilitate targeted migration of MSCs to the spinal cord. Additionally, the differentiation of MSCs into neurons overcomes the problem of the shortage of endogenous neural stem cells (NSCs) in the acupuncture-treated SCI patients. Therefore, the combination of acupuncture and MSCs transplantation could become a novel and effective strategy for the treatment of SCI. Such a possibility needs to be verified by basic and clinical research.

Abstract Background Cerebral edema, erupting simultaneously with severe ischemic stroke, might lead to increased intracranial pressure, cerebral herniation, and ultimately death. Studies conducted previously by our team have demonstrated the fact that bloodletting puncture at hand twelve Jing-well points (HTWP) could alleviate cerebral edema, which mainly results from the disruption of blood-brain barrier (BBB). The study, therefore, was first designed to demonstrate whether BBB-protection serves an important role in the edema-relief effect of HTWP bloodletting, based on which to research the molecular mechanism underlying. Methods The rats were made into model suffering from permanent middle cerebral artery occlusion (pMCAO) and then bloodletting puncture were treated at HTWP once a day. Wet and dry weight method was adopted to evaluate the degree of brain edema, evans blue extravasation and electron microscopy were used to evaluate the integrity of the BBB, and RT-qPCR was carried out to analyze the expression level of occludin, claudin-5, ICAM-1, and VEGF. Results Results revealed that bloodletting puncture treatment could reduce water content of brain and the permeability of BBB caused by ischemic stroke. In bloodletting puncture group, ameliorated tight junctions could be observed under electron microscopy. It was demonstrated in further study that, in bloodletting group, compared with pMCAO one, the expression levels of occludin and claudin-5 were up-regulated, while ICAM-1 and VEGF were down-regulated. Conclusions In conclusion, bloodletting puncture at HTWP might play a significant role in protecting the tight junctions of BBB, thus alleviating cerebral edema induced by ischemic stroke. Therefore, the therapy of bloodletting puncture at HTWP may be a promising strategy for acute ischemic stroke in the future.

Cpf1 has emerged as an alternative to the Cas9 RNA-guided nuclease. Here we show that gene targeting rates in mice using Cpf1 can meet, or even surpass, Cas9 targeting rates (approaching 100% targeting), but require higher concentrations of mRNA and guide. We also demonstrate that coinjecting two guides with close targeting sites can result in synergistic genomic cutting, even if one of the guides has minimal cutting activity.

The type II CRISPR/Cas9 system has been used widely for genome editing in zebrafish. However, the requirement for the 5′-NGG-3′ protospacer-adjacent motif (PAM) of Cas9 from Streptococcus pyogenes (SpCas9) limits its targeting sequences. Here, we report that a Cas9 ortholog from Staphylococcus aureus (SaCas9), and its KKH variant, successfully induced targeted mutagenesis with high frequency in zebrafish. Confirming previous findings, the SpCas9 variant, VQR, can also induce targeted mutations in zebrafish. Bioinformatics analysis of these new Cas targets suggests that the number of available target sites in the zebrafish genome can be greatly expanded. Collectively, the expanded target repertoire of Cas9 in zebrafish should further facilitate the utility of this organism for genetic studies of vertebrate biology.

Abstract The characterization of cancer stem‐like cells (CSCs) has profound implications for elucidating cancer biology and developing treatment strategies. Although surface markers are already used to identify CSCs, the expression of these markers is controversially linked to the phenotypes in different types of tumors and does not represent all functionally relevant of CSCs. Very recently, hyperactive HIF‐1α/glycolysis metabolic pathway is recognized as a master regulator of CSCs. In this study, a near‐infrared fluorescent small‐molecule, IR‐780, is identified for the exclusive characterization of human CSCs through the HIF‐1α/glycolysis dependent mitochondrial transporter ABCB10's activity. The results identified for the first time that ABCB10 is involved in the preferential uptake of IR‐780 in CSCs, which is regulated by HIF‐1α via the direct interaction with the binding site of ABCB10 gene promoter region. In addition, IR‐780 is demonstrated to conjugate with anticancer drug 5‐fluorouracil to act as a potential drug delivery carrier for CSC‐targeted therapy. Thus, the studies provide a new rational approach independent of surface markers to characterize CSCs via small‐molecule‐based imaging of HIF‐1α/glycolysis hyperactive metabolic pathway dependent mitochondrial transporter's activity, which holds promise for the further development of CSCs targeted diagnostic and therapeutic strategies.

Four new isocoumarin derivatives, botryospyrones A (1), B (2), C (3), and D (4), and a new natural tryptamine, (3aS, 8aS)-1-acetyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2,3b] indol-3a-ol (5), were isolated from a marine mangrove endophytic fungus Botryosphaeria ramosa L29, obtained from the leaf of Myoporum bontioides. Their structures were elucidated using spectroscopic analysis. The absolute configurations of compounds 3, 4, and 5 were determined by comparison of their circular dichroism (CD) spectra with the calculated data. The inhibitory activities of compound 1 on Fusarium oxysporum, of compounds 2 and 3 on F. oxysporum and Fusarium graminearum, and of compound 5 on F. oxysporum, Penicillium italicum, and F. graminearum were higher than those of triadimefon, widely used as an agricultural fungicide. Compound 5 was produced after using the strategy we called “using inhibitory stress from components of the host„ (UISCH), wherein (2R, 3R)-3, 5, 7-trihydroxyflavanone 3-acetate, a component of M. bontioides with weak growth inhibitory activity towards B. ramosa L29, was introduced into the culture medium.

Skin, the largest organ of the body, is a promising reservoir for adult stem cells. The epidermal stem cells and hair follicle stem cells have been well studied for their important roles in homeostasis, regeneration, and repair of the epidermis and appendages for decades. However, stem cells residing in dermis were not identified until the year 2001, when a variety of stem cell subpopulations have been isolated and identified from the dermis of mammalian skin such as neural crest stem cells, mesenchymal stem cell-like dermal stem cells, and dermal hematopoietic cells. These stem cell subpopulations exhibited capabilities of self-renewing, multipotent differentiating, and immunosuppressive properties. Hence, the dermis-derived stem cells showed extensive potential applications in regenerative medicine, especially for wound healing/tissue repair, neural repair, and hematopoietic recovery. Here we summarized current research on the stem cell subpopulations derived from the dermis and aimed to provide a comprehensive review on their isolation, specific markers, differentiation capacity, and the functional activities in homeostasis, regeneration, and tissue repair.

Ribosome biogenesis is an important biological process for proper cellular function and development. Defects leading to improper ribosome biogenesis can cause diseases such as Diamond-Blackfan anemia and Shwachman-Bodian-Diamond syndrome. Nucleolar proteins are a large family of proteins and are involved in many cellular processes, including the regulation of ribosome biogenesis. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish line carrying mutation in nucleolar protein with MIF4G domain 1 (nom1), which encodes a conserved nulceolar protein with a role in pre-rRNA processing. Zebrafish nom1 mutants exhibit major defects in endoderm development, especially in exocrine pancreas. Further studies revealed that impaired proliferation of ptf1a-expressing pancreatic progenitor cells mainly contributed to the phenotype. RNA-seq and molecular analysis showed that ribosome biogenesis and pre-mRNA splicing were both affected in the mutant embryos. Several defects of ribosome assembly have been shown to have a p53-dependent mechanism. In the nom1 mutant, loss of p53 did not rescue the pancreatic defect, suggesting a p53-independent role. Further studies indicate that protein phosphatase 1 alpha, an interacting protein to Nom1, could partially rescue the pancreatic defect in nom1 morphants if a human nucleolar localization signal sequence was artificially added. This suggests that targeting Pp1α into the nucleolus by Nom1 is important for pancreatic proliferation. Altogether, our studies revealed a new mechanism involving Nom1 in controlling vertebrate exocrine pancreas formation.