Wheat Ym2 originated from Aegilops sharonensis and confers resistance to soil-borne Wheat yellow mosaic virus infection to the roots.

Wheat yellow mosaic virus (WYMV) is a pathogen transmitted into its host's roots by the soil-borne vector Polymyxa graminis. Ym1 and Ym2 genes protect the host from the significant yield losses caused by the virus, but the mechanistic basis of these resistance genes remains poorly understood. Here, it has been shown that Ym1 and Ym2 act within the root either by hindering the initial movement of WYMV from the vector into the root and/or by suppressing viral multiplication. A mechanical inoculation experiment on the leaf revealed that the presence of Ym1 reduced viral infection incidence, rather than viral titer, while that of Ym2 was ineffective in the leaf. To understand the basis of the root specificity of the Ym2 product, the gene was isolated from bread wheat using a positional cloning approach. The candidate gene encodes a CC-NBS-LRR protein and it correlated allelic variation with respect to its sequence with the host's disease response. Ym2 (B37500) and its paralog (B35800) are found in the near-relatives, respectively, Aegilops sharonensis and Aegilops speltoides (a close relative of the donor of bread wheat's B genome), while both sequences, in a concatenated state, are present in several accessions of the latter species. Structural diversity in Ym2 has been generated via translocation and recombination between the two genes and enhanced by the formation of a chimeric gene resulting from an intralocus recombination event. The analysis has revealed how the Ym2 region has evolved during the polyploidization events leading to the creation of cultivated wheat.

A COBRA family protein, PtrCOB3, contributes to gelatinous layer formation of tension wood fibers in poplar.

Angiosperm trees usually develop tension wood (TW) in response to gravitational stimulation. TW comprises abundant gelatinous (G-) fibers with thick G-layers primarily composed of crystalline cellulose. Understanding of the pivotal factors governing G-layer formation in TW fiber remains elusive. This study elucidates the role of a Populus trichocarpa COBRA family protein, PtrCOB3, in the G-layer formation of TW fibers. PtrCOB3 expression was upregulated, and its promoter activity was enhanced during TW formation. Comparative analysis with wild-type trees revealed that ptrcob3 mutants, mediated by Cas9/gRNA gene editing, were incapable of producing G-layers within TW fibers and showed severely impaired stem lift. Fluorescence immunolabelling data revealed a dearth of crystalline cellulose in the tertiary cell wall (TCW) of ptrcob3 TW fibers. The role of PtrCOB3 in G-layer formation is contingent upon its native promoter, as evidenced by the comparative phenotypic assessments of pCOB11::PtrCOB3, pCOB3::PtrCOB3, and pCOB3::PtrCOB11 transgenic lines in the ptrcob3 background. Overexpression of PtrCOB3 under the control of its native promoter expedited G-layer formation within TW fibers. We further identified three transcription factors that bind to the PtrCOB3 promoter and positively regulate its transcriptional levels. Alongside the primary TCW synthesis genes, these findings enable the construction of a two-layer transcriptional regulatory network for the G-layer formation of TW fibers. Overall, this study uncovers mechanistic insight into TW formation, whereby a specific COB protein executes the deposition of cellulose, and consequently, G-layer formation within TW fibers.

Super-enhancers conserved within placental mammals maintain stem cell pluripotency.

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share an evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that displayed remarkable conservation in placental mammals and were sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR-Cas9 approach severely impaired stem cell pluripotency. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals.

Kir2.1 channel regulates macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway.

Macrophage polarization plays a key role in the inflammatory response. Various ion channels expressed in macrophages have been documented, but very little is known about their roles in macrophage polarization. We found that knockdown or blockade of the Kir2.1 (also known as KCNJ2) channel significantly inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. Lipopolysaccharide (LPS)-induced M1 polarization was also remarkably suppressed in high extracellular K+ solutions (70 mM K+), and this inhibition was partially abolished by adding Ca2+ to the culture medium. Ca2+ imaging showed that Ca2+ influx was dependent on the hyperpolarized membrane potential generated by the Kir2.1 channel. The upregulation of phospho (p)-CaMK II, p-ERK, and p-NF-κB proteins in macrophages from the RAW264.7 cell line that were stimulated with LPS was significantly reversed by blocking the Kir2.1 channel or culturing the cells with 70 mM K+ medium. Furthermore, in vivo studies showed that mice treated with a Kir2.1 channel blocker were protected from LPS-induced peritonitis. In summary, our data reveal the essential role of the Kir2.1 channel in regulating macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway.

PC71BM as Morphology Regulator for Highly Efficient Ternary Organic Solar Cells with Bulk Heterojunction or Layer-by-Layer Configuration.

The ternary strategy is one of the effective methods to regulate the morphology of the active layer in organic solar cells (OSCs). In this work, the ternary OSCs with bulk heterojunction (BHJ) or layer-by-layer (LbL) active layers are prepared by using the polymer donor PM6 and the non-fullerene acceptor L8-BO as the main system and the fullerene acceptor PC71BM as the third component. The power conversion efficiencies (PCEs) of BHJ OSCs and LbL OSCs are increased from 17.10% to 18.02% and from 17.20% to 18.20% by introducing PC71BM into the binary active layer, respectively. The in situ UV-vis absorption spectra indicate that the molecular aggregation and crystallization process can be prolonged by introducing PC71BM into the PM6:L8-BO or PM6/L8-BO active layer. The molecular orientation and molecular crystallinity in the active layer are optimized by introducing the PC71BM into the binary BHJ or LbL active layers, which can be confirmed by the experimental results of grazing incidence wide-angle X-ray scattering. This study demonstrates that the third component PC71BM can be used as a morphology regulator to regulate the morphology of BHJ or LbL active layers, thus effectively improving the performance of BHJ and LbL OSCs.

Highly Efficient Organic Solar Cells with the Highly Crystalline Third Component as a Morphology Regulator.

The morphology of the active layer is crucial for highly efficient organic solar cells (OSCs), which can be regulated by selecting a rational third component. In this work, the highly crystalline nonfullerene acceptor BTP-eC9 is selected as the morphology regulator in OSCs with PM6:BTP-BO-4Cl as the main system. The addition of BTP-eC9 can prolong the nucleation and crystallization progress of acceptor and donor molecules, thereby enhancing the order of molecular arrangement. Meanwhile, the nucleation and crystallization time of the donor is earlier than that of the acceptors after introducing BTP-eC9, which is beneficial for obtaining a better vertical structural phase separation. The exciton dissociation, charge transport, and charge collection are promoted effectively by the optimized morphology of the active layer, which improves the short-circuit current density and filling factor. After introducing BTP-eC9, the power conversion efficiencies (PCEs) of the ternary OSCs are improved from 17.31% to 18.15%. The PCE is further improved to 18.39% by introducing gold nanopyramid (Au NBPs) into the hole transport layer to improve photon utilization efficiency. This work indicates that the morphology can be optimized by selecting a highly crystalline third component to regulate the nucleation and crystallization progress of the acceptor and donor molecules.

VE-Cadherin Is Required for Cardiac Lymphatic Maintenance and Signaling.

BACKGROUND: The adherens protein VE-cadherin (vascular endothelial cadherin) has diverse roles in organ-specific lymphatic vessels. However, its physiological role in cardiac lymphatics and its interaction with lymphangiogenic factors has not been fully explored. We sought to determine the spatiotemporal functions of VE-cadherin in cardiac lymphatics and mechanistically elucidate how VE-cadherin loss influences prolymphangiogenic signaling pathways, such as adrenomedullin and VEGF (vascular endothelial growth factor)-C/VEGFR3 (vascular endothelial growth factor receptor 3) signaling. METHODS: Cdh5flox/flox;Prox1CreERT2 mice were used to delete VE-cadherin in lymphatic endothelial cells across life stages, including embryonic, postnatal, and adult. Lymphatic architecture and function was characterized using immunostaining and functional lymphangiography. To evaluate the impact of temporal and functional regression of cardiac lymphatics in Cdh5flox/flox;Prox1CreERT2 mice, left anterior descending artery ligation was performed and cardiac function and repair after myocardial infarction was evaluated by echocardiography and histology. Cellular effects of VE-cadherin deletion on lymphatic signaling pathways were assessed by knockdown of VE-cadherin in cultured lymphatic endothelial cells. RESULTS: Embryonic deletion of VE-cadherin produced edematous embryos with dilated cardiac lymphatics with significantly altered vessel tip morphology. Postnatal deletion of VE-cadherin caused complete disassembly of cardiac lymphatics. Adult deletion caused a temporal regression of the quiescent epicardial lymphatic network which correlated with significant dermal and cardiac lymphatic dysfunction, as measured by fluorescent and quantum dot lymphangiography, respectively. Surprisingly, despite regression of cardiac lymphatics, Cdh5flox/flox;Prox1CreERT2 mice exhibited preserved cardiac function, both at baseline and following myocardial infarction, compared with control mice. Mechanistically, loss of VE-cadherin leads to aberrant cellular internalization of VEGFR3, precluding the ability of VEGFR3 to be either canonically activated by VEGF-C or noncanonically transactivated by adrenomedullin signaling, impairing downstream processes such as cellular proliferation. CONCLUSIONS: VE-cadherin is an essential scaffolding protein to maintain prolymphangiogenic signaling nodes at the plasma membrane, which are required for the development and adult maintenance of cardiac lymphatics, but not for cardiac function basally or after injury.

Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes.

OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. METHODS: We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. RESULTS: The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. CONCLUSIONS: Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

Omeprazole taken once every other day can effectively prevent aspirin-induced gastrointestinal mucosal damage in rats.

BACKGROUND: Proton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs. METHODS: Sprague‒Dawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers. RESULTS: Both the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy. CONCLUSIONS: Omeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment.

Quality of working life and adaptability of returning to work in nurse cancer survivors: a cross-sectional study.

OBJECTIVE: To explore the relationship between quality of working life (QWL) and adaptability of returning to work (RTW) among nurse cancer survivors (NCSs). METHOD: We conducted a cross-sectional study on nurses previously diagnosed with cancer. QWL was quantified using the Quality of Working Life Scale (QWL7-32), and the level of RTW adaptability was assessed using the Adaptability of Returning to Work for Cancer Survivors (ARTW-CS) scale. Multiple linear regression analysis was used to control for confounding factors, and a simple effect analysis was performed on the interaction term. RESULTS: After controlling for sociodemographic, work-related, and health-related factors, the findings indicated a significant correlation between "adaptation and planning" and QWL score (p < 0.05). Further analysis revealed that "RTW gradualness" and "support seeking" had an interaction effect (p = 0.021). The simple effect analysis demonstrated that when the "RTW gradualness" score was ≥ 16 points, nurses with a high "support seeking" score (≥ 7 points) exhibited a significantly better QWL than those with a low "support seeking" score (< 7 points) (p < 0.001). CONCLUSION: The interaction between "RTW gradualness" and "support seeking" in the ARTW-CS scale significantly impacted the QWL of the NCSs, underscoring the importance of implementing a gradual career plan and seeking support to enhance QWL.

Genome-Wide Association Study and Identification of Candidate Genes Associated with Seed Number per Pod in Soybean.

Soybean (Glycine max [L.] Merr.) is one of the primary sources of plant protein and oil for human foods, animal feed, and industrial processing. The seed number per pod generally varies from one to four and is an important component of seed number per unit area and seed yield. We used natural variation in 264 landraces and improved cultivars or lines to identify candidate genes involved in the regulation of seed number per pod in soybean. Genome-wide association tests revealed 65 loci that are associated with seed number per pod trait. Among them, 11 could be detected in multiple environments. Candidate genes were identified for seed number per pod phenotype from the most significantly associated loci, including a gene encoding protein argonaute 4, a gene encoding histone acetyltransferase of the MYST family 1, a gene encoding chromosome segregation protein SMC-1 and a gene encoding exocyst complex component EXO84A. In addition, plant hormones were found to be involved in ovule and seed development and the regulation of seed number per pod in soybean. This study facilitates the dissection of genetic networks underlying seed number per pod in soybean, which will be useful for the genetic improvement of seed yield in soybean.

Genome-Wide Identification of TLP Gene Family in Populus trichocarpa and Functional Characterization of PtTLP6, Preferentially Expressed in Phloem.

Thaumatin-like proteins (TLPs) in plants are involved in diverse biotic and abiotic stresses, including antifungal activity, low temperature, drought, and high salinity. However, the roles of the TLP genes are rarely reported in early flowering. Here, the TLP gene family was identified in P. trichocarpa. The 49 PtTLP genes were classified into 10 clusters, and gene structures, conserved motifs, and expression patterns were analyzed in these PtTLP genes. Among 49 PtTLP genes, the PtTLP6 transcription level is preferentially high in stems, and GUS staining signals were mainly detected in the phloem tissues of the PtTLP6pro::GUS transgenic poplars. We generated transgenic Arabidopsis plants overexpressing the PtTLP6 gene, and its overexpression lines showed early flowering phenotypes. However, the expression levels of main flowering regulating genes were not significantly altered in these PtTLP6-overexpressing plants. Our data further showed that overexpression of the PtTLP6 gene led to a reactive oxygen species (ROS) burst in Arabidopsis, which might advance the development process of transgenic plants. In addition, subcellular localization of PtTLP6-fused green fluorescent protein (GFP) was in peroxisome, as suggested by tobacco leaf transient transformation. Overall, this work provides a comprehensive analysis of the TLP gene family in Populus and an insight into the role of TLPs in woody plants.

Quantifying multi-dimensional services of water ecosystems and breakpoint-based spatial radiation of typical regulating services considering the hierarchical clustering-based classification.

This study proposes a set of water ecosystem services (WES) research system, including classification, benefit quantification and spatial radiation effect, with the goal of promoting harmonious coexistence between humans and nature, as well as providing a theoretical foundation for optimizing water resources management. Hierarchical cluster analysis was applied to categorize WES taking in to account the four nature constraints of product nature, energy flow relationships, circularity, and human social utility. A multi-dimensional benefit quantification methodology system for WES was constructed by combining the emergy theory with multidisciplinary methods of ecology, economics, and sociology. Based on the theories of spatial autocorrelation and breaking point, we investigated the spatial radiation effects of typical services in the cyclic regulation category. The proposed methodology has been applied to Luoyang, China. The results show that the Resource Provisioning (RP) and Cultural Addition (CA) services change greatly over time, and drive the overall WES to increase and then decrease. The spatial and temporal distribution of water resources is uneven, with WES being slightly better in the southern region than the northern region. Additionally, spatial radiation effects of typical regulating services are most prominent in S County. This finding suggests the establishment of scientific and rational intra-basin or inter-basin water management systems to expand the beneficial impacts of water-rich areas on neighboring regions.

Temperature-Controlled Divergent Synthesis of Pyrazoles and 1-Tosyl-1H-pyrazoles under Transition-Metal-Catalyst- and Oxidant-Free Conditions.

Herein, a general and practical temperature-controlled approach for the divergent synthesis of pyrazoles and 1-tosyl-1H-pyrazoles via electrophilic cyclization in the absence of transition-metal catalysts and oxidants was developed. The desired products were obtained in moderate to excellent yields from common starting materials in both ionic liquids and ethanol by simply tuning the reaction temperature. This strategy employs easily synthesized substrates, mild reaction conditions, and excellent functional-group tolerance.

Study on the preservation effects of the amputated forelimb by machine perfusion at physiological temperature.

PURPOSE: Ischemia and hypoxia are the main factors limiting limb replantation and transplantation. Static cold storage (SCS), a common preservation method for tissues and organs, can only prolong limb ischemia time to 4 - 6 h. The normothermic machine perfusion (NMP) is a promising method for the preservation of tissues and organs, which can extend the preservation time in vitro by providing continuous oxygen and nutrients. This study aimed to evaluate the difference in the efficacy of the 2 limb preservation methods. METHODS: The 6 forelimbs from beagle dogs were divided into 2 groups. In the SCS group (n = 3), the limbs were preserved in a sterile refrigerator at 4 °C for 24 h, and in the NMP group (n = 3), the perfusate prepared with autologous blood was used for the oxygenated machine perfusion at physiological temperature for 24 h, and the solution was changed every 6 h. The effects of limb storage were evaluated by weight gain, perfusate biochemical analysis, enzyme-linked immunosorbent assay, and histological analysis. All statistical analyses and graphs were performed using GraphPad Prism 9.0 one-way or two-way analysis of variance. The p value of less than 0.05 was considered to indicate statistical significance. RESULTS: In the NMP group, the weight gained percentage was 11.72% ± 4.06%; the hypoxia-inducible factor-1α contents showed no significant changes; the shape of muscle fibers was normal; the gap between muscle fibers slightly increased, showing the intercellular distance of (30.19 ± 2.83) µm; and the vascular α-smooth muscle actin (α-SMA) contents were lower than those in the normal blood vessels. The creatine kinase level in the perfusate of the NMP group increased from the beginning of perfusion, decreased after each perfusate change, and remained stable at the end of perfusion showing a peak level of 4097.6 U/L. The lactate dehydrogenase level of the NMP group increased near the end of perfusion and reached the peak level of 374.4 U/L. In the SCS group, the percentage of weight gain was 0.18% ± 0.10%, and the contents of hypoxia-inducible factor-1α increased gradually and reached the maximum level of (164.85 ± 20.75) pg/mL at the end of the experiment. The muscle fibers lost their normal shape and the gap between muscle fibers increased, showing an intercellular distance of (41.66 ± 5.38) µm. The contents of vascular α-SMA were much lower in the SCS group as compared to normal blood vessels. CONCLUSIONS: NMP caused lesser muscle damage and contained more vascular α-SMA as compared to SCS. This study demonstrated that NMP of the amputated limb with perfusate solution based on autologous blood could maintain the physiological activities of the limb for at least 24 h.

[Effect of Lemiancao on Insomnia in Patients With Depressive Disorder].

Objective To investigate the effect of Lemiancao on insomnia in the patients with depressive disorder. Methods Totally 79 patients diagnosed with both insomnia and depressive disorder from February to August in 2022 in Peking University Sixth Hospital were selected and classified into a control group(n=40) and a Lemiancao group(n=39).The Lemiancao group received routine nursing and medical treatment combined with Lemiancao training in the morning and evening every day,while the control group received routine nursing and medical treatment.The sleep status was evaluated based on the Pittsburgh sleep quality index(PSQI),insomnia severity index(ISI),and 36-item short-form health survey(SF-36) before and after treatment. Results The general information of patients showed no significant difference between the two groups(all P>0.05).After a 2-week intervention with Lemiancao training,the Lemiancao group showed lower PSQI and ISI scores and higher SF-36 score than the control group(all P<0.001). Conclusion Lemiancao training has therapeutic effects on insomnia in the patients with depressive disorder.

Electrical stimulation accelerates Wallerian degeneration and promotes nerve regeneration after sciatic nerve injury.

Following peripheral nerve injury (PNI), Wallerian degeneration (WD) in the distal stump can generate a microenvironment favorable for nerve regeneration. Brief low-frequency electrical stimulation (ES) is an effective treatment for PNI, but the mechanism underlying its effect on WD remains unclear. Therefore, we hypothesized that ES could enhance nerve regeneration by accelerating WD. To verify this hypothesis, we used a rat model of sciatic nerve transection and provided ES at the distal stump of the injured nerve. The injured nerve was then evaluated after 1, 4, 7, 14 and 21 days post injury (dpi). The results showed that ES significantly promoted the degeneration and clearance of axons and myelin, and the dedifferentiation of Schwann cells. It upregulated the expression of BDNF and NGF and increased the number of monocytes and macrophages. Through transcriptome sequencing, we systematically investigated the effect of ES on the molecular processes involved in WD at 4 dpi. Evaluation of nerves bridged using silicone tubing after transection showed that ES accelerated early axonal and vascular regeneration while delaying gastrocnemius atrophy. These results demonstrate that ES promotes nerve regeneration by accelerating WD and upregulating the expression of neurotrophic factors.

Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route.

The lymphatic system has received increasing scientific and clinical attention because a wide variety of diseases are linked to lymphatic pathologies and because the lymphatic system serves as an ideal conduit for drug delivery. Lymphatic vessels exert heterogeneous roles in different organs and vascular beds, and consequently, their dysfunction leads to distinct organ-specific outcomes. Although studies in animal model systems have led to the identification of crucial lymphatic genes with potential therapeutic benefit, effective lymphatic-targeted therapeutics are currently lacking for human lymphatic pathological conditions. Here, we focus on the therapeutic roles of lymphatic vessels in diseases and summarize the promising therapeutic targets for modulating lymphangiogenesis or lymphatic function in preclinical or clinical settings. We also discuss considerations for drug delivery or targeting of lymphatic vessels for treatment of lymphatic-related diseases. The lymphatic vasculature is rapidly emerging as a critical system for targeted modulation of its function and as a vehicle for innovative drug delivery.

Ecological impacts of unsustainable sand mining: urgent lessons learned from a critically endangered freshwater cetacean.

Sand mining, which has tripled in the last two decades, is an emerging concern for global biodiversity. However, the paucity of sand mining data worldwide prevents understanding the extent of sand mining impacts and how it affects wildlife populations and ecosystems, which is critical for timely mitigation and conservation actions. Integrating remote sensing and field surveys over 14 years, we investigated mining impacts on the critically endangered Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) in Dongting Lake, China. We found that sand mining presented a consistent, widespread disturbance in Dongting Lake. Porpoises strongly avoided mining sites, especially those of higher mining intensity. The extensive sand mining significantly contracted the porpoise's range and restricted their habitat use in the lake. Water traffic for sand transportation further blocked the species's river-lake movements, affecting the population connectivity. In addition, mining-induced loss of near-shore habitats, a critical foraging and nursery ground for the porpoise, occurred in nearly 70% of the water channels of our study region. Our findings provide the first empirical evidence of the impacts of unregulated sand extractions on species distribution. Our spatio-temporally explicit approach and findings support regulation and conservation, yielding broader implications for sustainable sand mining worldwide.

Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates nonalcoholic fatty liver disease by activating farnesoid X receptor.

BACKGROUND AND AIMS: Hydrogen sulfide (H2 S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H2 S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear. APPROACH AND RESULTS: We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high-fat diet (HFD)-induced NAFLD mice or an oleic acid-induced hepatocyte model, the CSE/H2 S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte-specific CSE knockout mouse (CSELKO ). Feeding an HFD to CSELKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSELoxp control mice. By contrast, H2 S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H2 S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro-ß-muricholic acid (FXR activation elevated) was reduced in CSELKO . CSE/H2 S promoted a post-translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H2 S modulation noted in the CSELKO mice. CONCLUSIONS: FXR sulfhydration is a post-translational modification affected by hepatic endogenous CSE/H2 S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H2 S and FXR may be amenable to therapeutic drug treatment in NAFLD.