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Wenchengia alternifolia C.Y. Wu & S. Chow (Lamiaceae), the sole species of the genus Wenchengia C.Y. Wu & S. Chow, is extremely rare and is currently listed as Critically Endangered (CR) on the IUCN Red List. The species had long been considered endemic to Hainan Island, China and was once believed to be extinct until a small remnant population was rediscovered at the type locality in 2010. Four more populations were later found on Hainan and in Vietnam. In order to develop genomic resources for further studies on population genetics and conservation biology of this rare species, we identified infraspecific molecular markers in the present study, using genome skimming data of five individuals collected from two populations on Hainan Island and three populations in Vietnam respectively. The length of plastome of the five individuals varied from 152,961 bp to 150,204 bp, and exhibited a typical angiosperm quadripartite structure. Six plastid hotspot regions with the Pi > 0.01 (trnH-psbA, psbA-trnK, rpl22, ndhE, ndhG-ndhI and rps15-ycf1), 1621 polymorphic gSSRs, as well as 1657 candidate SNPs in 237 variant nuclear genes were identified, thereby providing important information for further genetic studies.

Tissue engineering is an alternative method for preparing small-caliber (6 mm) vascular grafts. Dynamic mechanical conditioning is being researched as a method to improve mechanical properties of tissue engineered blood vessels. This method attempts to induce unique reaction in implanted cells that regenerate the matrix around them, thereby improving the overall mechanical stability of the grafts. In this study, we used a bioreactor to seed endothelial cells and smooth muscle cells into the inner and outer layers of the electrospun spider silk protein scaffold respectively to construct vascular grafts. The cell proliferation, mechanical properties, blood compatibility and other indicators of the vascular grafts were characterized in vitro. Furthermore, the vascular grafts were implanted in Sprague Dawley rats, and the vascular grafts' patency, extracellular matrix formation, and inflammatory response were evaluated in vivo. We aimed to construct spider silk protein vascular grafts with the potential for in vivo implantation by using a pulsating flow bioreactor. The results showed that, when compared with the static culture condition, the dynamic culture condition improved cell proliferation on vascular scaffolds and enhanced mechanical function of vascular scaffolds. In vivo experiments also showed that the dynamic culture of vascular grafts was more beneficial for the extracellular matrix deposition and anti-thrombogenesis, as well as reducing the inflammatory response of vascular grafts. In conclusion, dynamic mechanical conditioning aid in the resolution of challenges impeding the application of electrospun scaffolds and have the potential to construct small-caliber blood vessels with regenerative function for cardiovascular tissue repair.

Recycling of coal resources left behind in goaf and the treatment and utilization of solid waste from mines are one topical issues faced by the global coal mining industry at present. With the annual reduction of recoverable reserves of coal resources and the dependence on coal resources that are difficult to replace, the problems have become increasingly prominent, seriously limiting the development of coal resources and the implementation of environmental protection work. In order to effectively extract high-quality residual coal resources that have not been extracted due to historical reasons such as technological limitations, the method of filling the goaf area is usually used to control the roof strata and extract coal seams. The problem of spatiotemporal interference during the filling process and the mining stage, as well as the problem of the excess shear stiffness of the filling material meeting the roof support strength, which affects the operation of the coal machine during the mining stage, urgently needs to be solved. To this end, a resource filling and replacement method for residual coal mining in goaf was proposed, and the connotation and key scientific issues of the replacement method for room-pillar type residual coal mining were systematically elaborated. The requirements for the mechanical properties of mixed coal filling materials under the control conditions of roof rock layers were given. A large-scale on-site industrial control group grouting loose coal coagulation experiment and a laboratory coal block high water material mixed coagulation curing strength experiment were conducted, Analyzed the scientific problems faced by various links in the process of coal seam reshaping and replacement mining technology(CRRM), and further proposed improvement methods, improved the technical system of filling and replacing abandoned coal, and developed new directions for efficient and safe recovery of abandoned coal resources worldwide in the future.

In this study, based on a closed bomb test combined with computational fluid dynamics, a structural finite element method, and an acoustic boundary element method, a fluid-solid acoustic one-way coupling calculation model is established for the combustion process of energetic materials in a closed bomb, and the effectiveness of the model is verified by experiments. It is found that the maximum peak sound pressure increases exponentially with an increase in loading doses or gas pressure. However, a change in the combustion coefficient of the energetic materials has little effect on the noise generated during the combustion process in the closed bomb. When the combustion coefficient is reduced by a multiple of 16, the maximum transient sound pressure is reduced by 1.79 dB, and the sound pressure level in the frequency band is reduced by 1.75 dB. With an increase in shell thickness, the combustion noise of the energetic materials in the closed bomb decreases, and the reduction range of the combustion noise increases with the increase in shell thickness.

Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multistage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan–life cycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.

Objective Synovial abnormalities are modifiable targets for hand pain and osteoarthritis. We examined the prevalence and distribution of ultrasound-detected hand synovial abnormalities in a community-derived sample of older people in China. Methods Within the Xiangya Osteoarthritis Study, a community-based study, we assessed synovial hypertrophy (SH), joint effusion, and Power Doppler signal (PDS) on all fingers and thumbs of both hands using standardized ultrasound examinations (score: 0–3). We assessed distribution patterns of SH and effusion using χ2-test and interrelationships of SH and effusion in different joints and hands by generalized estimating equations. Results Among 3,623 participants (mean age: 64.4 years; women: 58.1%), prevalence of SH, effusion and PDS were 85.5%, 87.3% and 1.5%, respectively. Prevalence of SH, effusion and PDS increased with age, was higher in the right hand than in the left hand and was more common in proximal than in distal hand joints. SH and effusion often occurred in multiple joints (P < 0.001). SH in one joint was strongly associated with presence of SH in the same joint of the opposite hand (odds ratio [OR]= 6.60, 95% confidence interval [CI]: 6.19–7.03) followed by SH in other joints in the same row, (OR=5.70, 95%CI: 5.32–6.11), and then other joints in the same ray of the same hand (OR=1.49, 95%CI: 1.39–1.60). Similar patterns were observed for effusion. Conclusion Hand synovial abnormalities are common among older people, often affect multiple hand joints and present a unique pattern. These findings suggest both systemic and mechanical factors play roles in their occurrence.

The development of high-throughput sequencing technology has made it possible to develop molecular markers such as EST-SSR from transcriptome sequences in non-model plants such as bulbous flowers. However, the EST-SSR markers that have been developed are weakly validated and low polymorphic due to the short read size and poor quality of the assembled sequences. This study therefore used the CandiSSR pipeline to identify 550 potential polymorphic SSR loci among 487 homologous unigenes based on the transcriptomic sequences of three varieties of colored calla lily, and 460 of these loci with appropriate flanking sequences were suitable for primer pairs design. A further validation with 200 randomly selected EST-SSRs demonstrated an increase of more than 30% and 100% in amplification validity and polymorphism, respectively, in comparison with our previous study. In addition, since most of the current varieties of colored calla lily are hybridized from a few species, which have low genetic diversity, we subsequently identified primary core germplasm for 160 colored calla lily accessions using the aforementioned 40 polymorphic EST-SSRs. It was concluded that the core germplasm containing 42 accessions derived from the M strategy incorporated into the software Power Core was the most representative of all 160 original germplasm, as evidenced by the preservation of 100% of the EST-SSR variation, with a higher level of genetic diversity and heterogeneity (Nei = 0.40, I = 0.66, PIC = 0.43). This study provides a practical example of polymorphism EST-SSR markers developed from multiple transcriptomes for non-model plants. A future breeding program for colored calla lily will also benefit from the core germplasm defined by those molecular markers.

Anthocyanin production in apple (Malus domestica) fruit and their consequent coloration can be induced by high-light treatment. The hormone ethylene is also essential for this coloration, but the regulatory relationships that link ethylene and light with anthocyanin-associated coloration are not well defined. In this study, we observed that high-light treatment of apple fruit increased anthocyanin accumulation more than moderate-light treatment did and was the main contributor of induced ethylene production and activation of anthocyanin biosynthesis. A transcriptome study of light-treated apple fruit suggested that a long noncoding RNA (lncRNA), MdLNC610, the corresponding gene of which is physically located downstream from the 1-aminocyclopropane-1-carboxylate oxygenase (ACO) ethylene biosynthesis gene MdACO1, likely affects anthocyanin biosynthesis under high-light treatment. Expression and promoter β-glucuronidase reporter analyses further showed that MdLNC610 upregulates expression of MdACO1 and so likely participates in high-light-induced ethylene biosynthesis. Overexpression of MdACO1 and MdLNC610 in apple fruit and calli indicated that a major increase in MdLNC610 expression activates MdACO1 expression, thereby causing an increase in ethylene production and anthocyanin levels. These results suggest that MdLNC610 participates in the regulation of high-light-induced anthocyanin production by functioning as a positive regulator to promote MdACO1 expression and ethylene biosynthesis. Our study provides insights into the relationship between mRNA and lncRNA networks in the ethylene biosynthetic pathway and anthocyanin accumulation in apple fruit.

ObjectivesHand synovitis, a potentially modifiable pathological lesion, is common and associated with pain and hand OA; nevertheless, its pathogenesis remains uncertain. This study investigated the relationship between gut microbiota dysbiosis and hand synovitis prevalence and evaluated whether bile acids mediate the association.MethodsParticipants were derived from a community-based observational study. Synovitis in each hand joint was assessed using US. Gut microbiota was evaluated using 16S ribosomal RNA amplicon sequencing on faeces, and plasma bile acids were measured by HPLC mass spectrometry. We examined the relationship between gut microbiota dysbiosis and hand synovitis prevalence, as well as the extent to which bile acids were involved in the association.ResultsAmong 1336 participants (mean age: 63.2 years; women: 58.8%), 18.3% had prevalent hand synovitis (unilateral in 13.6% and bilateral in 4.7%). β-diversity, but not α-diversity, of gut microbiota was significantly associated with prevalent hand synovitis. Higher relative abundance of the genus Prevotella and lower relative abundance of the genus Blautia were significantly associated with the prevalence of hand synovitis. Similar associations were also observed for laterality and the number of joints affected by hand synovitis. The association between Prevotella and hand synovitis was partially mediated through its effect on tauroursodeoxycholic acid and glycoursodeoxycholic acid, the mediation proportions being 25.7% and 21.6%, respectively.ConclusionOur findings suggest that gut microbiota dysbiosis is associated with the prevalence of hand synovitis. Such an association appears to be partially mediated by plasma bile acids.

Aiming at the problem of noise during the operation of the pyrotechnic separation device, this paper uses LS-DYNA software to simulate the separation process of the separation nut. Then uses the LMS Virtual.Lab software to predict and analyse the mechanical impact noise during the separation, and quantitatively decoupling the contribution rate of the mechanical noise generated by the movement of each component. The results indicate that the inner sleeve impact is the main source of mechanical noise during the separation (more than 90 %).

Rockburst is globally regarded as one of the most severe and complicated mining dynamic disasters to predict or control. Generally, the occurrence mechanism of rockbursts can be considered as a process of the elastic strain energy accumulation, emancipation, transmission, and occurrence. Tracing to the source, the reasons for large accumulation of elastic strain energy in coal and rock mass are the high stress of the roof layer that loads on the coal and rock masses around the mining space coupling effect with the natural horizontal tectonic stress. In this study, using the minimum energy theory and elasticity theory, the analytical formula for calculating elastic strain energy of the roof cantilever beam structure acting on the coal body load in front of the working face is deduced. Accordingly, we achieved a method of using hydraulic fracturing to improve the roof structure. In detail, we use a high-pressure jet to cut the cantilever roof structure, which can make a prelocated fracture surface, and then utilize the packers to make sure that the injected high-pressure fracturing fluid is propagating along the prelocated fracture surface and can cut off the cantilever roof structure eventually to prevent rockbursts in advance. Due to the rockburst occurrence mechanism and the quantitatively elastic strain energy analytical formula, a preconditioning water jet cutting induced fracture surface to create orientation-controllable hydraulic fracture strategy is proposed to guard against the high hazard caused by the massive elastic strain energy, which accumulated in the coal body in front of the working face and coal pillar.

Phylogenomic studies based on plastid genome have resolved recalcitrant relationships among various plants, yet the phylogeny of Dennstaedtiaceae at the level of family and genera remains unresolved due to conflicting plastid genes, limited molecular data and incomplete taxon sampling of previous studies. The present study generated 30 new plastid genomes of Dennstaedtiaceae (9 genera, 29 species), which were combined with 42 publicly available plastid genomes (including 24 families, 27 genera, 42 species) to explore the evolution of Dennstaedtiaceae. In order to minimize the impact of systematic errors on the resolution of phylogenetic inference, we applied six strategies to generate 30 datasets based on CDS, intergenic spacers, and whole plastome, and two tree inference methods (maximum-likelihood, ML; and multispecies coalescent, MSC) to comprehensively analyze the plastome-scale data. Besides, the phylogenetic signal among all loci was quantified for controversial nodes using ML framework, and different topologies hypotheses among all datasets were tested. The species trees based on different datasets and methods revealed obvious conflicts at the base of the polypody ferns. The topology of the “CDS-codon-align-rm3” (CDS with the removal of the third codon) matrix was selected as the primary reference or summary tree. The final phylogenetic tree supported Dennstaedtiaceae as the sister group to eupolypods, and Dennstaedtioideae was divided into four clades with full support. This robust reconstructed phylogenetic backbone establishes a framework for future studies on Dennstaedtiaceae classification, evolution and diversification. The present study suggests considering plastid phylogenomic conflict when using plastid genomes. From our results, reducing saturated genes or sites can effectively mitigate tree conflicts for distantly related taxa. Moreover, phylogenetic trees based on amino acid sequences can be used as a comparison to verify the confidence of nucleotide-based trees.

Calla lily (

The MIKC

TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer's disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer's disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ

Post-stroke cognitive impairment (PSCI) is a common condition following ischemic stroke. Neuronal loss and white matter injury are among the most common neuropathological characteristics in patients with PSCI. The present study tested our hypothesis that activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) reduces neuronal loss, white matter injury, and neurobehavioral deficits in a mouse model of PSCI and investigated the underlying protective mechanisms.PSCI was modeled in wildtype (WT) and Nrf2 knockout (KO), male and female mice, by distal middle cerebral artery occlusion (dMCAO), with intraperitoneal injections of the Nrf2 activator sulforaphane (Sfn) or vehicle. Long-term (35 days) sensorimotor and cognitive performances, white matter integrity, oligodendrogenesis by BrdU incorporation, and neurite sprouting using anterograde tract-tracing were evaluated up to 35 days after dMCAO. Neuronal apoptosis was evaluated three days after dMCAO. In vitro, primary neuronal cultures were applied to validate the in vivo findings.Compared to vehicle-injected controls, Sfn treatment improved long-term sensorimotor and cognitive deficits after dMCAO in WT male and female mice. Sfn-treated WT mice also had less myelin loss/axonal injury and showed evidence of Nrf2 activation. Sfn treatment failed to provide the same level of protection in Nrf2 KO mice. Mechanistically, the ability of Sfn to reduce neuronal death after ischemia in vitro and in vivo, augment axonal sprouting and enhance oligodendrogenesis after dMCAO was dependent on Nrf2 activation.Our results support that Nrf2 is critical for Sfn-afforded neuroprotection after ischemic stroke. Thus, targeting Nrf2 may be a promising strategy for the treatment of PSCI.

Anthocyanins are plant pigments with diverse biological functions that contribute to fruit quality and are beneficial to human health. Anthocyanin accumulation can be influenced by environmental signals, such as light, and plants have developed sophisticated systems to receive and transduce these signals. However, the associated molecular mechanisms are not well understood. In this study, we investigated the potential function of mitogen-activated protein kinases, which are members of the light signaling pathway, during light-induced anthocyanin accumulation in apple (Malus domestica) fruit peels. An antibody array and yeast two-hybrid screen indicated that proteins encoded by two MdMPK4 genes are light-activated and interact with the transcription factor and anthocyanin biosynthesis regulator MdMYB1. A phosphorylation assay showed that the MdMPK4 proteins phosphorylate MdMYB1, thereby increasing its stability under light conditions. Transient MdMPK4 and MdMYB1 overexpression assays further revealed that light-induced anthocyanin accumulation relies on MdMPK4 kinase activity, which is required for maximum MdMYB1 activity. Based on the expression of the chromosome 6 allele MdMPK4-06G under light conditions and the presence of light response elements in the MdMPK4-06G promoter, we concluded that it is more responsive to light than the chromosome 14 allele MdMPK4-14G. These results suggest a potential biotechnological strategy for increasing fruit anthocyanin content via light induction.

BackgroundSeveral studies have examined gut microbiota and sarcopenia using 16S ribosomal RNA amplicon sequencing; however, this technique may not be able to identify altered specific species and functional capacities of the microbes. We performed shotgun metagenomic sequencing to compare the gut microbiome composition and function between individuals with and without sarcopenia.MethodsParticipants were from a community-based observational study conducted among the residents of rural areas in China. Appendicular skeletal muscle mass was assessed using direct segmental multi-frequency bioelectrical impedance and grip strength using a Jamar Hydraulic Hand dynamometer. Physical performance was evaluated using the Short Physical Performance Battery, 5-time chair stand test and gait speed with the 6m walk test. Sarcopenia and its severity were diagnosed according to the Asian Working Group for Sarcopenia 2019 algorithm. The gut microbiome was profiled by shotgun metagenomic sequencing to determine the microbial composition and function. A gut microbiota-based model for classification of sarcopenia was constructed using the random forest model, and its performance was assessed using the area under receiver-operating characteristic curve (AUC).ResultsThe study sample included 1417 participants (women: 58.9%; mean age: 63.3years; sarcopenia prevalence: 10.0%). β-diversity indicated by Bray-Curtis distance (genetic level: P=0.004; taxonomic level of species: P=0.020), but not α-diversity indicated by Shannon index (genetic level: P=0.962; taxonomic level of species: P=0.922), was significantly associated with prevalent sarcopenia. After adjusting for potential confounders, participants with sarcopenia had higher relative abundance of Desulfovibrio piger (P=0.003, Q=0.090), Clostridium symbiosum (P&nbsp

Although extant lycophytes represent the most ancient surviving lineage of early vascular plants, their plastomic diversity has long been neglected. The ancient evolutionary history and distinct genetic diversity patterns of the three lycophyte families, each with its own characteristics, provide an ideal opportunity to investigate the interfamilial relationships of lycophytes and their associated patterns of evolution. To compensate for the lack of data on Lycopodiaceae, we sequenced and assembled 14 new plastid genomes (plastomes). Combined with other lycophyte plastomes available online, we reconstructed the phylogenetic relationships of the extant lycophytes based on 93 plastomes. We analyzed, traced, and compared the plastomic diversity and divergence of the three lycophyte families (Isoëtaceae, Lycopodiaceae, and Selaginellaceae) in terms of plastomic diversity by comparing their plastome sizes, GC contents, substitution rates, structural rearrangements, divergence times, ancestral states, RNA editings, and gene losses. Comparative analysis of plastid phylogenomics and plastomic diversity of three lycophyte families will set a foundation for further studies in biology and evolution in lycophytes and therefore in vascular plants.

Current best practice for the treatment of malaria relies on short half-life artemisinins that are failing against emerging Kelch 13 mutant parasite strains. Here, we introduce a liposome-like self-assembly of a dimeric artesunate glycerophosphocholine conjugate (dAPC-S) as an amphiphilic prodrug for the short-lived antimalarial drug, dihydroartemisinin (DHA), with enhanced killing of Kelch 13 mutant artemisinin-resistant parasites. Cryo-electron microscopy (cryoEM) images and the dynamic light scattering (DLS) technique show that dAPC-S typically exhibits a multilamellar liposomal structure with a size distribution similar to that of the liposomes generated using thin-film dispersion (dAPC-L). Liquid chromatography-mass spectrometry (LCMS) was used to monitor the release of DHA. Sustainable release of DHA from dAPC-S and dAPC-L assemblies increased the effective dose and thus efficacy against Kelch 13 mutant artemisinin-resistant parasites in an in vitro assay. To better understand the enhanced killing effect, we investigated processes for deactivation of both the assemblies and DHA, including the roles of serum components and trace levels of iron. Analysis of parasite proteostasis pathways revealed that dAPC assemblies exert their activity via the same mechanism as DHA. We conclude that this easily prepared multilamellar liposome-like dAPC-S with long-acting efficacy shows potential for the treatment of severe and artemisinin-resistant malaria.

Liliaceae, distributed mainly across the temperate Northern Hemisphere, are of great horticultural, culinary and medical importance, but are also a family with a long history of taxonomic uncertainty. Challenges in accurate species identification persist and phylogenetic relationships among genera in the family continue to be unresolved and/or weakly supported due to the use of limited molecular markers with insufficient variability. Here, nine newly sequenced plastomes for nine Liliaceae genera have been combined with previously published plastome data for this family, providing a total of 86 complete plastid genome sequences covering all 15 currently recognized genera for analyses. All these plastid genomes (146.9–158.3 kb) possess the typical quadripartite structure with conserved genome arrangement and content. Phylogenomic analyses strongly confirm the recognition of four subfamilies: Tricyrtidoideae with four genera; Medeoloideae with two genera; Lilioideae with eight genera and Calochortoideae, for Calochortus alone, as sister to Medeoloideae and Lilioideae. At least ten intergenic spacer regions that may serve as universal markers were identified in the family and, on a finer scale, nine and seven intergenic spacer regions are especially variable in Lilium and Fritillaria, respectively. The intergenic spacer regions rpoB-trnC, trnS-trnG, trnT-psbD and trnT-trnL, which showed high phylogenetic effectiveness, may be the best choices for future phylogenetic, phylogeographic and population genetic studies.

In this work, a simple dielectric metasurface hologram is proposed and designed by combining the electromagnetic vector analysis method and the immune algorithm, which can realize the holographic display of dual wavelength orthogonal-linear polarization light in visible light band, solve the problem of low efficiency of the traditional design method of metasurface hologram, and effectively improve the diffraction efficiency of metasurface hologram. The titanium dioxide metasurface nanorod based on rectangular structure is optimized and designed. When the x-linear polarized light with wavelength of 532 nm and y-linear polarized light with wavelength of 633 nm are incident on the metasurface respectively, different display output images with low cross-talk can be obtained on the same observation plane, and the transmission efficiencies of x-linear and y-linear polarized light are as high as 68.2% and 74.6% respectively in simulation. Then the metasurface is fabricated by Atomic Layer Deposition method. The experimental results are consistent with the design results, which proves that the metasurface hologram designed by this method can completely realize the feasibility of wavelength and polarization multiplexing holographic display, and has potential application value in holographic display, optical encryption, anti-counterfeiting, data storage and other fields.

Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop therapies that can mitigate brain inflammation and improve the outcome after TBI. This study investigated the transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and brain inflammation burden after TBI. Such phenotype-modulating effects of fludarabine on post-TBI Mi/MΦ were reproduced by tamoxifen-induced, selective KO of STAT1 in Mi/MΦ (STAT1 mKO). By propelling Mi/MΦ away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neurologic deficits and brain lesion size after TBI. Importantly, short-term fludarabine treatment after TBI elicited long-lasting improvement of TBI outcomes, but this effect was lost on STAT1 mKO mice. Together, our study provided the first line of evidence that STAT1 causatively determines the proinflammatory phenotype of brain Mi/MΦ after TBI. We also showed promising preclinical data supporting the use of fludarabine as a novel immunomodulating therapy to TBI. SIGNIFICANCE STATEMENT The functional phenotype of microglia and macrophages (Mi/MΦ) critically influences brain inflammation and the outcome after traumatic brain injury (TBI); however, no therapies have been developed to modulate Mi/MΦ functions to treat TBI. Here we report, for the first time, that the transcription factor STAT1 is a key mediator of proinflammatory Mi/MΦ responses in the post-TBI brain, the specific deletion of which ameliorates neuroinflammation and improves long-term functional recovery after TBI. We also show excellent efficacy of a selective STAT1 inhibitor fludarabine against TBI-induced functional deficits and brain injury using a mouse model, presenting STAT1 as a promising therapeutic target for TBI.

Selenium plays an indispensable role in antioxidant and antiinflammation processes. Oxidative stress and inflammation have been hypothesized to be involved in the pathogenesis of cartilage degeneration. We sought to examine the association between plasma selenium levels and the prevalence of radiographic osteoarthritis (ROA).A population-based cross-sectional study.Individuals aged ≥ 50 years were retrieved from the Xiangya Osteoarthritis (XO) Study, a community-based study conducted among the residents of the rural areas of China.Plasma selenium concentration was measured by inductively coupled plasma-dynamic reaction cell-mass spectrometry. ROA was defined as Kellgren/Lawrence score ≥ 2 in at least one knee, hip or hand joint. The association between plasma selenium levels and ROA was evaluated by applying logistic and spline regression.A total of 1,032 subjects (women: 52.5%; mean age: 63.1 years; ROA prevalence: 45.4%) were included. Compared with the highest tertile, the odds ratios (ORs) for ROA were 1.24 (95% confidence interval [CI]: 0.91 to 1.68) and 1.77 (95% CI: 1.31 to 2.40) in the middle and lowest tertile of plasma selenium, respectively (P for trend0.05). The results were not changed materially with adjustment of potential confounders. In addition, subjects who had lower plasma selenium levels exhibited a higher prevalence of ROA in a dose-response relationship manner (P=0.005).This study suggests that subjects with lower levels of plasma selenium exhibited a higher prevalence of ROA in a dose-response relationship manner. However, additional studies are still needed to verify the potential causal relationship.

After spinal cord injury (SCI), the irreversible loss of neurons and the dense glial scar are two of the leading causes of axon regeneration failure. The adult mammalian spinal cord lacks the ability to spontaneously produce new neurons, making it a key challenge to provide new neurons for spinal cord regeneration. Additionally, the dual role of the glial scar (both inhibitory and protective) makes it difficult to manipulate it for therapeutic purposes. In this study, using a single transcription factor Sry-related HMG-box 2 (Sox2) delivered by adeno-associated virus (AAV), we reprogrammed some of the astrocytes targeted by the viral vectors in the glial scar into neurons in a severe SCI model. We show that this astrocytic reprogramming alone can propel axon regeneration by not only replenishing the lost neurons, but also moderately reducing the density of the glial scar without interrupting its integrity. Beyond that, astrocytic reprogramming can significantly improve functional recovery when combined with running wheel rehabilitation, which provides use-dependent plasticity. These findings may provide us with a new idea for how to manipulate the glial scar and a promising therapeutic strategy that combines biological intervention with a rehabilitation strategy.

To assess the serum iron and ferritin levels in relation to the prevalence of hyperuricemia (HU) and the serum uric acid (SUA) level.Serum iron and ferritin concentrations were detected by Ferene method and chemiluminescence method, respectively. SUA level was detected by uricase-PAP method. HU was defined as SUA ≥ 416 μmol/L for male and ≥ 357 μmol/L for female. Multivariable-adjusted logistic regressions were constructed to investigate the associations between serum iron/ferritin levels and prevalence of HU. Pearson correlation analysis and multivariable linear regression were performed to examine the correlations between serum iron/ferritin levels and SUA level.A total of 2824 subjects (mean age 52.2 ± 7.2) were included. The overall prevalence of HU was 17.3%. Compared with the lowest quartile, the multivariable-adjusted odds ratios (OR) and its 95% confidence interval (CI) of HU were 1.33 (95%CI 0.97-1.82), 1.17 (95%CI 0.85-1.60), and 1.56 (95%CI 1.14-2.13) in the second, third, and fourth quartiles of serum iron, respectively (P for trend = 0.012), and were 1.29 (95%CI 0.89-1.88) in the second, 2.13 (95%CI 1.47-3.07) in the third, and 2.25 (95%CI 1.54-3.29) in the fourth quartile of serum ferritin (P for trend 0.001). Pearson correlation coefficient indicated a weak positive correlation between serum iron (r = 0.2, P 0.001) and ferritin (r = 0.3, P 0.001) levels and SUA. Such positive correlations were further confirmed by multiple linear regression (serum iron: standardized β = 0.059, P 0.001; serum ferritin: standardized β = 0.061, P = 0.001).Both serum iron and ferritin showed a positive correlation with the prevalence of HU, and a weak positive correlation with SUA level. Key Points • Subjects with higher levels of serum iron or ferritin had higher prevalence of HU. • There was a weak positive correlation between serum iron/ferritin levels and SUA level.

Acute ischemic stroke is a leading cause of death and disability worldwide. Therapeutic hypothermia has long been considered as one of the most robust neuroprotective strategies. Although the neuroprotective effects of hypothermia have only been confirmed in patients with global cerebral ischemia after cardiac arrest and in neonatal hypoxic ischemic encephalopathy, establishing standardized protocols and strictly controlling the key parameters may extend its application in other brain injuries, such as acute ischemic stroke. In this review, we discuss the potential neuroprotective effects of hypothermia, its drawbacks evidenced in previous studies, and its potential clinical application for acute ischemic stroke especially in the era of reperfusion. Based on the different conditions between bench and bedside settings, we demonstrate the importance of vascular recanalization for neuroprotection of hypothermia by analyzing numerous literatures regarding hypothermia in focal cerebral ischemia. Then, we make a thorough analysis of key parameters of hypothermia and introduce novel hypothermic therapies. We advocate in favor of the process of clinical translation of intra-arterial selective cooling infusion in the era of reperfusion and provide insights into the prospects of hypothermia in acute ischemic stroke.

In plants, parasitism triggers the reductive evolution of plastid genomes (plastomes). To disentangle the molecular evolutionary associations between feeding on other plants below- or aboveground and general transitions from facultative to obligate parasitism, we analyzed 34 complete plastomes of autotrophic, root- and stem-feeding hemiparasitic, and holoparasitic Santalales. We observed inexplicable losses of housekeeping genes and tRNAs in hemiparasites and dramatic genomic reconfiguration in holoparasitic Balanophoraceae, whose plastomes have exceptionally low GC contents. Genomic changes are related primarily to the evolution of hemi- or holoparasitism, whereas the transition from a root- to a stem-feeding mode plays no major role. In contrast, the rate of molecular evolution accelerates in a stepwise manner from autotrophs to root- and then stem-feeding parasites. Already the ancestral transition to root-parasitism coincides with a relaxation of selection in plastomes. Another significant selectional shift in plastid genes occurs as stem-feeders evolve, suggesting that this derived form coincides with trophic specialization despite the retention of photosynthetic capacity. Parasitic Santalales fill a gap in our understanding of parasitism-associated plastome degeneration. We reveal that lifestyle-genome associations unfold interdependently over trophic specialization and feeding mode transitions, where holoparasitic Balanophoraceae provide a system for exploring the functional realms of plastomes.

Alzheimer's disease (AD) is a neurodegenerative disease caused by lipid peroxidation and iron hemostasis of the brain. PPAR-α is regarded as the most encouraging therapeutic approach of several neurodegenerative and metabolic disorders, due to its potent regulatory effects. In this study, we examined the ameliorative effect and the mechanisms of a PPAR-α agonist, GW7647, on the established AD models using APP/PS1 mice and APPsw/SH-SY5Y cells. Through Aβ quantification and behavioral test, we found that GW7647 reduced Aβ burden and improved cognitive defect in APP/PS1 mice. Liquid chromatography-mass spectrometry analysis indicated that GW7647 could enter the brain after oral administration. Neuronal cell death and iron deposit were inhibited, accompanied by decreased lipid peroxidation and inflammation. In an in vitro study of APPsw cells, we found that PPAR-α directly bound with GPx4 intron3 to promote GPx4 transcription and reduced the iron transport capability. Our data suggested that activation of PPAR-α by GW7647 improved the disruption of iron homeostasis in the brain of APP/PS1 mice and alleviated neuronal inflammation and lipid peroxidation, which was possibly related to the upregulated transcription of GPx4 mediated by the interaction of GPx4 noncoding region and the PPAR-α.

Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that CD8+CD122+CD49dlo T regulatory-like cells (CD8+ TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by CD8+ TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for CD8+ TRLs. Upon brain entry, CD8+ TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor-like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in CD8+ TRLs. While IL-10 induction was important for the antiinflammatory effects of CD8+ TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of CD8+ TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique CD8+ TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.

Objective. Brachial plexus injuries (BPIs) result in serious dysfunction, especially brachial plexus defects which are currently treated using autologous nerve graft (autograft) transplantation. With the development of tissue engineering, tissue engineered nerve grafts (TENGs) have emerged as promising alternatives to autografts but have not yet been widely applied to the treatment of BPIs. Herein, we developed a TENG modified with extracellular matrix generated by skin-derived precursor Schwann cells (SKP-SCs) and expand its application in upper brachial plexus defects in rats. Approach. SKP-SCs were co-cultured with chitosan neural conduits or silk fibres and subjected to decellularization treatment. Ten bundles of silk fibres (five fibres per bundle) were placed into a conduit to obtain the TENG, which was used to bridge an 8 mm gap in the upper brachial plexus. The efficacy of this treatment was examined for TENG-, autograft- and scaffold-treated groups at several times after surgery using immunochemical staining, behavioural tests, electrophysiological measurements, and electron microscopy. Main results. Histological analysis conducted two weeks after surgery showed that compared to scaffold bridging, TENG treatment enhanced the growth of regenerating axons. Behavioural tests conducted four weeks after surgery showed that TENG-treated rats performed similarly to autograft-treated ones, with a significant improvement observed in both cases compared with the scaffold treatment group. Electrophysiological and retrograde tracing characterizations revealed that the target muscles were reinnervated in both TENG and autograft groups, while transmission electron microscopy and immunohistochemical staining showed the occurrence of the superior myelination of regenerated axons in these groups. Significance. Treatment with the developed TENG allows the effective bridging of proximal nerve defects in the upper extremities, and the obtained results provide a theoretical basis for clinical transformation to expand the application scope of TENGs.

Grading individual knee osteoarthritis (OA) features is a fine-grained knee OA severity assessment. Existing methods ignore following problems: (1) more accurately located knee joints benefit subsequent grades prediction; (2) they do not consider knee joints’ symmetry and semantic information, which help to improve grades prediction performance. To this end, we propose a SE-ResNext50-32x4d-based Siamese network with adaptive gated feature fusion method to simultaneously assess eight tasks. In our method, two cascaded small convolution neural networks are designed to locate more accurate knee joints. Detected knee joints are further cropped and split into left and right patches via their symmetry, which are fed into SE-ResNext50-32x4d-based Siamese network with shared weights, extracting more detailed knee features. The adaptive gated feature fusion method is used to capture richer semantic information for better feature representation here. Meanwhile, knee OA/non-knee OA classification task is added, which helps extract richer features. We specially introduce a new evaluation metric (top±1 accuracy) aiming to measure model performance with ambiguous data labels. Our model is evaluated on two public datasets: OAI and MOST datasets, achieving the state-of-the-art results comparing to competing approaches. It has the potential to be a tool to assist clinical decision making.

Knee osteoarthritis (OA) is a common musculoskeletal illness. To solve the problem that inaccurate knee joint localization and inadequate knee OA features extracted from plain radiographs affect the accuracy of knee OA diagnosis in X-rays, we propose a novel Two-Stage Convolutional Neural Network (TS-CNN) method, consisting of the KneeDetnet and the KLnet. The KneeDetnet with two small multi-task convolutional neural networks is proposed to locate knee joints, improving the accuracy of knee joint localization. Then KLnet is designed to assess knee OA, where a shared Siamese network via ResNet is used to extract more discriminative deep learning features that are fused with gender information for obtaining richer features. Our method is evaluated on public OAI and MOST datasets. The highest detection accuracy of knee joints can reach 99.93% and 99.02% on two datasets, respectively. The KLnet algorithm achieves 78.85% and 68.20% prediction accuracy on the OAI and MOST datasets, respectively. Experimental results show that our method outperforms the existing workhorse. The proposed approach may become a potentially useful tool for assisting physicians.

Background There is paucity of data on the prevalence of ultrasound-detected synovial abnormalities in the general population, and the relationship between synovial changes and knee pain remains unclear. We examined the prevalence of synovial abnormalities on ultrasound and the relationship of these features with knee pain and radiographic osteoarthritis (ROA) in a community sample. Methods Participants aged 50 years or over were from the Xiangya Osteoarthritis Study, a community-based cohort study. Participants were questioned about chronic knee pain and underwent (1) ultrasonography of both knees to determine presence of synovial hypertrophy (≥ 4 mm), effusion (≥ 4 mm), and Power Doppler signal [PDS; yes/no]; and (2) standard radiographs of both knees (tibiofemoral and patellofemoral views) to determine ROA. Results There were 3755 participants (mean age 64.4 years; women 57.4%). The prevalence of synovial hypertrophy, effusion, and PDS were 18.1% (men 20.2%; women 16.5%), 46.6% (men 49.9%; women 44.2%), and 4.9% (men 4.9%; women 5.0%), respectively, and increased with age (P for trend P for interaction were 0.004 and 0.067, respectively. Conclusions Knee synovial hypertrophy and effusion are more common and increase with age, affecting men more than women. All three ultrasound-detected synovial abnormalities associate both with knee pain and ROA, and knee synovial hypertrophy or effusion and ROA may interact to increase the risk of knee pain.

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder with slow onset in most cases. Clinically, dementia associated with AD is characterized by memory disorders, aphasia, executive dysfunction and personality and behavior changes. Currently, treatment strategies attempt to reduce certain symptoms, however there is no cure for AD. The aim of the present study was to identify a novel treatment strategy for AD. Thus, the protective effects of a κ‑opioid receptor (KOR) agonist, U50488H on neural damage in AD mice were investigated. The underlying mechanism of the Ca2+/calcium/calmodulin‑dependent protein kinase II/cyclic adenosine monophosphate‑response element binding protein (Ca2+/CaMKII/CREB) signaling pathway was evaluated. Amyloid precursor protein (APP)/presenilin‑1 (PS1) mice were treated subcutaneously with a KOR agonist for 28 days. The learning and memory abilities of the APP/PS1 mice were evaluated using the Morris water maze test. Damage to hippocampal neurons was assessed using hematoxylin and eosin staining. Inflammatory factors and brain injury markers were detected using ELISA. Neurons were examined using immunofluorescence and dendritic spines were observed using Golgi‑Cox staining. Western blotting was used to detect NOD‑, LRR‑ and pyrin domain‑containing protein 3, microglial ptosis and the Ca2+/CaMKII/CREB‑related protein pathway. The KOR agonist significantly improved the brain injury observed in APP/PS1 mice, inhibited microglia pyroptosis and improved the synaptic plasticity of APP/PS1 mice, which was reversed by a KOR antagonist. Thus, the KOR agonist improved the symptoms of APP/PS1 mice by inhibiting the Ca2+/CaMKII/CREB signaling pathway.

The activity of the proteasome 20S catalytic core is regulated by protein complexes that bind to one or both ends. The PA28 regulator stimulates 20S proteasome peptidase activity in vitro, but its role in vivo remains unclear. Here, we show that genetic deletion of the PA28 regulator from Plasmodium falciparum (Pf) renders malaria parasites more sensitive to the antimalarial drug dihydroartemisinin, indicating that PA28 may play a role in protection against proteotoxic stress. The crystal structure of PfPA28 reveals a bell-shaped molecule with an inner pore that has a strong segregation of charges. Small-angle X-ray scattering shows that disordered loops, which are not resolved in the crystal structure, extend from the PfPA28 heptamer and surround the pore. Using single particle cryo-electron microscopy, we solved the structure of Pf20S in complex with one and two regulatory PfPA28 caps at resolutions of 3.9 and 3.8 A, respectively. PfPA28 binds Pf20S asymmetrically, strongly engaging subunits on only one side of the core. PfPA28 undergoes rigid body motions relative to Pf20S. Molecular dynamics simulations support conformational flexibility and a leaky interface. We propose lateral transfer of short peptides through the dynamic interface as a mechanism facilitating the release of proteasome degradation products. Small-angle X-ray scattering and crystal structures of the PA28 proteasome regulator from Plasmodium falciparum, combined with cryo-electron microscopy structures of the 20S proteasome in complex with these regulatory PA28 proteins and molecular dynamics simulations, elucidate the regulatory mechanisms of parasite proteasome degradation.

AIM To systematically examine the existing literature on the associations between chondrocalcinosis (CC) and osteoarthritis (OA) at different joints, and to quantify such associations through meta-analysis. METHODS PubMed, Embase and Scopus databases were searched through from inception to June 2017. Cohort, case-control or cross-sectional studies were included if they examined the association between CC and OA. Data on the odds ratios (OR) and their 95% confidence intervals (CI) of the prevalence or progression of OA between the CC group and non-CC group with respect to the same joint were extracted. RESULTS A total of 14 studies were identified. Twelve studies were eligible for assessing the association between knee CC and knee OA. The combined data showed a positive association between them (OR = 2.84; 95% CI, 2.12-3.81; P

Peripheral nerve injuries (PNIs) often result in persistent neuropathic pain, seriously affecting quality of life. Existing therapeutic interventions for PNI-induced neuropathic pain are far from satisfactory. Extracellular signal-regulated kinases (ERKs) and p38 have been found to participate in triggering and maintaining PNI-induced neuropathic pain. However, ERK and p38 also contribute to axonal regeneration and motor function recovery after PNI, making it difficult to inhibit ERK and p38 for therapeutic purposes. In this study, we simultaneously characterized neuropathic pain and motor function recovery in a mouse sciatic nerve crush injury model to identify the time window for therapeutic interventions. We further demonstrated that delayed delivery of a combination of ERK and p38 inhibitors at three weeks after PNI could significantly alleviate PNI-induced neuropathic pain without affecting motor function recovery. Additionally, the combined use of these two inhibitors could suppress pain markedly better than either inhibitor alone, possibly reducing the required dose of each inhibitor and alleviating the side effects and risks of the inhibitors when used individually.

Background: Circadian clock plays a critical role in synchronizing the inner molecular, metabolic and physiological processes to the environmental cues which cycle with a period of 24 h. Misalignment in the circadian rhythms leads to decrease in adaptation, performance and increased risk of associated disorders. The non-24-h schedules and shift schedules are commonly used in maritime operations, both of which could result in disturbance in circadian rhythms. The comprehensive effects of these schedules remain to be further elucidated.Methods: In this study, we firstly conducted an experiment in which the volunteers followed a 3-d rotary schedule with consecutive shift in sleep time (rotatory schedule), and analyzed the changes in salivary cortisol rhythms and blood variables. Next we conducted another experiment in which the volunteers followed an 8 h on and 4 h off schedule (non-24-h schedule) to compare the changes in blood/serum variables. Furthermore, the plasma miRNAs from the volunteers following the rotatory schedule were subject for miRNA sequencing. Results: The rotatory schedule led to elevated levels of serum cortisol during the early stage, and the phase became delayed during the early and stages. The results show both of the schedules caused comprehensive changes in blood/serum biochemical variable, and consistently, the increase in phosphate levels. In addition, a subset of serum miRNAs targeting genes involved in circadian rhythms, sleep homeostasis and multiple important physiological processes or pathways were identified in the experiment with rotatory schedule.Conclusions: This study revealed an increased stress during the rotatory schedule. Circadian misalignment caused by either non-24-h or rotatory schedule lead to extensive changes in blood/serum variables. As to the rotatory schedule, altered expression of serum miRNAs may account for the consequences of circadian misalignment. These findings would help understand the deleterious effects of shift schedules and optimize to enhance performance and welfare of the personnel working with similar schedules.

The Malaria Drug Accelerator (MalDA) is a consortium of 15 leading scientific laboratories. The aim of MalDA is to improve and accelerate the early antimalarial drug discovery process by identifying new, essential, druggable targets. In addition, it seeks to produce early lead inhibitors that may be advanced into drug candidates suitable for preclinical development and subsequent clinical testing in humans. By sharing resources, including expertise, knowledge, materials, and reagents, the consortium strives to eliminate the structural barriers often encountered in the drug discovery process. Here we discuss the mission of the consortium and its scientific achievements, including the identification of new chemically and biologically validated targets, as well as future scientific directions.

IntroductionBone health affects the ability of human body to stay active, and its degradation can cause considerable morbidity and mortality. The factors related to bone health play an important role in preventing osteoporosis and its adverse consequences. However, the risk factors for osteoporosis have not been fully elucidated. Deficiency in the trace element selenium may be one of the risk factors for the development of osteoporosis. Previous studies have investigated the effects of selenium on osteoporosis; however, the results are inconclusive. Therefore, the present study aimed to systematically examine the existing literature on the associations between dietary or serum selenium and bone mineral density (BMD), osteoporosis or osteoporotic fractures, and to quantify such associations through meta-analysis.Methods and analysisPubMed, Embase and Cochrane Library will be searched using a specified search strategy to identify relevant studies up to October 2019. Both interventional and observational studies in humans will be included. The outcomes will include BMD and the prevalence or incidence of osteoporosis and osteoporotic fractures. For dietary or serum selenium and BMD, osteoporosis or osteoporotic fractures pooled analyses, estimates will be expressed as the mean difference, and the pooled OR, relative risk, HR or beta coefficient, and corresponding 95% CIs. Heterogeneity of the studies and publication bias will be investigated accordingly. To assess the quality and the risk of bias of the included studies, the Newcastle-Ottawa Quality Scale or the Cochrane risk of bias assessment tool will be used where appropriate.Ethics and disseminationSince no private and confidential patient data will be included in the reporting, approval from an ethics committee is not required. The results will be published in a peer-reviewed journal. The study raises no ethical issues.PROSPERO registration numberCRD42019147188.

Anthocyanin pigments contribute to plant coloration and are valuable sources of antioxidants in the human diet as components of fruits and vegetables. Their production is known to be induced by light in apple fruit (Malus domestica); however, the underlying molecular mechanism responsible for early-stage light-induced anthocyanin biosynthesis remains unclear. Here, we identified an ethylene response factor (ERF) protein, ERF109, involved in light-induced anthocyanin biosynthesis and found that it promotes coloration by directly binding to anthocyanin-related gene promoters. Promoter::β-glucuronidase reporter analysis and Hi-C sequencing showed that a long noncoding RNA, MdLNC499, located nearby MdERF109, induces the expression of MdERF109. A W-box cis-element in the MdLNC499 promoter was found to be regulated by a transcription factor, MdWRKY1. Transient expression in apple fruit and stable transformation of apple calli allowed us to reconstruct a MdWRKY1–MdLNC499–MdERF109 transcriptional cascade in which MdWRKY1 is activated by light to increase the transcription of MdLNC499, which in turn induces MdERF109. The MdERF109 protein induces the expression of anthocyanin-related genes and the accumulation of anthocyanins in the early stages of apple coloration. Our results provide a platform for better understanding the various regulatory mechanisms involved in light-induced apple fruit coloration.