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[This corrects the article DOI: 10.3389/fcell.2023.1218807.].

Background & aimsBreast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT).MethodsUsing Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation.ResultsOur results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils.ConclusionsThese data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10 weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Abstract The color of red-skinned pear (Pyrus spp.) is primarily attributed to accumulation of anthocyanins, which provide nutritional benefits for human health and are closely associated with the commercial value of fruits. Here, we reported the functional characterization of a R2R3-MYB repressor PyMYB107, which forms an ‘activator-repressor’ loop to control anthocyanin accumulation in the red-skinned pear. PyMYB107 overexpression inhibited anthocyanin biosynthesis in both pear calli and fruits, while virus-induced gene silencing of PyMYB107 increased anthocyanin accumulation in pear fruits. Furthermore, ectopic expression of PyMYB107 decreased anthocyanin accumulation in tomato, strawberry and tobacco. PyMYB107 can competitively bind to PybHLH3 with PyMYB10/MYB114, thereby suppressing the transcriptional activation of key anthocyanin biosynthesis genes, PyANS and PyUFGT. Site-directed mutagenesis showed that mutations within the R3 domain and EAR motif of PyMYB107 eliminated its repressive activity. Additionally, PyMYB107 exhibited a comparable expression pattern to PyMYB10/MYB114 and was transcriptionally activated by them. Our finding advanced comprehension of the repression mechanism underlying anthocyanin accumulation, providing valuable molecular insights into improving quality of pear fruits.

In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.

Abstract The mechanisms underlying the organization and evolution of the telencephalic pallium are not yet clear.. To address this issue, we first performed comparative analysis of genes critical for the development of the pallium (Emx1/2 and Pax6) and subpallium (Dlx2 and Nkx1/2) among 500 vertebrate species. We found that these genes have no obvious variations in chromosomal duplication/loss, gene locus synteny or Darwinian selection. However, there is an additional fragment of approximately 20 amino acids in mammalian Emx1 and a poly-(Ala)6–7 in Emx2. Lentiviruses expressing mouse or chick Emx2 (m-Emx2 or c-Emx2 Lv) were injected into the ventricle of the chick telencephalon at embryonic Day 3 (E3), and the embryos were allowed to develop to E12–14 or to posthatchling. After transfection with m-Emx2 Lv, the cells expressing Reelin, Vimentin or GABA increased, and neurogenesis of calbindin cells changed towards the mammalian inside-out pattern in the dorsal pallium and mesopallium. In addition, a behavior test for posthatched chicks indicated that the passive avoidance ratio increased significantly. The study suggests that the acquisition of an additional fragment in mammalian Emx2 is associated with the organization and evolution of the mammalian pallium.

Abstract Nickel-rich layered oxide cathodes promise ultrahigh energy density but is plagued by the mechanical failure of the secondary particle upon (de)lithiation. Existing approaches for alleviating the structural degradation could retard pulverization, yet fail to tune the stress distribution and root out the formation of cracks. Herein, we report a unique strategy to uniformize the stress distribution in secondary particle via Kirkendall effect to stabilize the core region during electrochemical cycling. Exotic metal/metalloid oxides (such as Al2O3 or SiO2) is introduced as the heterogeneous nucleation seeds for the preferential growth of the precursor. The calcination treatment afterwards generates a dopant-rich interior structure with central Kirkendall void, due to the different diffusivity between the exotic element and nickel atom. The resulting cathode material exhibits superior structural and electrochemical reversibility, thus contributing to a high specific energy density (based on cathode) of 660 Wh kg−1 after 500 cycles with a retention rate of 86%. This study suggests that uniformizing stress distribution represents a promising pathway to tackle the structural instability facing nickel-rich layered oxide cathodes.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1β, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown.MethodsTo investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce in vivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). In vitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs.ResultsMyeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1β induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. In vitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes.ConclusionsThe study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.

Abstract Fiber-reinforced polymer (FRP) composites have gained widespread applications in many engineering fields, making it imperative to study long-term performance under service conditions. Due to their heterogeneity and multifield coupling conditions, the long-term performance of FRP composites has become a complex scientific problem that involves multiscale and multidisciplinary aspects. With advancements in nanotechnology and computational power, researchers have increasingly conducted studies on the deterioration mechanisms and durability of FRP composites using top-down experiments and bottom-up multiscale simulations. Here, we review micro- and nano-mechanics in relation to the durability of FRP composites, including progress in the use of atomic and molecular simulations. We elucidate the role of multiscale methods, particularly molecular dynamics simulations, in the study of FRP composites and outline its prospects, to illustrate how micro- and nano-mechanics contribute to research on the durability of FRP composites.

Fruit quality is dependent on various factors including flavour, texture and colour. These factors are determined by the ripening process, either climacteric or non-climacteric. In grape berry, which is non-climacteric, the process is signalled by a complex set of hormone changes. Abscisic acid (ABA) is one of the key hormones involved in ripening, while sugar availability also plays a significant role in certain ripening aspects such as anthocyanin production. To understand the relative influence of hormone and sugar signalling in situ can prove problematic due to the physiological and environmental (abiotic and biotic) factors at play in vineyards. Here we report on the use of in vitro detached berry culture to investigate the comparative significance of ABA and sugar in the regulation of Pinot noir berry anthocyanin production under controlled conditions. Using a factorial experimental design, pre-véraison berries were cultured on media with various concentrations of sucrose and ABA. After 15 days of in vitro culture, the berries were analysed for changes in metabolites, hormones and gene expression. Results illustrated a stimulatory effect of sucrose and ABA on enhancing berry colour and a corresponding increase in anthocyanins. Increased ABA concentration was able to boost anthocyanin production in berries when sucrose supply was low. The sucrose and ABA effects on berry anthocyanins were primarily manifested through the up-regulation of transcription factors and other genes in the phenylpropanoid pathway, while in other parts of the pathway a down-regulation of key proanthocyanindin transcription factors and genes corresponded to sharp reduction in berry proanthocyanidins, irrespective of sucrose supply. Similarly, increased ABA was correlated with a significant reduction in berry malic acid and associated regulatory genes. These findings suggest a predominance of berry ABA over berry sugar in coordinating the physiological and genetic regulation of anthocyanins and proanthocyanins in Pinot noir grape berries.

Talaromyce marneffei is an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous studies have suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense against T. marneffei remains unclear. We show that T. marneffei yeasts but not conidia induce potent IL-1β production. The IL-1β response to T. marneffei yeasts is differently regulated in different cell types; T. marneffei yeasts alone are able to induce IL-1β production in human PBMCs and monocytes, whereas LPS priming is essential for IL-1β response to yeasts. We also find that Dectin-1/Syk signaling pathway mediates pro-IL-1β production, and NLRP3-ASC-caspase-1 inflammasome is assembled to trigger the processing of pro-IL-1β into IL-1β. In vivo, mice deficient in NLRP3 or caspase-1 exhibit higher mortality rate and fungal load compared to wild-type mice after systemic T. marneffei infection, which correlates with the diminished recruitment of CD4 T cells into granulomas in knockout mice. Thus, our study first demonstrates that NLRP3 inflammasome contributes to host defense against T. marneffei infection.

Abstract Background Minimally invasive plate osteosynthesis (MIPO) via percutaneous plate placement on the distal medial tibia can be performed with minimizes soft tissue injury and produces good clinical results. However, the difficulty with MIPO lies in how to achieve satisfactory fracture reduction and maintain that reduction via indirect reduction techniques to facilitate internal fixation. The purpose of this study was to compare the effects of AO distractor and manual traction reduction techniques combined with MIPO in the treatment of distal tibia fractures. Methods Between January 2013 and December 2019, 58 patients with a distal tibia fracture were treated using MIPO. Patients were divided into two groups according to the indirect reduction method that was used: 26 patients were reduced with manual traction(group M), and 32 were reduced with an AO distractor (group A).Time until union and clinical outcomes including AOFAS ankle-rating score and ankle range of ankle motion at final follow-up were compared. Mean operative time, incision length, blood loss and postoperative complications were recorded via chart review. Radiographic results at final follow-up were assessed for tibial angulation and shortening by a blinded reader. Results Mean operative time, incision length, and blood loss in group A were significantly lower than in group M(p = 0.019, 0.018 and 0.016, respectively).Radiographic evidence of bony union was seen in all cases, and mean time until union was equivalent between the two groups (p = 0.384).Skin irritation was noted in one case(3.1%) in group A and three cases(11.5%)in group M, but the symptoms were not severe and the plate was removed after bony union. There was no statistically significant difference in postoperative complications between the two groups(p = 0.461). Mean AOFAS score and range of ankle motion were equivalent between the two groups, as were varus deformity, valgus deformity, anterior angulation and posterior angulation. No patients had gross angular deformity. Mean tibial shortening was not significantly different between the two groups, and no patients had tibial shortening > 10 mm. Conclusion Both an AO distractor and manual traction reduction techniques prior to MIPO in the treatment of distal tibial fractures permit a high fracture healing rate and satisfying functional outcomes with few wound healing complications. An AO distractor is an excellent indirect reduction method that may improve operative efficiency and reduce the risk of soft tissue injury.

Abstract A stable { $$\stackrel{\mathrm{-}}{1}{\text{10}}$$ 1 - 10 } single component sharp texture was obtained during ambient temperature tube High-Pressure Shearing (t-HPS) of 99.999% purity aluminum. It is shown that the grain size and the grain aspect ratio saturate at ~ 8 μm and ~ 1.6, respectively, at an equivalent strain of ~ 30 and the high-angle grain boundary fraction continues to decrease after this saturation even to equivalent strains exceeding ~ 200. The { $$\stackrel{\mathrm{-}}{1}{\text{10}}$$ 1 - 10 } texture emerges at an equivalent strain of ~ 6 to 9 with the completion of recrystallization and develops gradually as a sole component sharp texture with increasing intensity upon further processing. This component is a stable orientation in t-HPS processing although it was not previously observed experimentally as a shear texture. Thus, t-HPS processing provides a new and effective experimental tool for simple shear testing that is distinctly different from earlier shear strain methods such as torsional processing.

Abstract Background Structural variants (SVs) play important roles in adaptation evolution and species diversification. Especially, in plants, many phenotypes of response to the environment were found to be associated with SVs. Despite the prevalence and significance of SVs, long insertions remain poorly detected and studied in all but model species. Results We used whole-genome resequencing of paired reads from 80 Asian butternuts to detect long insertions and further analyse their characteristics and potential functional effects. By combining of mapping-based and de novo assembly-based methods, we obtained a multiple related species pangenome representing higher taxonomic groups. We obtained 89,312 distinct contigs totaling 147,773,999 base pair (bp) of new sequences, of which 347 were putative long insertions placed in the reference genome. Most of the putative long insertions appeared in multiple species; in contrast, only 62 putative long insertions appeared in one species, which may be involved in the response to the environment. 65 putative long insertions fell into 61 distinct protein-coding genes involved in plant development, and 105 putative long insertions fell into upstream of 106 distinct protein-coding genes involved in cellular respiration. 3,367 genes were annotated in 2,606 contigs. We propose PLAINS ( https://github.com/CMB-BNU/PLAINS.git ), a streamlined, comprehensive pipeline for the prediction and analysis of long insertions using whole-genome resequencing. Conclusions Our study lays down an important foundation for further whole-genome long insertion studies, allowing the investigation of their effects by experiments.

This review summarized the latest research progress on the active components and comprehensive utilization of R. chingii Hu, and points out that the active components and functional characteristics of R. chingii Hu should be further explored, and it should be widely used in the fields of medical care, food and daily chemical products.

CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.

Abstract The energy density of commercial lithium (Li) ion batteries with graphite anode is reaching the limit. It is believed that directly utilizing Li metal as anode without a host could enhance the battery’s energy density to the maximum extent. However, the poor reversibility and infinite volume change of Li metal hinder the realistic implementation of Li metal in battery community. Herein, a commercially viable hybrid Li-ion/metal battery is realized by a coordinated strategy of symbiotic anode and prelithiated cathode. To be specific, a scalable template-removal method is developed to fabricate the porous graphite layer (PGL), which acts as a symbiotic host for Li ion intercalation and subsequent Li metal deposition due to the enhanced lithiophilicity and sufficient ion-conducting pathways. A continuous dissolution-deintercalation mechanism during delithiation process further ensures the elimination of dead Li. As a result, when the excess plating Li reaches 30%, the PGL could deliver an ultrahigh average Coulombic efficiency of 99.5% for 180 cycles with a capacity of 2.48 mAh cm−2 in traditional carbonate electrolyte. Meanwhile, an air-stable recrystallized lithium oxalate with high specific capacity (514.3 mAh g−1) and moderate operating potential (4.7–5.0 V) is introduced as a sacrificial cathode to compensate the initial loss and provide Li source for subsequent cycles. Based on the prelithiated cathode and initial Li-free symbiotic anode, under a practical-level 3 mAh capacity, the assembled hybrid Li-ion/metal full cell with a P/N ratio (capacity ratio of LiNi0.8Co0.1Mn0.1O2 to graphite) of 1.3 exhibits significantly improved capacity retention after 300 cycles, indicating its great potential for high-energy-density Li batteries.

Talaromyces (Penicillium) marneffei is an AIDS-defining infection in Southeast Asia and is associated with high mortality. It is rare in non-immunosuppressed individuals, especially children. Little is known about host immune response and genetic susceptibility to this endemic fungus. Genetic defects in the interferon-gamma (IFN-γ)/STAT1 signaling pathway, CD40/CD40 ligand- and IL12/IL12-receptor-mediated crosstalk between phagocytes and T-cells, and STAT3-mediated Th17 differentiation have been reported in HIV-negative children with talaromycosis and other endemic mycoses such as histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis. There is a need to design a diagnostic algorithm to evaluate such patients. In this article, we review a cohort of pediatric patients with disseminated talaromycosis referred to the Asian Primary Immunodeficiency Network for genetic diagnosis of PID. Using these illustrative cases, we propose a diagnostics pipeline that begins with immunoglobulin pattern (IgG, IgA, IgM, and IgE) and enumeration of lymphocyte subpopulations (T-, B-, and NK-cells). The former could provide clues for hyper-IgM syndrome and hyper-IgE syndrome. Flow cytometric evaluation of CD40L expression should be performed for patients suspected to have X-linked hyper-IgM syndrome. Defects in interferon-mediated JAK-STAT signaling are evaluated by STAT1 phosphorylation studies by flow cytometry. STAT1 hyperphosphorylation in response to IFN-α or IFN-γ and delayed dephosphorylation is diagnostic for gain-of-function STAT1 disorder, while absent STAT1 phosphorylation in response to IFN-γ but normal response to IFN-α is suggestive of IFN-γ receptor deficiency. This simple and rapid diagnostic algorithm will be useful in guiding genetic studies for patients with disseminated talaromycosis requiring immunological investigations.

How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.

IntroductionA large number of people in China are affected by depression, yet tend to delay seeking treatment. This study aims to explore persons living with depression and their journey of diagnoses and seeking professional medical help in China.MethodsSemi-structured interviews were conducted with 20 persons who visiting physicians to be diagnosed and receive professional help from a large mental health center in Guangzhou, Guangdong province, China. Individual interviews were conducted and data were analyzed using content analysis.ResultsThree themes were identified from the findings: (1) “noticed something was wrong”; (2) negotiated decisions with their own narratives and the personal suggestions of others; and (3) gave new meaning to their experiences of depression, whereby they sought medical treatment.DiscussionThe findings of the study indicated that the impact of progressive depressive symptoms on the participants’ daily lives was a strong motivation for them to seek professional help. The obligation to care for and support their family prevented them from initially disclosing their depressive symptoms to family members, but eventually prompted them to seek professional help and persist in follow-up treatment. Some participants experienced unexpected benefits (e.g., relief at no longer feeling “alone”) during their first visit to the hospital for depression or when they were diagnosed with depression. The results suggest a need to continue to actively screen for depression and provide more public education to prevent negative assumptions and reduce public and personal stigmatization of those with mental health problems.

Summary: Potatoes consist of flavonoids that provide health benefits for human consumers. To learn more about how potato tuber flavonoid accumulation and flesh pigmentation are controlled, we analyzed the transcriptomic and metabolomic profile of potato tubers from three colored potato clones at three developmental phases using an integrated approach. From the 72 flavonoids identified in pigmented flesh, differential abundance was noted for anthocyanins, flavonols, and flavones. Weighted gene co-expression network analysis further allowed modules and candidate genes that positively or negatively regulate flavonoid biosynthesis to be identified. Furthermore, an R2R3-MYB repressor StMYB3 and an R3-MYB repressor StMYBATV involved in the modulation of anthocyanin biosynthesis during tuber development were identified. Both StMYB3 and StMYBATV could interact with the cofactor StbHLH1 and repress anthocyanin biosynthesis. Our results indicate a feedback regulatory mechanism of a coordinated MYB activator-repressor network on fine-tuning of potato tuber pigmentation during tuber development.

The genetic link between apple red flesh (RF) coloration and the internal flesh browning disorder (FBD) is a major challenge when breeding high fruit quality RF apple cultivars. A genome-wide association study (GWAS) was conducted in a population of about 900 red-leaved seedlings to identify genomic regions and putative candidate genes using whole genome sequencing of the pools of extreme phenotypes (XP) for the RF colour coverage (using the weighted cortex index (WCI)) and FBD. This study identified novel genomic regions contributing to WCI and FBD variation in the red-leaved seedlings. The FBD-associated regions were enriched for genes regulating senescence, heat shock proteins, cytochrome P450, ascorbate metabolism and pectin methyl esterases. Although there were no significant regions in common for WCI and FBD, there were several genes (e.g. MYB85, MYB66, ethylene insensitive 3, DNAJ heat shock protein, WRKY7, and NAC42) enriched commonly between the genomic regions associated with these traits, potentially underpinning the genetic connection between WCI and FBD. Some of the differentially expressed genes between the R6:MdMYB10 and white-fleshed ‘control’ apples resided within the GWAS hotspot for WCI (e.g. chalcone synthase, UDP-Glycosyl transferase) and FBD (e.g. Rho GTPase activating protein, lipoxygenase 1, phytoene synthase) – validating the XP-GWAS findings. Paralogs of several genes resided in the trait-associated genomic regions, suggesting that whole genome duplication plays an important role in the regulation of these traits. Adverse genetic correlations between WCI and sensory traits were observed, and strategies to develop FBD-free high fruit quality RF cultivars are discussed.

Abstract Security risks of flammability and explosion represent major problems with the use of conventional lithium rechargeable batteries using a liquid electrolyte. The application of solid‐state electrolytes could effectively help to avoid these safety concerns. However, integrating the solid‐state electrolytes into the all‐solid‐state lithium batteries is still a huge challenge mainly due to the high interfacial resistance present in the entire battery, especially at the interface between the cathode and the solid‐state electrolyte pellet and the interfaces inside the cathode. Herein, recent progress made from investigations of cathode/solid‐state electrolyte interfacial behaviors including the contact problem, the interlayer diffusion issue, the space‐charge layer effect, and electrochemical compatibility is presented according to the classification of oxide‐, sulfide‐, and polymer‐based solid‐state electrolytes. We also propose strategies for the construction of ideal next‐generation cathode/solid‐state electrolyte interfaces with high room‐temperature ionic conductivity, stable interfacial contact during long cycling, free formation of the space‐charge region, and good compatibility with high‐voltage cathodes.

Summary: Alternative splicing is crucial for a wide range of biological processes. However, limited by the availability of reference genomes, genome-wide patterns of alternative splicing remain unknown in most nonmodel organisms. We present an attention-based convolutional neural network model, DeepASmRNA, for predicting alternative splicing events using only transcriptomic data. DeepASmRNA consists of two parts: identification of alternatively spliced transcripts and classification of alternative splicing events, which outperformed the state-of-the-art method, AStrap, and other deep learning models. Then, we utilize transfer learning to increase the performance in species with limited training data and use an interpretation method to decipher splicing codes. Finally, applying Amborella, DeepASmRNA can identify more AS events than AStrap while maintaining the same level of precision, suggesting that DeepASmRNA has superior sensitivity to identify alternative splicing events. In summary, DeepASmRNA is scalable and interpretable for detecting genome-wide patterns of alternative splicing in species without a reference genome.

Abstract Background Alternative splicing (AS) is an important mechanism of posttranscriptional modification and dynamically regulates multiple physiological processes in plants, including fruit ripening. However, little is known about alternative splicing during fruit development in fleshy fruits. Results We studied the alternative splicing at the immature and ripe stages during fruit development in cucumber, melon, papaya and peach. We found that 14.96–17.48% of multiexon genes exhibited alternative splicing. Intron retention was not always the most frequent event, indicating that the alternative splicing pattern during different developmental process differs. Alternative splicing was significantly more prevalent at the ripe stage than at the immature stage in cucumber and melon, while the opposite trend was shown in papaya and peach, implying that developmental stages adopt different alternative splicing strategies for their specific functions. Some genes involved in fruit ripening underwent stage-specific alternative splicing, indicating that alternative splicing regulates fruits ripening. Conserved alternative splicing events did not appear to be stage-specific. Clustering fruit developmental stages across the four species based on alternative splicing profiles resulted in species-specific clustering, suggesting that diversification of alternative splicing contributes to lineage-specific evolution in fleshy fruits. Conclusions We obtained high quality transcriptomes and alternative splicing events during fruit development across the four species. Dynamics and nonconserved alternative splicing were discovered. The candidate stage-specific AS genes involved in fruit ripening will provide valuable insight into the roles of alternative splicing during the developmental processes of fleshy fruits.

Abstract A key challenge for solid-state-batteries development is to design electrode-electrolyte interfaces that combine (electro)chemical and mechanical stability with facile Li-ion transport. However, while the solid-electrolyte/electrode interfacial area should be maximized to facilitate the transport of high electrical currents on the one hand, on the other hand, this area should be minimized to reduce the parasitic interfacial reactions and promote the overall cell stability. To improve these aspects simultaneously, we report the use of an interfacial inorganic coating and the study of its impact on the local Li-ion transport over the grain boundaries. Via exchange-NMR measurements, we quantify the equilibrium between the various phases present at the interface between an S-based positive electrode and an inorganic solid-electrolyte. We also demonstrate the beneficial effect of the LiI coating on the all-solid-state cell performances, which leads to efficient sulfur activation and prevention of solid-electrolyte decomposition. Finally, we report 200 cycles with a stable capacity of around 600 mAh g−1 at 0.264 mA cm−2 for a full lab-scale cell comprising of LiI-coated Li2S-based cathode, Li-In alloy anode and Li6PS5Cl solid electrolyte.

Due to advances in the industrial development of light-emitting diodes (LEDs), much research has been conducted in recent years to get a better understanding of how plants respond to these light sources. This study investigated the effects of different LED-based light regimes on strawberry plant development and performance. The photosynthetic pigment content, biochemical constituents, and growth characteristics of strawberry plants were investigated using a combination of different light intensities (150, 200, and 250 μmol m−2 s−1), qualities (red, green, and blue LEDs), and photoperiods (14/10 h, 16/8 h, and 12/12 h light/dark cycles) compared to the same treatment with white fluorescent light. Plant height, root length, shoot fresh and dry weight, chlorophyll a, total chlorophyll/carotenoid content, and most plant yield parameters were highest when illuminated with LM7 [intensity (250 μmol m−2 s−1) + quality (70% red/30% blue LED light combination) + photoperiod (16/8 h light/dark cycles)]. The best results for the effective quantum yield of PSII photochemistry Y(II), photochemical quenching coefficient (qP), and electron transport ratio (ETR) were obtained with LM8 illumination [intensity (250 μmol m−2 s−1) + quality (50% red/20% green/30% blue LED light combination) + photoperiod (12 h/12 h light/dark cycles)]. We conclude that strawberry plants require prolonged and high light intensities with a high red-light component for maximum performance and biomass production.

Abstract Global navigation satellite systems (GNSSs) are increasingly used for multi‐satellite missions in space service volume (SSV). However, the performance of GNSS‐based autonomous orbit determination (AOD) for SSV users is severely constrained by limited measurement accuracy and signal availability. Relative measurement and orbital dynamic models can be used to improve the AOD performance when the estimator is prone to divergence due to the cross‐correlation of the distributed formation network. In this paper, a sequential game‐theoretic (SGT) optimization algorithm is proposed to deal with cross‐correlation issues when fusing the GNSS and relative measurements for dynamic AOD in the SSV field. A four geostationary Earth orbit satellite mission is simulated as the case study for the AOD performance analysis. The conventional sequential covariance intersection (SCI) is also presented for comparison purposes. The simulation results show that with the combination of GNSS and relative measurements with 10 m and 0.1 m precision, the SGT‐based AOD can achieve about 1.9 m three‐dimensional positioning accuracy, which is 80% better than in the GNSS‐only case. It is also demonstrated that the SGT‐based AOD is superior to the SCI‐based AOD by 50% in the fusion of GNSS and relative measurements in the range of 1–10 m and with 0.1–0.001 m accuracy.

Abstract Background With the rapid development of accurate sequencing and assembly technologies, an increasing number of high-quality chromosome-level and haplotype-resolved assemblies of genomic sequences have been derived, from which there will be great opportunities for computational pangenomics. Although genome graphs are among the most useful models for pangenome representation, their structural complexity makes it difficult to present genome information intuitively, such as the linear reference genome. Thus, efficiently and accurately analyzing the genome graph spatial structure and coordinating the information remains a substantial challenge. Results We developed a new method, a colored superbubble (cSupB), that can overcome the complexity of graphs and organize a set of species- or population-specific haplotype sequences of interest. Based on this model, we propose a tri-tuple coordinate system that combines an offset value, topological structure and sample information. Additionally, cSupB provides a novel method that utilizes complete topological information and efficiently detects small indels (

Serological tumor markers are useful for the detection of malignancies and evaluation of disease progression. These markers are not checked as part of a routine examination for patients with benign diseases and without any clinical suspicion of malignancy. However, some markers appear to be elevated in patients with benign diseases and without malignancies. We present a case of pyogenic liver abscesses with an elevated serum carcinoembryonic antigen (CEA) level associated with neither evidence of malignancy nor elevation of other tumor markers such as carbohydrate antigen (CA 19-9) and alpha-fetoprotein (AFP) levels. The serological level of CEA decreased and subsequently became within normal limits with treatment. This case also demonstrates that diabetic patients with a liver abscess may present with no infectious symptoms and that fine-needle aspiration is as effective as catheter drainage in the treatment of pyogenic liver abscess.

In recent years, lots of efforts have been applied to improve the initial Coulombic efficiency (ICE) of lithium-ion batteries (LIBs), among which prelithiation is considered to be one of the most promising schemes. Here we report a modified LixSi with high lithium reserves and great environmental adaptability as the prelithiation reagent, which can make up for the capacity loss of the negative electrode in the first cycle. Through the chemical reaction between aluminum isopropoxide and LixSi, a protective layer consisting of LixAlySiOz/Li2O is formed on the surface of LixSi particles. This synthesized material provides a new idea for the actual industrial production of prelithiation.

AbstractPopulation-specific, positive selection promotes the diversity of populations and drives local adaptations in the population. However, little is known about population-specific, recent positive selection in the populations of cultivated cucumber (Cucumis sativus

Abstract Background Alternative splicing (AS) plays a critical regulatory role in modulating transcriptome and proteome diversity. In particular, it increases the functional diversity of proteins. Recent genome-wide analysis of AS using RNA-Seq has revealed that AS is highly pervasive in plants. Furthermore, it has been suggested that most AS events are subject to tissue-specific regulation. Description To reveal the functional characteristics induced by AS and tissue-specific splicing events, a database for exploring these characteristics is needed, especially in plants. To address these goals, we constructed a database of annotated transcripts generated by alternative splicing in cucumbers (CuAS: http://cmb.bnu.edu.cn/alt_iso/index.php ) that integrates genomic annotations, isoform-level functions, isoform-level features, and tissue-specific AS events among multiple tissues. CuAS supports a retrieval system that identifies unique IDs (gene ID, isoform ID, UniProt ID, and gene name), chromosomal positions, and gene families, and a browser for visualization of each gene. Conclusion We believe that CuAS could be helpful for revealing the novel functional characteristics induced by AS and tissue-specific AS events in cucumbers. CuAS is freely available at http://cmb.bnu.edu.cn/alt_iso/index.php .

The innate immune system senses cytosolic dsDNA and bacterial cyclic dinucleotides and initiates signaling via the adaptor STING to induce type 1 interferon (IFN) response. We demonstrate here that BTK-deficient cells have impaired IFN-β production and TBK1/IRF3 activation when stimulated with agonists or infected with pathogens that activate STING signaling. BTK interacts with STING and DDX41 helicase. The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. Modeling studies further indicate that phospho-Tyr414 strengthens DDX41's interaction with STING. Hence, BTK plays a critical role in the activation of DDX41 helicase and STING signaling.

Wufanshu (Vaccinium bracteatum Thunb.), which is a wild member of the genus Vaccinium, accumulates high concentration of anthocyanin in its berries. In this study, the accumulated anthocyanins and their derivatives in Wufanshu berries were identified through UHPLC–MS/MS analysis. Candidate anthocyanin biosynthetic genes were identified from the transcriptome of Wufanshu berries. qRT-PCR analyses showed that the expression of anthocyanin structural genes correlated with anthocyanin accumulation in berries. The R2R3-MYB, VbMYBA, which is a homolog of anthocyanin promoting R2R3-MYBs from other Vaccinium species, was also identified. Transient expression of VbMYBA in Nicotiana tabacum leaves confirmed its role as an anthocyanin regulator, and produced a higher anthocyanin concentration when compared with blueberry VcMYBA expression. Dual-luciferase assays further showed that VbMYBA can activate the DFR and UFGT promoters from other Vaccinium species. VbMYBA has an additional 23 aa at the N terminus compared with blueberry VcMYBA, but this was shown not to affect the ability to regulate anthocyanins. Taken together, our results provide important information on the molecular mechanisms responsible for the high anthocyanin content in Wufanshu berries.

The use of avidin or streptavidin in the purification of biotinylated proteins has been highly restricted due to the harsh and denaturing elution conditions. Here, we use biotinylated bovine serum albumin as a working model to demonstrate a simple and rapid method for biotin-tagged protein purification under non-denaturing conditions. The biotinylated bovine serum albumin is specifically bound to the anti-biotin antibody agarose beads and competitively eluted with free biotin under near-neutral conditions. The optimized elution conditions include using 4 mg/ml biotin (pH 8.5) as the elution buffer and allowing the buffer to incubate with agarose beads for 30 min prior to elution. The elution recovery rate is over 85% without apparent protein denaturation. The method is applicable for both immunoprecipitation and column chromatography.

Plum is one of the most important stone fruits in the world and anthocyanin-rich plums are increasingly popular due to their health-promoting potential. In this study, we investigated the mechanisms of anthocyanin accumulation in the flesh of the red-fleshed mutant of the yellow-fleshed plum ‘Sanyueli’. RNA-Seq and qRT-PCR showed that anthocyanin biosynthetic genes and the transcription factor PsMYB10.2 were upregulated in the flesh of the mutant. Functional testing in tobacco leaves indicated that PsMYB10.2 was an anthocyanin pathway activator and can activate the promoter of the anthocyanin biosynthetic genes PsUFGT and PsGST. The role of PsMYB10.2 in anthocyanin accumulation in the flesh of plum was further confirmed by virus-induced gene silencing. These results provide information for further elucidating the underlying mechanisms of anthocyanin accumulation in the flesh of plum and for the breeding of new red-fleshed plum cultivars.

Red coloration contributes to fruit quality and is determined by anthocyanin content in peach (Prunus persica). Our previous study illustrated that anthocyanin accumulation is strongly regulated by light, and the effect of induction differs according to light quality. Here we showed that both ultraviolet-A (UVA) and ultraviolet-B (UVB) irradiation promoted anthocyanin biosynthesis in “Hujingmilu” peach fruit, and a combination of UVA and UVB had additional effects. The expression of anthocyanin biosynthesis and light signaling related genes, including transcription factor genes and light signaling elements, were induced following UV irradiation as early as 6 h post-treatment, earlier than apparent change in coloration which occurred at 72 h. To investigate the molecular mechanisms for UVA- and UVB-induced anthocyanin accumulation, the genes encoding ELONGATED HYPOCOTYL 5 (HY5), CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), Cryptochrome (CRY), and UV RESISTANCE LOCUS 8 (UVR8) in peach were isolated and characterized through functional complementation in corresponding Arabidopsis (Arabidopsis thaliana) mutants. PpHY5 and PpCOP1.1 restored hypocotyl length and anthocyanin content in Arabidopsis mutants under white light; while PpCRY1 and PpUVR8.1 restored AtHY5 expression in Arabidopsis mutants in response to UV irradiation. Arabidopsis PpHY5/hy5 transgenic lines accumulated higher amounts of anthocyanin under UV supplementation (compared with weak white light only), especially when UVA and UVB were applied together. These data indicated that PpHY5, acting as AtHY5 counterpart, was a vital regulator in UVA and UVB signaling pathway. In peach, the expression of PpHY5 was up-regulated by UVA and UVB, and PpHY5 positively regulated both its own transcription by interacting with an E-box in its own promoter, and the transcription of the downstream anthocyanin biosynthetic genes chalcone synthase 1 (PpCHS1), chalcone synthase 2 (PpCHS2), and dihydroflavonol 4-reductase (PpDFR1) as well as the transcription factor gene PpMYB10.1. In summary, functional evidence supports the role of PpHY5 in UVA and UVB light transduction pathway controlling anthocyanin biosynthesis. In peach this is via up-regulation of expression of genes encoding biosynthetic enzymes, as well as the transcription factor PpMYB10.1 and PpHY5 itself.

In recent years, much effort has been devoted to understanding the response of plants to various light sources, largely due to advances in industry light-emitting diodes (LEDs). In this study, the effect of different light modes on rocket (Eruca sativa. Mill.) photosynthetic performance and other physiological traits was evaluated using an orthogonal design based on a combination between light intensity, quality, and photoperiod factors. Some morphological and biochemical parameters and photosynthetic efficiency of the plants were analyzed. Plants grew in a closed chamber where three light intensities (160, 190, and 220 μmol m-2 s-1) provided by LEDs with a combination of different ratios of red, green, and blue (R:G:B- 7:0:3, 3:0:7, and 5:2:3) and three different photoperiods (light/dark -10/14 h, 12/12 h, and 14/10 h) were used and compared with white fluorescent light (control). This experimental setup allowed us to study the effect of 9 light modes (LM) compared to white light. The analyzes performed showed that the highest levels of chlorophyll a, chlorophyll b, and carotenoids occurred under LM4, LM3, and LM1, respectively. Chlorophyll a fluorescence measurement showed that the best effective quantum yield of PSII photochemistry Y(II), non-photochemical quenching (NPQ), photochemical quenching coefficient (qP), and electron transport ratio (ETR) were obtained under LM2. The data showed that the application of R7:G0:B3 light mode with a shorter photoperiod than 14/10 h (light/dark), regardless of the light intensity used, resulted in a significant increase in growth as well as higher photosynthetic capacity of rocket plants. Since, a clear correlation between the studied traits under the applied light modes was not found, more features should be studied in future experiments.

Anthocyanins: Coloring Kiwifruit The genetic processes that determine the colors in purple kiwifruit have been revealed by researchers in New Zealand. Anthocyanin pigments are not only essential for plant growth and development, but also provide color to make fruit attractive to pollinators and indicate ripeness for the food industry. Andrew Allan and co-workers at the University of Auckland and The New Zealand Institute for Plant and Food Research Limited examined several different kiwifruit species, and found that their color was determined by the ratio of red cyanidin-based to blue delphinidin-based anthocyanins. The team identified four biosynthetic genes that are crucial for accumulating anthocyanins, and showed that two of those genes control the red-to-blue pigment ratio. This new understanding of the anthocyanin profile could allow metabolic engineering of novel fruit colors, possibly with greater health benefits for humans.

Sodium–sulfur batteries operating at a high temperature between 300 and 350°C have been used commercially, but the safety issue hinders their wider adoption. Here the authors report a “cocktail optimized” electrolyte system that enables higher electrochemical performance and room-temperature operation.

Abstract Background Temperature is a major determinant of spontaneous mutation, but the precise mode, and the underlying mechanisms, of the temperature influences remain less clear. Here we used a mutation accumulation approach combined with whole-genome sequencing to investigate the temperature dependence of spontaneous mutation in an Escherichia coli strain. Experiments were performed under aerobic conditions at 25, 28 and 37 °C, three temperatures that were non-stressful for the bacterium but caused significantly different bacterial growth rates. Results Mutation rate did not differ between 25 and 28 °C, but was higher at 37 °C. Detailed analyses of the molecular spectrum of mutations were performed; and a particularly interesting finding is that higher temperature led to a bias of mutation to coding, relative to noncoding, DNA. Furthermore, the temperature response of mutation rate was extremely similar to that of metabolic rate, consistent with an idea that metabolic rate predicts mutation rate. Conclusions Temperature affects mutation rate and the types of mutation supply, both being crucial for the opportunity of natural selection. Our results help understand how temperature drives evolutionary speed of organisms and thus the global patterns of biodiversity. This study also lend support to the metabolic theory of ecology for linking metabolic rate and molecular evolution rate.