Domestication and selection footprints in Persian walnuts (Juglans regia).

Walnut (Juglans) species are economically important hardwood trees cultivated worldwide for both edible nuts and high-quality wood. Broad-scale assessments of species diversity, evolutionary history, and domestication are needed to improve walnut breeding. In this study, we sequenced 309 walnut accessions from around the world, including 55 Juglans relatives, 98 wild Persian walnuts (J. regia), 70 J. regia landraces, and 86 J. regia cultivars. The phylogenetic tree indicated that J. regia samples (section Dioscaryon) were monophyletic within Juglans. The core areas of genetic diversity of J. regia germplasm were southwestern China and southern Asia near the Qinghai-Tibet Plateau and the Himalayas, and the uplift of the Himalayas was speculated to be the main factor leading to the current population dynamics of Persian walnut. The pattern of genomic variation in terms of nucleotide diversity, linkage disequilibrium, single nucleotide polymorphisms, and insertions/deletions revealed the domestication and selection footprints in Persian walnut. Selective sweep analysis, GWAS, and expression analysis further identified two transcription factors, JrbHLH and JrMYB6, that influence the thickness of the nut diaphragm as loci under selection during domestication. Our results elucidate the domestication and selection footprints in Persian walnuts and provide a valuable resource for the genomics-assisted breeding of this important crop.

Mathematical kinetic modelling followed by in vitro and in vivo assays reveal the bifunctional rice GTPCHII/DHBPS enzymes and demonstrate the key roles of OsRibA proteins in the vitamin B2 pathway.

BACKGROUND: Riboflavin is the precursor of several cofactors essential for normal physical and cognitive development, but only plants and some microorganisms can produce it. Humans thus rely on their dietary intake, which at a global level is mainly constituted by cereals (> 50%). Understanding the riboflavin biosynthesis players is key for advancing our knowledge on this essential pathway and can hold promise for biofortification strategies in major crop species. In some bacteria and in Arabidopsis, it is known that RibA1 is a bifunctional protein with distinct GTP cyclohydrolase II (GTPCHII) and 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) domains. Arabidopsis harbors three RibA isoforms, but only one retained its bifunctionality. In rice, however, the identification and characterization of RibA has not yet been described. RESULTS: Through mathematical kinetic modeling, we identified RibA as the rate-limiting step of riboflavin pathway and by bioinformatic analysis we confirmed that rice RibA proteins carry both domains, DHBPS and GTPCHII. Phylogenetic analysis revealed that OsRibA isoforms 1 and 2 are similar to Arabidopsis bifunctional RibA1. Heterologous expression of OsRibA1 completely restored the growth of the rib3∆ yeast mutant, lacking DHBPS expression, while causing a 60% growth improvement of the rib1∆ mutant, lacking GTPCHII activity. Regarding OsRibA2, its heterologous expression fully complemented GTPCHII activity, and improved rib3∆ growth by 30%. In vitro activity assays confirmed that both OsRibA1 and OsRibA2 proteins carry GTPCHII/DHBPS activities, but that OsRibA1 has higher DHBPS activity. The overexpression of OsRibA1 in rice callus resulted in a 28% increase in riboflavin content. CONCLUSIONS: Our study elucidates the critical role of RibA in rice riboflavin biosynthesis pathway, establishing it as the rate-limiting step in the pathway. By identifying and characterizing OsRibA1 and OsRibA2, showcasing their GTPCHII and DHBPS activities, we have advanced the understanding of riboflavin biosynthesis in this staple crop. We further demonstrated that OsRibA1 overexpression in rice callus increases its riboflavin content, providing supporting information for bioengineering efforts.

A UPLC-MS/MS method for quantification of metabolites in the ethylene biosynthesis pathway and its biological validation in Arabidopsis.

The plant hormone ethylene is of vital importance in the regulation of plant development and stress responses. Recent studies revealed that 1-aminocyclopropane-1-carboxylic acid (ACC) plays a role beyond its function as an ethylene precursor. However, the absence of reliable methods to quantify ACC and its conjugates malonyl-ACC (MACC), glutamyl-ACC (GACC), and jasmonyl-ACC (JA-ACC) hinders related research. Combining synthetic and analytical chemistry, we present the first, validated methodology to rapidly extract and quantify ACC and its conjugates using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Its relevance was confirmed by application to Arabidopsis mutants with altered ACC metabolism and wild-type plants under stress. Pharmacological and genetic suppression of ACC synthesis resulted in decreased ACC and MACC content, whereas induction led to elevated levels. Salt, wounding, and submergence stress enhanced ACC and MACC production. GACC and JA-ACC were undetectable in vivo; however, GACC was identified in vitro, underscoring the broad applicability of the method. This method provides an efficient tool to study individual functions of ACC and its conjugates, paving the road toward exploration of novel avenues in ACC and ethylene metabolism, and revisiting ethylene literature in view of the recent discovery of an ethylene-independent role of ACC.

Auxin-independent effects of apical dominance induce changes in phytohormones correlated with bud outgrowth.

The inhibition of shoot branching by the growing shoot tip of plants, termed apical dominance, was originally thought to be mediated by auxin. Recently, the importance of the shoot tip sink strength during apical dominance has re-emerged with recent studies highlighting roles for sugars in promoting branching. This raises many unanswered questions on the relative roles of auxin and sugars in apical dominance. Here we show that auxin depletion after decapitation is not always the initial trigger of rapid cytokinin (CK) increases in buds that are instead correlated with enhanced sugars. Auxin may also act through strigolactones (SLs) which have been shown to suppress branching after decapitation, but here we show that SLs do not have a significant effect on initial bud outgrowth after decapitation. We report here that when sucrose or CK is abundant, SLs are less inhibitory during the bud release stage compared to during later stages and that SL treatment rapidly inhibits CK accumulation in pea (Pisum sativum) axillary buds of intact plants. After initial bud release, we find an important role of gibberellin (GA) in promoting sustained bud growth downstream of auxin. We are, therefore, able to suggest a model of apical dominance that integrates auxin, sucrose, SLs, CKs, and GAs and describes differences in signalling across stages of bud release to sustained growth.

Distribution characteristics of sulfonamide antibiotics between water and extracellular polymeric substances in municipal sludge.

The interaction between extracellular polymeric substances (EPS) in municipal sludge and antibiotics in wastewater is critical in wastewater treatment, resource recovery, and sludge management. Therefore, it is increasingly urgent to investigate the distribution coefficient (Log K) of sulfonamide antibiotics (SAs) in EPS, particularly in sludge-derived dissolved organic carbon (DOC) and aqueous phase systems. Herein, through balance experiments, the concentrations of SAs were determined using alkaline extraction EPS (AEPS) and alginate-like extracellular polymer (ALE) systems, and the Log KDOC values were determined. The results showed that the Log KDOC of AEPS was higher than that of ALE, which exhibited a negative KDOC value, indicating an inhibitory effect on dissolution. For the three SAs studied, the Log KDOC values were in the following order: sulfamethoxazole > sulfapyridine > sulfadiazine. This order can be attributed to the differing physicochemical properties, such as polarity, of the SAs. Three-dimensional excitation-emission matrix fluorescence spectra and fitting results indicated a lack of aromatic proteins dominated by tryptophan and humus-like substances in ALE. Meanwhile, the hydrophobic interaction of aromatic proteins dominated by tryptophan was the main driving force in the binding process between AEPS and SAs.

The function and mechanisms of action of circular RNAs in Urologic Cancer.

Kidney, bladder, and prostate cancer are the three major tumor types of the urologic system that seriously threaten human health. Circular RNAs (CircRNAs), special non-coding RNAs with a stabile structure and a unique back-splicing loop-forming ability, have received recent scientific attention. CircRNAs are widely distributed within the body, with important biologic functions such as sponges for microRNAs, as RNA binding proteins, and as templates for regulation of transcription and protein translation. The abnormal expression of circRNAs in vivo is significantly associated with the development of urologic tumors. CircRNAs have now emerged as potential biomarkers for the diagnosis and prognosis of urologic tumors, as well as targets for the development of new therapies. Although we have gained a better understanding of circRNA, there are still many questions to be answered. In this review, we summarize the properties of circRNAs and detail their function, focusing on the effects of circRNA on proliferation, metastasis, apoptosis, metabolism, and drug resistance in kidney, bladder, and prostate cancers.

Super-Hydrophilic Microporous Ni(OH)x/Ni3 S2 Heterostructure Electrocatalyst for Large-Current-Density Hydrogen Evolution.

Exploiting active and stable non-precious metal electrocatalysts for alkaline hydrogen evolution reaction (HER) at large current density plays a key role in realizing large-scale industrial hydrogen generation. Herein, a self-supported microporous Ni(OH)x/Ni3 S2 heterostructure electrocatalyst on nickel foam (Ni(OH)x/Ni3 S2 /NF) that possesses super-hydrophilic property through an electrochemical process is rationally designed and fabricated. Benefiting from the super-hydrophilic property, microporous feature, and self-supported structure, the electrocatalyst exhibits an exceptional HER performance at large current density in 1.0 M KOH, only requiring low overpotential of 126, 193, and 238 mV to reach a current density of 100, 500, and 1000 mA cm-2 , respectively, and displaying a long-term durability up to 1000 h, which is among the state-of-the-art non-precious metal electrocatalysts. Combining hard X-rays absorption spectroscopy and first-principles calculation, it also reveals that the strong electronic coupling at the interface of the heterostructure facilitates the dissociation of H2 O molecular, accelerating the HER kinetics in alkaline electrolyte. This work sheds a light on developing advanced non-precious metal electrocatalysts for industrial hydrogen production by means of constructing a super-hydrophilic microporous heterostructure.

Mild Hypothermia Alleviates Complement C5a-Induced Neuronal Autophagy During Brain Ischemia-Reperfusion Injury After Cardiac Arrest.

After restoration of spontaneous circulation (ROSC) following cardiac arrest, complements can be activated and excessive autophagy can contribute to the brain ischemia-reperfusion (I/R) injury. Mild hypothermia (HT) protects against brain I/R injury after ROSC, but the mechanisms have not been fully elucidated. Here, we found that HT significantly inhibited the increases in serum NSE, S100ß, and C5a, as well as neurologic deficit scores, TUNEL-positive cells, and autophagic vacuoles in the pig brain cortex after ROSC. The C5a receptor 1 (C5aR1) mRNA and the C5a, C5aR1, Beclin 1, LC3-II, and cleaved caspase-3 proteins were significantly increased, but the P62 protein and the PI3K/Akt/mTOR pathway-related proteins were significantly reduced in pigs after ROSC or neuronal oxygen-glucose deprivation/reoxygenation. HT could significantly attenuate the above changes in NT-treated neurons. Furthermore, C5a treatment induced autophagy and apoptosis and reduced the PI3K/Akt/mTOR pathway-related proteins in cultured neurons, which could be reversed by C5aR1 antagonist PMX205. Our findings demonstrated that C5a could bind to C5aR1 to induce neuronal autophagy during the brain I/R injury, which was associated with the inhibited PI3K/Akt/mTOR pathway. HT could inhibit C5a-induced neuronal autophagy by regulating the C5a-C5aR1 interaction and the PI3K/Akt/mTOR pathway, which might be one of the neuroprotective mechanisms underlying I/R injury. The C5a receptor 1 (C5aR1) mRNA and the C5a, C5aR1, Beclin 1, LC3-II, and cleaved caspase-3 proteins were significantly increased, but the P62 protein and the PI3K/Akt/mTOR pathway-related proteins were significantly reduced in pigs after ROSC or neuronal oxygen-glucose deprivation/reoxygenation. Mild hypothermia (HT) could significantly attenuate the above changes in NT-treated neurons. Furthermore, C5a treatment induced autophagy and apoptosis and reduced the PI3K/Akt/mTOR pathway-related proteins in cultured neurons, which could be reversed by C5aR1 antagonist PMX205. Proposed mechanism by which HT protects against brain I/R injury by repressing C5a-C5aR1-induced excessive autophagy. Complement activation in response to brain I/R injury generates C5a that can interact with C5aR1 to inactivate mTOR, probably through the PI3K-AKT pathway, which can finally lead to autophagy activation. The excessively activated autophagy ultimately contributes to cell apoptosis and brain injury. HT may alleviate complement activation and then reduce C5a-induced autophagy to protect against brain I/R injury. HT, mild hypothermia; I/R, ischemia reperfusion.

Ultrafine FeF3·0.33H2O Nanocrystal-Doped Graphene Aerogel Cathode Materials for Advanced Lithium-Ion Batteries.

FeF3 has been extensively studied as an alternative positive material owing to its superior specific capacity and low cost, but the low conductivity, large volume variation, and slow kinetics seriously hinder its commercialization. Here, we propose the in situ growth of ultrafine FeF3·0.33H2O NPs on a three-dimensional reduced graphene oxide (3D RGO) aerogel with abundant pores by a facile freeze drying process followed by thermal annealing and fluorination. Within the FeF3·0.33H2O/RGO composites, the three-dimensional (3D) RGO aerogel and hierarchical porous structure ensure rapid diffusion of electrons/ions within the cathode, enabling good reversibility of FeF3. Benefiting from these advantages, a superior cycle behavior of 232 mAh g-1 under 0.1C over 100 cycles as well as outstanding rate performance is achieved. These results provide a promising approach for advanced cathode materials for Li-ion batteries.

Multifunctional Covalent Organic Framework-Based Microneedle Patch for Melanoma Treatment.

Melanoma is resistant to conventional chemotherapy and radiotherapy. Therefore, it is essential to develop a targeted, low-toxic, and minimally invasive treatment. Here, DTIC/ICG-Fe3O4@TpBD BSP/HA microneedles (MNs) were designed and fabricated, which can enhance targeting to melanoma and perform photothermal therapy (PTT) and chemotherapy simultaneously to synergistically exert anticancer effects. The system consisted of magnetic nanoparticles (DTIC/ICG-Fe3O4@TpBD), dissoluble matrix (Bletilla polysaccharide (BSP)/hyaluronic acid (HA)), and a polyvinyl alcohol backing layer. Due to the good magnetic responsiveness of Fe3O4@TpBD, dacarbazine (DTIC) and indocyanine green (ICG) can be better targeted to the tumor tissue and improve the therapeutic effect. BSP and HA have good biocompatibility and transdermal ability, so that the MNs can completely penetrate the tumor tissue, be dissolved by the interstitial fluid, and release DTIC and ICG. Under near-infrared (NIR) light irradiation, ICG converts light energy into thermal energy and induces ablation of B16-OVA melanoma cells. In vivo results showed that DTIC/ICG-Fe3O4@TpBD BSP/HA MNs combined with chemotherapy and PTT could effectively inhibit the growth of melanoma without tumor recurrence or significant weight loss in mice. Therefore, DTIC/ICG-Fe3O4@TpBD BSP/HA MNs are expected to provide new ideas and therapeutic approaches for the clinical treatment of melanoma.

Ancestral sequence reconstruction of the CYP711 family reveals functional divergence in strigolactone biosynthetic enzymes associated with gene duplication events in monocot grasses.

The strigolactone (SL) class of phytohormones shows broad chemical diversity, the functional importance of which remains to be fully elucidated, along with the enzymes responsible for the diversification of the SL structure. Here we explore the functional evolution of the highly conserved CYP711A P450 family, members of which catalyze several key monooxygenation reactions in the strigolactone pathway. Ancestral sequence reconstruction was utilized to infer ancestral CYP711A sequences based on a comprehensive set of extant CYP711 sequences. Eleven ancestral enzymes, corresponding to key points in the CYP711A phylogenetic tree, were resurrected and their activity was characterized towards the native substrate carlactone and the pure enantiomers of the synthetic strigolactone analogue, GR24. The ancestral and extant CYP711As tested accepted GR24 as a substrate and catalyzed several diversifying oxidation reactions on the structure. Evidence was obtained for functional divergence in the CYP711A family. The monocot group 3 ancestor, arising from gene duplication events within monocot grasses, showed both increased catalytic activity towards GR24 and high stereoselectivity towards the GR24 isomer resembling strigol-type SLs. These results are consistent with a role for CYP711As in strigolactone diversification in early land plants, which may have extended to the diversification of strigol-type SLs.

Boron Coordination Effect in Ni-Nx Doped Graphene Catalysts on the ORR Performance Based on DFT Calculations.

The coordination atoms of metal active site in transition metal N-doped carbon single atom electrocatalysts play a vital role in dominating the catalytic performance of oxygen reduction reaction (ORR) at the cathode of fuel cells or metal-air cells. In view of weak adsorption ability of Ni active site in NiN4 -C catalysts to oxygen intermediate states, herein we introduce boron atoms with smaller electronegativity than N and C atoms to modulate the local coordination environment and electronic structures of Ni site. First-principles density functional calculations reveal that both B substitution for N atoms (NiN2 B2 -C) and B coordinating with N and C (NiN4 B8 -C) can effectively optimize the Gibbs free energy of oxygen intermediate states and hence improve the catalytic activity of the materials. In addition, we propose that the trend change in catalytic activity is mainly governed by the filling of antibonding orbitals between Ni-3d and O-2p states near the Fermi level.

Early high-dose continuous veno-venous hemofiltration alleviates the alterations of CD4+ T lymphocyte subsets in septic patients combined with acute kidney injury.

BACKGROUND: This study aims to determine whether early high-dose continuous venous-venous hemofiltration (CVVH) alleviates the alterations in CD4+ T lymphocyte subsets in septic patients combined with acute kidney injury. METHODS: Enrolled septic patients combined with acute kidney injury were randomized into CVVH (n = 50) and conventional treatment (non-CVVH, n = 53) groups. Healthy volunteers (n = 21) were enrolled. CVVH was initiated within 12 h of intensive care unit (ICU) admission with doses of 35~60 ml/kg/h and maintained for at least 72 h. Th1, Th2, Th17, and Treg were measured by flow cytometry on days 1, 3, and 7 of ICU admission. Sequential organ failure assessment (SOFA) scores were calculated. RESULTS: Th1 percentages and Th1/Th2 ratios were lower, and Th2, Th17, and Treg percentages and Th17/Treg ratios were higher in septic patients compared to healthy volunteers. CVVH significantly increased Th1 percentages and Th1/Th2 ratios, and significantly decreased Th2, Th17, and Treg percentages and Th17/Treg ratios compared to non-CVVH. Th1 percentages and Th1/Th2 ratios were negatively correlated with SOFA scores, while Th2, Th17, and Treg percentages and Th17/Treg ratios were positively correlated with SOFA scores. Patients with CVVH had significantly lower SOFA scores on day 7 of ICU admission and a shorter ICU stay compared to those with non-CVVH. CONCLUSIONS: Septic patients combined with acute kidney injury exhibit different alterations of CD4+ T lymphocyte subsets. Early high-dose CVVH alleviates the alterations, which may be one of the factors associated with improved sepsis severity.

Construction of a robust prognostic model for adult adrenocortical carcinoma: Results from bioinformatics and real-world data.

This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large-scale multiomics analysis and real-world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis-related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI's GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P < .001), TFRC (P < .001), TSC1 (P < .001) expression indicated significantly worse overall survival for adult ACC patients. Risk assessment suggested significantly a strong predictive capacity of IPRPs model for poor overall survival (P < .05). IPRPs model showed a little stronger ability for predicting prognosis than Ki-67 protein in FUSCC cohort (P = .003, HR = 3.947; P = .005, HR = 3.787). In external validation of IPRPs model using gene expression data, IPRPs model showed strong ability for predicting prognosis in TCGA cohort (P = .005, HR = 3.061) and it exhibited best ability for predicting prognosis in GSE10927 cohort (P = .0898, HR = 2.318). This research constructed IPRPs model for predicting adult ACC patients' prognosis using proteomic data, gene expression data and real-world data and this prognostic model showed stronger predictive value than other biomarkers (Ki-67, Beta-catenin, etc) in multi-cohorts.

HEXOKINASE1 signalling promotes shoot branching and interacts with cytokinin and strigolactone pathways.

Plant architecture is controlled by several endogenous signals including hormones and sugars. However, only little information is known about the nature and roles of the sugar signalling pathways in this process. Here we test whether the sugar signalling pathway mediated by HEXOKINASE1 (HXK1) is involved in the control of shoot branching. To test the involvement of HXK1 in shoot branching and in the hormonal network controlling this process, we modulated the HXK1 pathway using physiological and genetic approaches in rose, pea and arabidopsis. Mannose-induced HXK signalling triggered bud outgrowth in rose and pea. In arabidopsis, both HXK1 deficiency and defoliation led to decreased shoot branching and conferred hypersensitivity to auxin. Complementation of the HXK1 knockout mutant gin2 with a catalytically inactive HXK1, restored shoot branching to the wild-type level. HXK1-deficient plants displayed decreased cytokinin levels and increased expression of MAX2, which is required for strigolactone signalling. The branching phenotype of HXK1-deficient plants could be partly restored by cytokinin treatment and strigolactone deficiency could override the negative impact of HXK1 deficiency on shoot branching. Our observations demonstrate that HXK1 signalling contributes to the regulation of shoot branching and interacts with hormones to modulate plant architecture.

Rational design of nano-Fe3O4encapsulated in 3D honeycomb biochar for enhanced lithium storage performance.

Developing green materials applied in lithium-ion batteries is of significant importance for the present-day society. Herein, a feasible strategy to construct Fe3O4nanoparticles (NPs) embedded in three-dimensional (3D) honeycomb biochar derived from pleurotus eryngii was proposed. The obtained material consists of Fe3O4NPs (35-85 nm) encapsulated in 3D honeycomb biochar possesses a high specific capacity of 723 mAh g-1at 1.5 A g-1after 1000 cycles. The effectively enhanced cycling life of Fe3O4@C nanocomposites can be ascribed to the small Fe3O4NPs provide lower degree of cracking and high specific capacity, while the honeycomb biochar function like a cage to inhibit huge volume change of Fe3O4NPs during the charge-discharge process.

The Association between Interleukin-6 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus: A Meta-analysis with Trial Sequential Analysis.

BACKGROUND: Molecular epidemiological studies have sought associations between interleukin-6 (IL-6) polymorphisms and the risk of systemic lupus erythematosus (SLE); however, the results are controversial. Therefore, we conducted a meta-analysis with trial sequential analysis to evaluate a more accurate estimation of the associations. METHODS: Published literatures reporting the relationships of two IL-6 polymorphisms (G-174C and G-572C) and SLE risk were retrieved from electronic databases such as PubMed and EMBASE. The most appropriate genetic model was chosen for each polymorphism. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was introduced to assess the information size and the positive results. RESULTS: With 17 studies (2780 cases and 3100 controls) included, a dominant association (CC+GC vs. GG) was suggested for G-174C polymorphism, and compared with the GG genotype, the CC+GC genotype of G-174C was associated with a decreased SLE risk (OR = 0.71; 95% CI = 0.56-0.88, P =.02). No association was found for G-572C under all genetic models (e.g. OR and 95%CI for CC+GC vs. GG: 0.89, 0.73-1.08, P =.22). Subgroup analyses indicated that SLE risk decreased in G-174C polymorphism by subgroups of Caucasian population, publications after 2010, studies with high quality, and studies complied with Hardy-Weinberg equilibrium (HWE). TSA suggested that the sample sizes used for G-572C were insufficient. CONCLUSION: We found that the minor allele C of IL6G-174C polymorphism is a protective factor in SLE. Further studies with a larger sample size are needed to confirm the null association for G-572C.

Large-scale transcriptome profiles reveal robust 20-signatures metabolic prediction models and novel role of G6PC in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common and highly malignant pathological type of kidney cancer. We sought to establish a metabolic signature to improve post-operative risk stratification and identify novel targets in the prediction models for ccRCC patients. A total of 58 metabolic differential expressed genes (MDEGs) were identified with significant prognostic value. LASSO regression analysis constructed 20-mRNA signatures models, metabolic prediction models (MPMs), in ccRCC patients from two cohorts. Risk score of MPMs significantly predicts prognosis for ccRCC patients in TCGA (P < 0.001, HR = 3.131, AUC = 0.768) and CPTAC cohorts (P = 0.046, HR = 2.893, AUC = 0.777). In addition, G6PC, a hub gene in PPI network of MPMs, shows significantly prognostic value in 718 ccRCC patients from multiply cohorts. Next, G6Pase was detected high expressed in normal kidney tissues than ccRCC tissues. It suggested that low G6Pase expression significantly correlated with poor prognosis (P < 0.0001, HR = 0.316) and aggressive progression (P < 0.0001, HR = 0.414) in 322 ccRCC patients from FUSCC cohort. Meanwhile, promoter methylation level of G6PC was significantly higher in ccRCC samples with aggressive progression status. G6PC significantly participates in abnormal immune infiltration of ccRCC microenvironment, showing significantly negative association with check-point immune signatures, dendritic cells, Th1 cells, etc. In conclusion, this study first provided the opportunity to comprehensively elucidate the prognostic MDEGs landscape, established novel prognostic model MPMs using large-scale ccRCC transcriptome data and identified G6PC as potential prognostic target in 1,040 ccRCC patients from multiply cohorts. These finding could assist in managing risk assessment and shed valuable insights into treatment strategies of ccRCC.

The pomegranate (Punica granatum L.) draft genome dissects genetic divergence between soft- and hard-seeded cultivars.

Complete and highly accurate reference genomes and gene annotations are indispensable for basic biological research and trait improvement of woody tree species. In this study, we integrated single-molecule sequencing and high-throughput chromosome conformation capture techniques to produce a high-quality and long-range contiguity chromosome-scale genome assembly of the soft-seeded pomegranate cultivar 'Tunisia'. The genome covers 320.31 Mb (scaffold N50 = 39.96 Mb; contig N50 = 4.49 Mb) and includes 33 594 protein-coding genes. We also resequenced 26 pomegranate varieties that varied regarding seed hardness. Comparative genomic analyses revealed many genetic differences between soft- and hard-seeded pomegranate varieties. A set of selective loci containing SUC8-like, SUC6, FoxO and MAPK were identified by the selective sweep analysis between hard- and soft-seeded populations. An exceptionally large selective region (26.2 Mb) was identified on chromosome 1. Our assembled pomegranate genome is more complete than other currently available genome assemblies. Our results indicate that genomic variations and selective genes may have contributed to the genetic divergence between soft- and hard-seeded pomegranate varieties.

α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice.

Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and ß-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-ß1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.